Key
• Male and female, ≥ 18 years
• Documented advanced or metastatic malignancy
• Eastern Cooperative Oncology Group performance status of 0 or 1 with no deterioration over the 2 weeks prior to baseline or day of first dosing
• All participants must provide a tumour sample for tissue-based analysis
• At least 1 measurable lesion not previously irradiated, except Substudy 3 (Prostate Cancer) which allows participants with non measurable bone metastatic disease
• Adequate bone marrow reserve and organ function
• Minimum life expectancy of 12 weeks
• At the time of screening, contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
• All women of childbearing potential must have a negative serum pregnancy test documented during screening
• Female participants must be 1 year post-menopausal, surgically sterile, or using 1 highly effective form of birth control. Female participants must not donate, or retrieve for their own use, ova at any time during this study
• Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile, avoid intercourse, or use a highly effective method of contraception. Male participants must not freeze or donate sperm at any time during this study.
• Capable of giving signed informed consent
• Provision of signed and dated written optional genetic research informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative Key
• Any evidence of diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol
• History of another primary malignancy except for adequately resected basal cell carcinoma or in situ squamous cell carcinoma of the skin, or other solid malignancy treated with curative intent
• Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved
• Spinal cord compression or brain metastases unless treated
• Leptomeningeal carcinomatosis
• Clinically significant corneal disease
• Active hepatitis or uncontrolled hepatitis B or C virus infection
• Uncontrolled infection requiring IV antibiotics, antivirals or antifungals, for example prodromal symptoms
• Known HIV infection that is not well controlled
• Active TB infection
• Significant cardiac diseases
• History of non-infectious Interstitial lung disease (ILD)/pneumonitis that required steroids
• Has severe pulmonary function compromise
• Prior exposure to chloroquine/hydroxychloroquine without an adequate treatment washout period
• Receipt of live, attenuated vaccine within 30 days prior to the first dose of study intervention
• Prior exposure to anticancer therapies without an adequate treatment washout period prior to enrolment or any concurrent anticancer treatment
• Major surgical procedure or significant traumatic injury within ≤ 3 weeks of the first dose of study intervention or an anticipated need for major surgery during the study
• Prior treatment with TROP2-directed Anti-drug antibody, ADC Antibody-drug conjugate (ADCs), other ADCs with deruxtecan payload
• Severe hypersensitivity to monoclonal antibodies
• Pregnant, breastfeeding, planning to become pregnant

• STEP 0 INCLUSION CRITERIA
• Histologically proven mucosal melanoma by local pathology
• Central PD-L1 tumor tissue submission
• STEP 1 INCLUSION CRITERIA
• Receipt of the central PD-L1 testing results available
• Disease status-Resected R0 or R1 disease patients. Patients eligible for randomization have resected R0 or R1 disease (with negative margins or positive microscopic margins) that must meet one of the following 4 criteria as defined below:
• Regional lymph node (LN) involvement; OR
• In-transit metastases/satellite primary disease; OR
• Single localized, primary disease meeting one of the following site-specific requirements:
• Head/neck
•Sinonasal (including nasopharynx): any primary lesion; Nasal or oral cavity; pT4a or above, given slightly improved OS
• NOTE: Conjunctival: does not meet the qualification for eligibility
• Anorectal
•any primary lesion
• Vaginal/cervical
•any primary, as they have 5 year OS rates of 5-25
• Urinary tract
•any primary urethral or bladder tumor
• Penile
• Vulvar- AJCC cutaneous stage IIB or higher
• Esophageal/gallbladder
•any primary
• Locoregionally recurrent following prior resection, meeting at least one of the above criteria
• In addition, patients must have undergone cross-sectional imaging of the brain, chest, abdomen and pelvis with no evidence of distant metastatic disease
• Disease status-Non-resected R2 or metastatic disease patients
• Non-resected R2 or metastatic disease that is assessable and measurable radiographically or by physical examination
• Prior Treatment:
• No prior systemic checkpoint inhibitor therapy of mucosal melanoma, including in the adjuvant setting, is allowed. Prior adjuvant chemotherapy or interferon is allowed.
• No other active, concurrent malignancy that requires ongoing systemic treatment or interferes with radiographic assessment of melanoma response as determined by the investigator. Exceptions may allow for adjuvant no evidence of disease (NED) cancers undergoing hormone based therapy may be eligible pending the other eligibility criteria are met and the principal investigator (PI) affirms the hormonal agent would not change the melanoma response.
• Any radiation must have completed 28 days prior to randomization and the patient must have adequately recovered from its effects.
• For resectable patients only: Surgery must have completed 28 days prior to randomization.
• For resectable patients only: Surgery must have completed no more than 84 days prior to randomization.
• Not pregnant and not nursing, because this study has an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) >= 50mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Albumin >= 2.8 g/dL
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• No cardiovascular disease, including:
• No history of acute coronary syndromes (including myocardial infarction and unstable angina), coronary artery bypass graft (CABG) coronary angioplasty, or stenting within 6 months prior to study entry.
• No history of current class II or higher congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system.
• No refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg despite adequate attempts at anti-hypertensive therapy.
• No history of myocarditis.
• No history of syncope of cardiovascular etiology, uncontrolled cardiac arrhythmia, history of Mobitz II second degree or third degree heart block without a permanent pacemaker in Association (NYHA) class II to IV heart failure, or stroke/transient ischemic attack (TIA) within the past 3 months.
• No corrected QT interval by Fridericia's formula (QTcF) > 500 msec. Note: if initial QTcF is found to be > 500 ms, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard.
• No underlying hematologic issues, including:
• Congenital bleeding diathesis
• Gastrointestinal (GI) bleeding requiring intervention within the past 6 months, unless directly related to mucosal melanoma
• Active hemoptysis within 42 days prior to study enrollment.
• Active tumor lesions with cavitations or tumor lesions which invade, encase, or abut major blood vessels. The anatomic location and characteristics of primary tumors or metastases as well as the medical history should be carefully reviewed in the selection of subjects for treatment with cabozantinib/placebo.
• Pulmonary emboli or deep vein thromboses (DVT) that require an active anticoagulation regimen.
• No known or suspected history of cytopenia (low white blood cell [WBC], hemoglobin or platelet count) of greater than 3 months duration with an unknown cause, myelodysplastic syndrome, or hematologic malignancies.
• No clinical, laboratory or radiographic evidence of an active bacterial, fungal, or viral infection requiring treatment at the time of pre-registration (e.g., active symptoms of COVID-19 infection or a post-infectious symptomatic autoimmune syndrome, serious bacterial infections requiring antibiotics).
• No known or suspected gastrointestinal disorder affecting absorption of oral medications.
• Comorbid conditions:
• No active autoimmune disease or any condition requiring systemic treatment with either corticosteroids (> 10 mg daily of prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• No history of autoimmune motor neuropathy (e.g., Guillain-Barre syndrome, myasthenia gravis) or non-infectious pneumonitis.
• No history of severe allergic reactions to an unknown allergen or any components of the study drugs or its excipients.
• No history of gastrointestinal perforation or abdominal fistula.
• No clinically suspected central nervous system (CNS) (leptomeningeal or parenchymal) metastases. Patients with a history of CNS metastasis(s) will be allowed as long as
• The metastatic site(s) were adequately treated as demonstrated by clinical and radiographic improvement, AND
• The patient has recovered from the intervention (no residual adverse events > Common Terminology Criteria for Adverse Events [CTCAE] grade 1), AND
• The patient has remained without occurrence of new or worsening CNS symptoms for a period of 28 days prior to enrollment.
• No history of seizure or any condition that may increase the patient's seizure risk (e.g., prior cortical stroke, significant brain trauma) within 2 years.
• No clinically active or chronic liver disease resulting in moderate/severe hepatic impairment (Child-Pugh class B or C), ascites, coagulopathy or bleeding due to liver dysfunction.
• No untreated spinal cord compression or evidence of spinal metastases with a risk of impending fracture or spinal cord compression. Spinal metastases must have completed planned radiation or surgical therapy prior to registration.
• Concomitant medications:
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 5 days prior to the start of study treatment.
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 5 days prior to the start of study treatment.

• Participants must have histologically and pathologically confirmed melanoma that has metastasized to the brain
• Any primary (cutaneous, acral/mucosal, etc) or unknown origin are permitted, except that participants with uveal primary are not eligible
• Participants must have BRAF-V600 mutant melanoma documented by a Clinical Laboratory Improvement Act (CLIA)-certified laboratory
• All participants must have an magnetic resonance imaging (MRI) of the brain within 28 days prior to registration and must have central nervous system metastases with at least one measurable brain metastasis >= 0.5 cm in size (per modified RECIST 1.1) that has not been irradiated, or progressed (in the opinion of the treating physician) after prior radiation therapy. Participating sites MUST use MRI slice thickness of =< 1.5 mm and are recommended to adhere to the 'minimum' Brain Tumor Imaging Protocol for Clinical Trials in Brain Metastases (BTIP-BM) compliant MRI acquisition protocol. Computed tomography (CT) of the head cannot substitute for brain MRI. (NOTE: All central nervous system [CNS] disease must be documented on BOTH the Brain Metastases Baseline Tumor Assessment Form, using modified RECIST, and the Baseline Tumor Assessment Form [RECIST 1.1] using RECIST 1.1.)
• Participants may have measurable or non-measurable extracranial disease. All measurable disease must be assessed within 28 days prior to randomization; all non-measurable disease must be assessed within 42 days prior to randomization. Please note, while any extracranial disease will also be assessed and followed, participants are NOT required to have extracranial disease for randomization. NOTE: All disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1). CNS disease must be documented on BOTH the Brain Metastases Baseline Tumor Assessment Form, using modified RECIST, and the Baseline Tumor Assessment Form (RECIST 1.1) using RECIST 1.1
• Participants may have leptomeningeal disease
• Participants may be receiving corticosteroids for brain metastases at a dose of up to 8 mg of dexamethasone per day. The dose must not have exceeded 8 mg per day for at least 7 days prior to randomization
• Participants must have Zubrod performance status =< 2
• Participants must have complete history and physical examination within 28 days prior to randomization
• Participants must be able to swallow and retain pills
• Hemoglobin >= 8.0 g/dL (within 28 days prior to randomization)
• Absolute neutrophil count >= 1,500/mcL (within 28 days prior to randomization)
• Platelets >= 75,000/mcL (within 28 days prior to randomization)
• Total bilirubin =< 1.5 institutional upper limit of normal (ULN) (within 28 days prior to randomization)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN (in participants with liver metastases =< 5 x ULN) (within 28 days prior to randomization)
• Creatinine =< 2.0 institutional ULN (within 28 days prior to randomization)
• Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better
• Participants with a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Participants with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 90 days prior to randomization
• Participants with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment must have an undetectable HCV viral load prior to randomization
• Participants must agree to participate in image banking. Images must be submitted via the Triad System
• Participants must be offered the opportunity to participate in specimen and blood collections
• Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines
• As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
• Participants must not have received prior systemic therapy for metastatic disease. Prior systemic therapy received only in the neoadjuvant and/or adjuvant setting (e.g., BRAF/MEK inhibitor therapy, anti-PD-1 therapy or anti-CTLA4 therapy, alfa-interferon, etc.) is permitted. If patients received prior neoadjuvant/adjuvant therapy, they must have had eventual disease relapse prior to randomization
• Participants must not have had prior radiation therapy within 7 days prior to randomization
• Participants must not be planning to require any additional form of systemic anti-tumor therapy for melanoma while on protocol treatment
• Participants must not be planning to use hormonal contraceptives
• Participants must not have a serious active infection requiring systemic therapy at time of randomization in the opinion of the treating physician
• Participants must not have active autoimmune disease that has required treatment in the past 6 months with use of biologic disease modifying agents (.e.g. infliximab, adalimumab). Patients on non-biologic disease modifying agents (e.g. methotrexate) or patients on corticosteroids =< 10 mg prednisone daily or equivalent (to treat auto-immune disease), or on replacement therapy (e.g., thyroxine, insulin) are eligible if deemed in the best interest of the patient by treating physician
• Participants must not have had grade 3 or 4 immune-related adverse events on ipilimumab or nivolumab that required more than 12 weeks of immune suppression with corticosteroids
• Participants must not have had adverse events related to encorafenib and/or binimetinib specifically, that required discontinuation of one or both drugs. (Please note this does not apply to other BRAF/MEK inhibitor drugs.)
• Participants must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use an effective method of contraception. (NOTE: Patients must agree to not use hormonal contraceptives, as encorafenib can result in decreased concentration and loss of efficacy.) A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures

• All patients must be enrolled on APEC14B1 (NCT02402244) and consented to the Molecular Characterization Initiative (Part A) prior to enrollment and treatment on ARST2032 (this trial).
• Patients must be =< 21 years at the time of enrollment.
• Patients must have newly diagnosed embryonal rhabdomyosarcoma (ERMS), spindle cell/sclerosing RMS, or FOXO1 fusion negative alveolar rhabdomyosarcoma (ARMS) (institutional FOXO1 fusion results are acceptable). RMS types included under ERMS include those classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassified in the 2020 World Health Organization (WHO) classification as ERMS (classic, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and the newly recognized sclerosing RMS variant). Enrollment in APEC14B1 is required for all patients.
• All patients will be evaluated for stage and clinical group. Note that clinical group designation assigned at the time of enrollment on study remains unchanged regardless of any second-look operation that may be performed.
• Patients will be eligible for the very low-risk stratum (Regimen VA) if they have Stage 1, CG I disease.
• Patients will be eligible for the low-risk stratum (Regimen VAC/VA) if they have Stage 1, CG II disease, Stage 2, CG I or II disease, or Stage 1, CG III (orbit only) disease.
• Paratesticular Tumors: Staging ipsilateral retroperitoneal lymph node sampling (SIRLNS) is required for all patients >= 10 years of age with paratesticular tumors who do not have gross nodal involvement on imaging.
• Extremity Tumors: Regional lymph node sampling is required for histologic evaluation in patients with extremity tumors.
• Clinically or radiographically enlarged nodes must be sampled for histologic evaluation.
• Patients must have a Lansky (for patients =< 16 years of age) or Karnofsky (for patients > 16 years of age) performance status score of >= 50. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing performance score.
• Peripheral absolute neutrophil count (ANC) >= 750/uL (within 7 days prior to enrollment).
• Platelet count >= 75,000/uL (transfusion independent) (within 7 days prior to enrollment).
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine (within 7 days prior to enrollment) based on age/gender as follows:
• Age: 1 month to < 6 months; Maximum serum creatinine (mg/dL): 0.4 (male) : 0.4 (female)
• Age: 6 months to < 1 year; Maximum serum creatinine (mg/dL): 0.5 (male) : 0.5 (female)
• Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male) : 0.6 (female)
• Age: 2 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 (male) : 0.8 (female)
• Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male) : 1 (female)
• Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male) : 1.2 (female)
• Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male) : 1.4 (female)
• Age >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male) : 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment), and
• If there is evidence of biliary obstruction by the tumor, then the total bilirubin must be < 3 x ULN for age.
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L.
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment).
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.
• Patients who have received prior chemotherapy and/or radiation therapy for cancer prior to enrollment. Surgical resection alone of previous cancer(s) is permitted.
• Patients who have received chemotherapy or radiation for non-malignant conditions (e.g., autoimmune diseases) are eligible. Patients must discontinue chemotherapy for non-malignant conditions prior to starting protocol therapy.
• Vincristine is sensitive substrate of the CYP450 3A4 isozyme. Patients must not have received drugs that are moderate to strong CYP3A4 inhibitors and inducers within 7 days prior to study enrollment.
• Patients unable to undergo radiation therapy, if necessary, as specified in the protocol.
• Evidence of uncontrolled infection.
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.

• Provision of signed and dated, written informed consent form ICF in accordance with ICH-GCP and local legislation prior to any trial-specific procedures, sampling, or analyses.
• Pathologically documented, advanced solid tumors.
• Patients fulfilling one or more of the following criteria:
• Radiologically documented disease progression or relapse
• Patients who are not eligible to receive standard of care treatments, and for whom no proven treatments exist.
• Patients with MDM2 amplified sarcomas who require first line treatment (for Ph Ib/dose expansion
•Cohort 1 only).
• Patients with MDM2 amplified sarcomas may fulfil any one of the above three criteria to be considered eligible.
• Phase Ia (dose escalation) only:
• Patient has a tumor with either a known TP53 wild type status, or unknown TP53 status, and regardless of MDM2 amplification status, at the time of study entry.
• Phase Ib (expansion phase) only:
• Cohort 1: TP53 wt and MDM2-amplified sarcoma with advanced/metastatic disease at any line of therapy. If TP53 status is not available during screening, the patient may be included with unknown TP53 status if a tissue sample is submitted for central laboratory assessment. If TP53 status cannot be evaluated, the patient may be included if agreed between the Investigator and Sponsor.
• Cohort 2: TP53 wt and MDM2- amplified NSCLC, urothelial, gastric, biliary tract (including cholangiocarcinoma, intra- and extrahepatic biliary tree, gall blander and ampulla of vater) or pancreatic solidPDAC tumors who have had at least one previous line of therapy for advanced/metastatic disease. If TP53 status cannot be evaluated the patient may be included if agreed between the Investigator and Sponsor
• Phase Ia (dose escalation) only:
• Patient with either measurable or non-measurable disease.
• Non-evaluable disease allowed.
• Phase Ib (expansion phase) only:
• At least one target lesion that can be accurately measured per RECIST v.1.1.
• Phase Ia:
• Patient must be willing to undergo blood sampling for PK, pharmacodynamic, biomarker, and PGx analyses.
• Phase Ib:
• Patient must be willing to undergo tumor biopsy sampling for pharmacodynamic analyses and blood sampling for PK, pharmacodynamics, and biomarker analyses.
• Willingness to provide a fresh tumor tissue sample obtained after relapse/ progression during or after prior therapy. In case a fresh biopsy cannot be obtained (e.g. inaccessible lesions or patient safety concern), an archived specimen, collected before screening within 12 months of enrollment, may be submitted. If these requirements cannot be met, then the patient may be allowed to enter the study at Sponsor discretion, after agreement between the Investigator and Sponsor.
• Further inclusion criteria apply
• Previous administration of BI 907828 (brigimadlin) or any other MDM2-p53 or MDMX (MDM4)-p53 antagonist.
• Known TP53 mutant tumor.
• Symptomatic metastases from non-brain tumors. Note: Patients with previously treated brain metastases may participate provided they are stable, without evidence of progression by imaging (using the identical imaging modality for each assessment, either MRI or computed tomography (CT) scan), for at least four weeks prior to the first dose of trial treatment, and any neurologic symptoms have returned to baseline; have no evidence of new or enlarging brain metastases. Patients on corticosteroids must have a stable dose for at least 5 days prior to baseline MRI.
• Patients with history of bleeding diathesis.
• Major surgery (major according to the Investigator's assessment) performed within 12 weeks prior to start of study treatment, or planned within 12 months after screening (e.g. hip replacement).
• Any other documented active or suspected malignancy or history of malignancy within 3 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix, or other local tumors considered cured by local treatment.
• Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial.
• Further exclusion criteria apply.

1. ECOG PS 0 or 1 2. HLA-A*02:01 positive 3. PRAME positive tumor 4. Relapsed from, refractory to, or intolerant of standard therapies; or, in combination with standard therapies 5. If applicable, must agree to use highly effective contraception 1. Symptomatic or untreated central nervous system metastasis 2. Recent bowel obstruction 3. Ongoing ascites or effusion requiring recent drainages 4. Significant immune-mediated adverse event with prior immunotherapy (patients in checkpoint inhibitor combination treatment) 5. Inadequate washout from prior anticancer therapy 6. Significant ongoing toxicity from prior anticancer treatment 7. Out-of-range laboratory values 8. Clinically significant lung, heart, or autoimmune disease 9. Ongoing requirement for immunosuppressive treatment 10. Prior solid organ or bone marrow transplant 11. Active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection 12. Significant secondary malignancy 13. Hypersensitivity to study drug or excipients 14. Antibiotics, vaccines or surgery within 2-4 weeks prior to the first dose of study intervention 15. Pregnant or lactating 16. Any other contraindication for applicable combination partner based on local prescribing information

• Patients must have histologically confirmed malignancy that is metastatic or unresectable with participation in this clinical trial determined to be the best option for next treatment in the opinion of the investigator
• Patients must have a solid tumor with HER2-positivity as determined by any one or more of the following:
• HER2 overexpression defined by IHC 3+
• ERBB2 amplification by ISH or next-generation sequencing as determined by any CLIA certified lab
• A known HER2 activating mutation
• HER2 overexpression by IHC/ISH will follow histology specific ASCO-CAP guidelines for breast and gastric cancers. For tumor histologies without specific guidelines the following criteria will apply:
• HER2 IHC should be performed first, followed by ISH methods in cases showing 2+ (equivocal) expression by IHC. Positive (IHC 3+) or negative (IHC 0 or 1+) do not require further ISH testing. Cases with HER2:CEP17 ratio ≥2 or an average HER2 copy number ≥6.0 signals per cell are considered positive by ISH
• Known HER2 activating mutations:
• G309A/E
• S310F/Y
• S653C
• V659E
• G660D
• R678Q
• E693K
• Q709L
• L755S/P
• Del. 755-759
• D769Y/H
• G776V/C
• V777L
• V842I
• T862A
• L869R
• H878Y
• All exon 20 insertions, including:
• A771_Y772insYVMA
• A775_G776insYVMA
• Y772_A775dup
• P780_Y781insGSP
• G778_P780dup
• V697L
• T733I
• D769N
• L841V
• L866M
• R896C
• If a different mutation is identified, contact the study chair for conferral. Synonymous mutations are not eligible
• Patients must have received at least 1 prior line of therapy in the advanced/metastatic setting. No limitation on number of prior therapies; however, patients may not have received neratinib or DS-8201a previously. Prior HER2-targeted therapy other than neratinib or DS-8201a is allowed (e.g., trastuzumab, pertuzumab, TDM-1, lapatinib, etc.)
• Age >= 18 years. Because no dosing or adverse event data are currently available on the use of neratinib in combination with DS-8201a in patients < 18 years of age, children are excluded from this study
• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
• Hemoglobin >= 9.0 g/dL (>= 8.0 g/dL for gastric cancer [GC] only) (within 14 days of enrollment)
• No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
• Serum albumin >= 2.5 g/dL (within 14 days of enrollment)
• Leukocytes >= 3.0 K/cumm (within 14 days of enrollment)
• Absolute neutrophil count >= 1.5 K/cumm (within 14 days of enrollment)
• No administration of granulocyte colony-stimulating factor (G-CSF) is allowed within 1 week prior to screening assessment
• Platelets >= 100 K/cumm (within 14 days of enrollment)
• No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
• Total bilirubin =< 1.5 × institutional upper limit of normal (ULN), (< 3 × ULN in the presence of documented Gilbert's syndrome or liver metastases at baseline) (within 14 days of enrollment)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN (if liver metastases are present =< 5 x ULN) (within 14 days of enrollment)
• International normalized ratio (INR)/prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 x institutional ULN (within 14 days of enrollment)
• This applies only to patients who are not receiving therapeutic anticoagulation that may affect INR. Those who are on therapeutic anticoagulation, should be on a stable dose for 4 weeks and should be considered within therapeutic range
• Creatinine =< 1.5 x institutional ULN OR Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 (using the Cockcroft-Gault equation) (within 14 days of enrollment)
• Patients who are human immunodeficiency virus (HIV)-positive may participate IF they meet the following eligibility requirements:
• They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective
• They must have a CD4 count of greater than 250 cells/mcL over the past 6 months on this same anti-retroviral regimen and must not have had a CD4 count < 200 cells/ul over the past 2 years, unless it was deemed related to THE CANCER AND/OR CHEMOTHERAPY-induced bone marrow suppression
• For patients who have received chemotherapy in the past 6 months, a CD4 count < 250 cells/ul during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy
• They must have an undetectable viral load and a CD4 count >= 250 cells/uL within 7 days of enrollment
• They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months HIV-infected patients should be monitored every 12 weeks for viral load and CD4 counts
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with treated brain metastases are eligible if the following criteria are met: 1) follow-up brain imaging done at least in 4 weeks after central nervous system (CNS)-directed therapy shows no evidence of progression and 2) the patient no longer requires steroids, or is on a stable steroid dose > 4 weeks
• Patients with radiographically new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible only if has no progressive clinical symptoms and if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy
• Patients should be New York Heart Association functional classification of class 2B or better
• Patients must have left ventricular ejection fraction (LVEF) >= 50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before randomization/enrollment
• Dose expansion phase (PD cohort): Patients must have disease that is evaluable or measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Dose expansion phase (PD cohort): Patients must have at least one lesion suitable for biopsy without significant risk to the patient. The biopsiable lesion can be the same as the evaluable lesion for response by RECIST 1.1
• Patients who had clinically significant side effects from prior cancer therapy must have recovered to grade 1 or below
• HER2 antibody conjugated to a topoisomerase 1 inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic; thus, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 1 month after the last dose of neratinib, or at least 7 months after the last dose of DS-8201a, whichever is longer (women of childbearing potential [WOCBP] only). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after the last dose of neratinib, or 4 months after completion of DS-8021a administration, whichever is longer
• Women of non-child-bearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone [FSH] > 40 mIU/mL and estradiol < 40 pg/mL [< 147 pmol/L] is confirmatory) are eligible. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of child-bearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method
• Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and at least 4 months after the final study drug administration. Preservation of sperm should be considered prior to enrollment in this study
• Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration
• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible
• With the exception of medications that are under investigation in the study (e.g., standard of care, comparators, or combination therapies), the following medications, treatment, and procedures will be prohibited during the treatment period. The sponsor must be notified if a subject receives any of these during the study:
• Other anticancer therapy, including small-molecule targeted agents within 2 weeks or five half-lives, whichever is longer; chemotherapy otherwise not specified (including, but not limited to cytotoxic chemotherapy, antibody drug conjugates, retinoid therapy, hormonal therapy) within 3 weeks; immunotherapy or monoclonal antibody within 4 weeks; and nitrosureas or mitomycin C within 6 weeks (concurrent use of hormones for noncancer-related conditions [e.g., insulin for diabetes and hormone replacement therapy] is acceptable)
• Other investigational therapeutic agents
• Patients who have had major surgery or radiation within 4 weeks; palliative stereotactic radiation within 2 weeks (except for palliative radiation to known metastatic sites as long as it does not affect assessment of response or interrupt treatment for more than the maximum time specified in dose modification section)
• Radiotherapy to the thorax (palliative radiation to known metastatic sites in the thoracic spine is permitted in this study)
• Concomitant use of chronic systemic (IV or oral) corticosteroids or other immunosuppressive medications except for managing adverse events (inhaled steroids or intra-articular steroid injections are permitted in this study); chronic replacement dose steroids (e.g., for those with adrenal insufficiency) are permitted in this study
• Subjects with bronchopulmonary disorders who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study
• Concomitant treatment with chloroquine or hydroxychloroquine is not allowed during the study treatment due to concern for overlapping toxicities. If treatment with chloroquine and hydroxychloroquine treatment is absolutely required, study treatment must be interrupted. If chloroquine or hydroxychloroquine is administered, then a wash-out period of more than 14 days is required before restarting study treatment
• Patients with a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
• Patients with clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion, etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e. rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior pneumonectomy
• Patients with history of allergic reactions attributed to compounds of similar chemical or biologic composition to DS-8201a, the inactive ingredients in the drug product, or neratinib
• Patients who have a history of severe hypersensitivity reactions to other monoclonal antibodies
• Patients receiving any medications or substances that are moderate or strong inhibitors or inducers of CYP3A4 and P-glycoprotein are ineligible. Avoid concomitant use with proton pump inhibitors and P-glycoprotein substrates. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Patients with a medical history of myocardial infarction within 6 months before enrollment, or symptomatic congestive heart failure (CHF) (New York Heart Association class II to IV)
• Patients with a corrected QT interval (QTc) prolongation to > 470 ms (females) or > 450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG)
• Patients with clinically significant corneal disease in the opinion of the investigator
• Patients with a pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART). (Drainage and CART are not allowed within 2 weeks prior to screening assessment) (GC indication)
• Patients with spinal cord compression
• Patients with an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Patients with unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade =< 1 or baseline. Subjects with chronic grade 2 toxicities may be eligible per the discretion of the investigator after consultation with the sponsor medical monitor or designee (e.g., grade 2 chemotherapy-induced neuropathy)
• Patients with substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results
• Pregnant women are excluded from this study because DS-8201a is a HER2 antibody conjugated to a topoisomerase 1 inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with DS-8201a, breastfeeding should be discontinued if the mother is treated with DS-8201a. These potential risks may also apply to other agents used in this study
• Prior treatment with neratinib or DS-8201a
• Clinically significant chronic gastrointestinal disorder with diarrhea as a major symptom; G2 or greater diarrhea at baseline. Please contact the study PI for any patient with more than two episodes of diarrhea per day averaged over at least a 7 day period at time of screening to determine whether the diarrhea would be considered clinically significant
• Inability to swallow tablets
• Patients with active additional malignancy or a personal history of additional malignancy that may affect outcome of disease under treatment (patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen at the discretion of the treating investigator are allowed)
• Patients with prior allogeneic organ transplantation including allogeneic stem cell transplantation

-Participant intended to receive SOC therapy per Investigator's judgment and local practice. Cohort A: Participants with chronic kidney disease who will receive a kidney transplant from a living or deceased donor. Cohort B: Participants who are kidney transplant recipients diagnosed with active AMR.
• BMI ≤ 40 kg/m2.
• Contraceptive use by women during the treatment period, and for at least 49 weeks after the last administration of IMP (BIVV020 + SOC arm participant) or last treatment period visit (SOC arm participant).
• Contraceptive use by men during the treatment period, and for at least 49 weeks after the last administration of IMP (BIVV020 + SOC arm participant) or last treatment period visit (SOC arm participant).
• Participants who are ABO incompatible with their donors.
• Participants with known active ongoing infection as per below: 1. Positive HIV. 2. Positive HBV. 3. HCV with detectable HCV RNA. 4. Within 4 weeks of first study intervention: any serious infection, or any active bacterial infection, or any other infection which is clinically significant in the option of the Investigator, unless it can be confirmed that infection was cleared at least 3 days prior to first study intervention.
• History of active tuberculosis (TB) regardless of treatment.
• Participants with clinical diagnosis of systemic lupus erythematosus (SLE).
• Prior treatment with complement system inhibitor within 5 times the half-life.
• Current enrollment in any other clinical study where the last investigational study treatment administration was within 5 half-lives from study intervention initiation. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

• Participants with a cancer diagnosis: Documentation of disease:
• Histologic documentation: Histologically confirmed diagnosis of invasive cancer
• Stage: Stage I-IV per American Joint Committee on Cancer (AJCC) 7th edition, with the exception of patients with leukemia, lymphoma, and multiple myeloma
• For leukemia: Type (chronic lymphocytic leukemia [CLL], chronic myeloid leukemia [CML], acute lymphoblastic lymphoma [ALL], acute myeloid leukemia [AML])
• For lymphoma: Stage I-IV based on Ann Arbor staging
• For multiple myeloma: Stage I, II, III based on Revised International Staging System (RISS)
• One of the following tumor types:
• Colorectal
• Bladder
• Head and neck
• Hepatobiliary
• Lung
• Lymphoma
• Leukemia
• Ovary *** For these specific cancer types only, patients may be enrolled prior to histologic confirmation of malignancy. Sites are required to contact the study chairs to review appropriateness for enrollment
• Pancreas *** For these specific cancer types only, patients may be enrolled prior to histologic confirmation of malignancy. Sites are required to contact the study chairs to review appropriateness for enrollment
• Multiple myeloma
• Gastric, esophageal or gastroesophageal
• Breast
• Thyroid
• Kidney
• For these specific cancer types only, patients may be enrolled prior to histologic confirmation of malignancy. Sites are required to contact the study chairs to review appropriateness for enrollment
• Endometrium
• Prostate
• Melanoma *** For these specific cancer types only, patients may be enrolled prior to histologic confirmation of malignancy. Sites are required to contact the study chairs to review appropriateness for enrollment
• Sarcoma
• Participants with a cancer diagnosis: No prior definitive systemic or local anti-cancer intervention
• Participants with a cancer diagnosis: Age >= 40 and =< 75
• Participants with a cancer diagnosis: No known current pregnancy by self-report
• Participants with a cancer diagnosis: No known or prior history of in situ or invasive malignancy (excluding in situ non-melanoma skin cancers) other than the current cancer diagnosis
• Participants with a cancer diagnosis: Willingness to provide blood samples for research use
• Participants with a cancer diagnosis: Absence of medical contraindications to a research blood draw volume of 60 mL
• Participants with a cancer diagnosis: No history of organ transplantation
• Participants with a cancer diagnosis: Ability to read and comprehend English or Spanish * Eligibility is restricted to individuals who can comprehend and read English or Spanish given that participation in the study will require the ability to read and complete questionnaires that are available only in those two languages
• Participants without a cancer diagnosis and without suspicion of cancer: Age >= 40 and =< 75
• Participants without a cancer diagnosis and without suspicion of cancer: No known current pregnancy by self-report
• Participants without a cancer diagnosis and without suspicion of cancer: No known or prior history of in situ or invasive malignancy (excluding in situ non-melanoma skin cancers)
• Participants without a cancer diagnosis and without suspicion of cancer: Willingness to provide blood samples for research use
• Participants without a cancer diagnosis and without suspicion of cancer: Absence of medical contraindications to a research blood draw volume of 60 mL
• Participants without a cancer diagnosis and without suspicion of cancer: No history of organ transplantation
• Participants without a cancer diagnosis and without suspicion of cancer: Ability to read and comprehend English or Spanish * Eligibility is restricted to individuals who can comprehend and read English or Spanish given that participation in the study will require the ability to read and complete questionnaires that are available only in those two languages
• Participants with a high suspicion of cancer: High suspicion of ovarian cancer, pancreatic cancer, kidney cancer, or melanoma by clinical and/or radiological assessment, with plans for histologic or cytologic confirmation within 28 days after study blood draw * Examples of highly suspicious cases include: elevated CA125 and abnormal transvaginal ultrasound, suspicious renal or pancreatic mass on imaging, suspicious cutaneous lesion concerning for melanoma
• Participants with a high suspicion of cancer: Central review of radiology reports and/or clinical documentation conducted by study chairs
• Participants with a high suspicion of cancer: Age >= 40 and =< 75
• Participants with a high suspicion of cancer: No known current pregnancy by self-report
• Participants with a high suspicion of cancer: No known or prior history of in situ or invasive malignancy (excluding in situ non-melanoma skin cancers) other than the current cancer diagnosis
• Participants with a high suspicion of cancer: Willingness to provide blood samples for research use
• Participants with a high suspicion of cancer: Absence of medical contraindications to a research blood draw volume of 60 mL
• Participants with a high suspicion of cancer: No history or organ transplantation
• Participants with a high suspicion of cancer: Ability to read and comprehend English or Spanish * Eligibility is restricted to individuals who can comprehend and read English and Spanish given that participation in the study will require the ability to read and complete questionnaires that are available only in those two languages

• Age 2-21 years
• Body weight ≥ 10 kg
• Subject has histologically confirmed diagnosis of any one of the following cancers: (A) Synovial Sarcoma, (B) MPNST, (C) Neuroblastoma, or (D) Osteosarcoma
• Must have previously received a systemic chemotherapy
• Measurable disease according to RECIST v1.1 (or INCR, 2017 Neuroblastoma only).
• HLA-A*02 positive
• Tumor shows MAGE-A4 expression confirmed by central laboratory.
• Performance Status: ECOG 0-1 or Lansky Score ≥ 80
• HLA-A*02:05 in either allele; or any A*02 having same protein sequence as HLA-A*02:05
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine, cyclophosphamide.
• History of autoimmune or immune mediated disease
• Known central nervous system (CNS) metastases.
• Other prior malignancy that is not considered by the Investigator to be in complete remission
• Clinically significant cardiovascular disease
• Active infection with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, or human T cell leukemia virus
• Pregnant or breastfeeding

• Patient must have measurable disease
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status between 0-2 OR patient must have Lansky performance status of >= 50% or Karnofsky performance status of >= 50%
• Patient must be deemed potentially eligible for a ComboMATCH Treatment Trial as assessed by the enrolling provider
• All patients must have sequencing results available from a National Cancer Institute (NCI) credentialed Designated Laboratory (DL)
• Patients must have locally advanced or advanced histologically documented solid tumors requiring therapy and meet one of the following criteria:
• Patients must have progressed on at least one line of standard systemic therapy OR
• Patients whose disease has no standard treatment that has been shown to prolong overall survival
• Patient must meet one of the following requirements:
• Patients 18 years and older who have tumor amenable to minimal risk image-guided or direct vision biopsy and must be willing and able to undergo a tumor biopsy to obtain samples for research if the patient is to enroll in a ComboMATCH treatment trial OR
• Patients 18 years and older who do not have disease that is biopsiable at minimal risk to the patient must confirm availability of an archival tumor tissue specimen for submission for research if the patient enrolls to a ComboMATCH Treatment Trial. This tumor tissue must meet the following criteria:
• Tissue must have been collected within 12 months prior to registration to the EAY191 Registration Trial
• Patient must not have had a Response Evaluation Criteria in Solid Tumors (RECIST) response (complete response [CR] or partial response [PR]) to any intervening therapy after collection of the tissue
• Formalin-fixed paraffin-embedded tumor tissue block(s) or slides must be available OR
• Patients under 18 years old must confirm availability of an archival tumor tissue specimen for submission for research if patient enrolls to a ComboMATCH Treatment Trial. This tumor tissue must meet the following criteria:
• Formalin-fixed paraffin-embedded tumor tissue block(s) or slides must be available
• NOTE: See specific ComboMATCH Treatment Trial protocol for tissue collection and management instructions. Performance of the mandatory research biopsy or submission of pre-trial formalin-fixed paraffin-embedded (FFPE) and collection and submission of the blood specimens for the integrated studies will be performed under the consent authority of the specific treatment trial protocol to which the patient is registered. No procedures to collect specimens for research only are to be performed for patients registered to the EAY191 Registration Trial only
• NOTE: Each ComboMATCH Treatment Trial contains specific eligibility criteria. If patient is found to not be eligible for the assigned ComboMATCH Treatment Trial, indication of ineligibility will trigger re-evaluation and potential assignment to another Treatment Trial

• Patient must have enrolled onto EAY191 and must have been given a treatment assignment to ComboMATCH to EAY191-S3 based on the presence of an actionable mutation as defined in EAY191
• GENERAL COMBOMATCH EAY191 REGISTRATION INCLUSION CRITERIA:
• Participants must be enrolled on the ComboMATCH Master Registration Trial EAY191
• Participants must have an activating AKT mutation (a known mutation in AKT1, AKT2, or AKT3, a single nucleotide variant, insertion, or deletion) as determined by the ComboMATCH screening assessment
• GENERAL COMBOMATCH EAY191 REGISTRATION EXCLUSION CRITERIA:
• Participants must not have an activating KRAS, NRAS, HRAS, or BRAF mutation (a single nucleotide variant, insertion, or deletion) as determined by the ComboMATCH screening assessment
• Participants must have disease that can be safely biopsied and agree to a pre-treatment biopsy or have archival tissue available from within 12 months prior to the date of registration on the ComboMATCH Registration Trial (EAY191)
• Participants must have a histologically confirmed non-breast solid malignancy
• Participants must have locally advanced, unresectable, or metastatic disease in the opinion of the treating investigator
• Participants must have measurable disease documented by CT or MRI. Measurable disease must be assessed within 28 days prior to registration. Non-measurable disease must be assessed within 42 days prior to registration. The CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic quality. All known sites of disease must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1). Participants whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to registration
• Participants with known brain metastases must have a CT/MRI scan to evaluate for central nervous system (CNS) disease and show no evidence of progression within 42 days prior to registration
• Participants must have completed any CNS-directed therapy and/or local therapy for spinal cord compression at least 28 days prior to registration
• Participants must not have spinal cord compression or brain metastases unless: (1) metastases have been locally treated and have remained clinically controlled and asymptomatic for at least 14 days prior to registration, AND (2) participant has no residual neurological dysfunction and has been off corticosteroids for at least 24 hours prior to registration
• Participants must not have leptomeningeal disease
• Participants must have progressed within 6 months of taxane-based therapy in the neoadjuvant/adjuvant or metastatic setting
• Participants must not have received any prior AKT inhibitor (e.g., capivasertib or ipatasertib); prior PI3K/mTOR inhibitor is acceptable
• Participants must not be planning to receive any concurrent chemotherapy, immunotherapy, biologic, radiation, or hormonal therapy for cancer treatment while receiving treatment on this study
• Participants must be >= 18 years of age
• Participants must be able to swallow oral medications whole
• Participants must have a pre-study history and physical exam done within 28 days prior to registration
• Participants must have a Zubrod performance status of 0-2 within 28 days prior to registration
• Participants must have adverse events resolved =< grade 1 related to any prior therapy, except alopecia within 14 days prior to registration
• Participants with neuropathy must have resolved to < grade 2 within 14 days prior to registration
• Leukocytes >= 3 x 10^3/uL (within 28 days prior to registration)
• Absolute neutrophil count >= 1.5 x 10^3/uL (within 28 days prior to registration)
• Platelets >= 100 x 10^3/uL (within 28 days prior to registration)
• Total bilirubin =< institutional upper limit of normal (ULN) unless history of Gilbert's disease. Participants with history of Gilbert's disease must have total bilirubin =< 5 x institutional ULN (within 28 days prior to registration)
• Aspartate aminotransferase (AST) & alanine aminotransferase (ALT) =< 3 x institutional ULN (within 28 days prior to registration)
• Participants must have adequate cardiac function, class IIB (2B) or better. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification
• Participants must have a measured OR calculated creatinine clearance >= 50 mL/min using the following Cockcroft-Gault formula. This specimen must have been drawn within 28 days prior to registration
• Participants with known human immunodeficiency virus (HIV)-infection must be receiving anti-retroviral therapy and have an undetectable viral load test on the most recent test results obtained within 6 months prior to registration
• Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy within 28 days prior to registration
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to registration
• Participants must have an electrocardiography (ECG) performed (if clinically indicated with a corrected QTc interval of =< 470 msec) within 28 days prior to registration
• Participants must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ipatasertib and/or paclitaxel
• Participants must not have an active small/large bowel inflammation such as ulcerative colitis or Crohn's disease
• Participants must not have grade 2 or higher uncontrolled intercurrent illness
• NOTE: To receive an agent, participant must not have any uncontrolled intercurrent illness requiring antibiotic/antiviral/antifungal therapy or interventional procedures. Participants with infections unlikely to be resolved within 2 weeks following registration should not be considered for the trial
• Participants must not have a known grade 2 or higher uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia
• Participants must not have any of the following:
• Cirrhosis at a level of Child-Pugh B (or worse),
• Cirrhosis (any degree) and a history of hepatic encephalopathy, or
• Clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
• Participants must not be receiving any medications or substances that are inhibitors or inducers of CYP3A. Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug is prohibited.
• NOTE: Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product. The participant wallet card should be presented to the participant
• Participants must not have baseline fasting glucose (after 8-hour fast) > 160 mg/dL (8.9 mmol/L) within 28 days prior to registration
• Participants with known diabetes mellitus must not require insulin therapy or have a baseline fasting glucose >150 mg/dL (8.3 mmol/L) or high glycosylated hemoglobin (Hb)A1c, (>= 8.0%), suggesting poorly controlled diabetes
• Participants who are on a stable dose of oral diabetes medication >= 2 weeks prior to initiation of study drug treatment are eligible for enrollment
• Participants with a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) must not have a potential to interfere with the safety or efficacy assessment of the investigational regimen
• Participants must not have lung disease requiring active systemic therapy or placing participants at increased risk of toxicity related to study-directed therapy including, but not limited to pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia)
• Participants must not be pregnant or nursing. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is of "reproductive potential". In addition to routine contraceptive methods, "effective contraception" also includes surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen
• Participants must not have psychiatric illness/social situations that would limit compliance with study requirements

• Diagnosis of a solid tumour which meets the criteria for an open trial cohort:
• Cohorts 1 and 1-CN (biliary tract adenocarcinoma): Locally advanced or metastatic biliary tract adenocarcinoma (intra- and extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary cancer).Patients must have unresectable disease and have received all available conventional therapies known to confer clinical benefit for their disease based on local approved standards; or (in the opinion of the investigator) patients are unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.
• Cohort 2 (pancreatic ductal adenocarcinoma): Locally advanced or metastatic pancreatic ductal adenocarcinoma. Patients must have unresectable disease and have received all available conventional therapies known to confer clinical benefit for their disease based on local approved standards.
• Cohort 3 (lung adenocarcinoma): Locally advanced or metastatic lung adenocarcinoma. Patients must have unresectable disease and have received all available conventional therapies known to confer clinical benefit for their disease based on local approved standards.
• Cohort 4 (urothelial bladder cancer): Locally advanced or metastatic urothelial bladder cancer. Patients must have unresectable disease and have received all available conventional therapies known to confer clinical benefit for their disease based on local approved standards.
• Written pathology report / molecular profiling report indicating Mouse double minute 2 homolog (MDM2) amplification or a copy number ≥8 and tumor protein 53 (TP53) wild-type status. This must have been confirmed with a tissue-based test. A test with liquid biopsy is not accepted.
• Archival tissue (formalin fixed paraffin embedded [FFPE] tumour blocks or slides) must be provided for retrospective confirmation of MDM2 amplification and TP53 status.
• Presence of at least 1 measurable target lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
• Patient must be willing to donate mandatory blood samples for the pharmacokinetics, pharmacodynamics, and biomarker analyses
• Adequate organ function
• All toxicities related to previous anti-cancer therapies have resolved to ≤Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 prior to trial treatment administration (except for alopecia and amenorrhea / menstrual disorders which can be of any grade and peripheral neuropathy which must be ≤CTCAE Grade 2).
• Life expectancy ≥3 months at the start of treatment in the opinion of the investigator.
• Provision of signed and dated, written informed consent form (ICF) in accordance with ICH-GCP and local legislation prior to any trial-specific procedures, sampling, or analyses.
• Male or female patients ≥18 years old at the time of signature of the ICF. Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use 2 medically acceptable methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly beginning at screening, during trial participation, and until 6 months and 12 days after last dose for women and 102 days after last dose for men. A list of contraception methods meeting these criteria is provided in the patient information.
• Previous administration of brigimadlin (BI 907828) or any other MDM2-p53 or mouse double minute 4 (MDMX, MDM4)-p53 antagonist.
• Active bleeding, significant risk of haemorrhage (e.g. previous severe gastrointestinal bleeding, previous haemorrhagic stroke at any time), or current bleeding disorder (e.g. haemophilia, von Willebrand disease).
• Major surgery (major according to the investigator's assessment) performed within 4 weeks prior to start of trial treatment or planned within 6 months after screening (e.g. hip replacement).
• Clinically significant previous or concomitant malignancies in the opinion of the investigator affecting the efficacy and/or outcome of the trial.
• Patients who must or intend to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial.
• Currently enrolled in another investigational device or drug trial.
• Any history of, or concomitant condition that, in the opinion of the investigator, would compromise the patient's ability to comply with the trial or interfere with the evaluation of the safety and efficacy of the trial drug.
• Patients not expected to comply with the protocol requirements or not expected to complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition that, in the investigator's opinion, makes the patient an unreliable trial participant). Further exclusion criteria apply.

General (applies to all cohorts) 1. Signed written informed consent. 2. Male or female patients aged ≥ 18 years. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at study entry and an estimated life expectancy of at least 3 months. 4. Adequate hematological function. 5. Adequate hepatic function. 6. Adequate renal function. 7. Effective contraception for women of child bearing potential (WOCBP) patients as defined by World Health Organization (WHO) guidelines for 1 "highly effective" method or 2 "effective" methods. Dose Escalation (Monotherapy and Combination) 1. Histologically or cytologically proven locally advanced or metastatic solid tumors of epithelial origin with documented EGFR expression on tumor tissue by IHC and must have progressed on standard of care therapy. 2. Evidence of objective disease, but participation does not require a measurable lesion. Safety PK/PD Expansion Cohorts 1. Histologically or cytologically proven locally advanced or metastatic solid tumor from the following list, where standard therapy has failed, that has been confirmed to have EGFR expression via archival or fresh biopsy tissue prior to study enrollment. i. NSCLC ii. HNSCC iii. CRC iv. Esophageal adenocarcinoma v. Gastric cancer vi. Renal cell carcinoma vii. Pancreatic cancer 2. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1. 3. Able and willing to have a fresh tumor biopsy obtained during the screening window and an on-treatment biopsy for pharmacodynamic analysis. Head and Neck Squamous Cell Carcinoma (HNSCC) Expansion Cohorts 1. Histologically or cytologically documented relapsed or metastatic HNSCC that has been confirmed to have EGFR expression via archival or fresh biopsy tissue prior to study enrollment. Primary tumor locations include oropharynx, oral cavity, hypopharynx, or larynx. Participants may not have a primary tumor site of nasopharynx (any histology). 2. Participants must have radiographic disease progression while on or after having received both platinum-based chemotherapy and an anti-PD-(L)1 antibody, administered either concurrent or sequentially. 3. Documented EGFR expression by IHC. 4. Able and willing to have a fresh tumor biopsy obtained during the screening window and an on-treatment biopsy for pharmacodynamic analysis. Colorectal Cancer (CRC) Expansion Cohorts 1. Histologically or cytologically documented relapsed or metastatic colorectal cancer that has been confirmed to have EGFR expression via archival or fresh biopsy tissue prior to study enrollment. 2. Must have received 1 line of either FOLFOX, CAPOX, FOLFIRI, or FOLFOXIRI with or without a biological agent. Prior treatment with an anti-EGFR antibody is required for RAS wild-type participants. 3. Participants cannot be known mismatch repair (MMR)/MSI high. 4. Participants must not have received an anti-PD-(L)1. 5. Participants must have radiographic disease progression while or after receiving treatment for their advanced (recurrent/unresectable/metastatic) disease. 6. Presence of at least 1 tumor lesion accessible for biopsy. A fresh tumor biopsy must be obtained and shipped for analysis at the Sponsor-designated laboratory during the screening window and while on study treatment in accordance with the study Laboratory Manual. Non-Small Cell Lung Cancer (NSCLC) Expansion Cohorts 1. Histologically confirmed NSCLC meeting stage criteria for stage IIIB, stage IV (per the 7th IASCLC classification of NSCLC), or recurrent disease that has been confirmed to have EGFR expression via archival or fresh biopsy tissue prior to study enrollment. 2. Patients must have recurrent or progressive disease during or after first line combination therapy with checkpoint inhibitors and platinum-based chemotherapy. They must not have received any subsequent lines of therapy. 3. Patients with Stage IIIB must be ineligible for local therapies with curative intent (eg, radiotherapy or surgery). 4. Patients must have received and progressed on or after anti-PD-(L)1 therapy including those with actionable genomic alterations. 5. Status for actionable mutations (EGFR, ALK, ROS1, RET, etc.) must be known (when testing is available as per country/region standard of care practices); patients with actionable mutations must have received and progressed on, have been intolerant to, or not be a candidate for standard TKIs (as available per country/region standard of care practices). 6. Presence of at least 1 tumor lesion accessible for biopsy. A fresh tumor biopsy must be obtained and shipped for analysis at the Sponsor-designated laboratory during the screening window and while on study treatment in accordance with the study Laboratory Manual. 1. Participants must not have had chemotherapy, radiotherapy (other than palliative bone-directed radiotherapy), or major surgery, or received another investigational agent within 28 days or 5-half-lives of the drug (if known), whichever is shorter, before the start of study treatment. 2. Concurrent anticancer treatment (eg, cytoreductive therapy, radiotherapy [except for palliative bone-directed radiotherapy], immune therapy, or cytokine therapy [except for erythropoietin]), major surgery (excluding prior diagnostic biopsy), concurrent systemic therapy with steroids or other immunosuppressive agents, or use of any investigational drug within 28 days or 5-half-lives of the drug (if known), whichever is shorter, before the start of study treatment. Short-term administration of systemic steroids (eg, for allergic reactions or the management of irAEs) is allowed. Note: Participants receiving bisphosphonate or denosumab are eligible, provided treatment was initiated at least 14 days before the first dose of DF9001. 3. Previous malignant disease other than the target malignancy to be investigated in this study within the last 3 years, with the exception of basal or squamous cell carcinoma of the skin, low-grade prostate cancer (Gleason score of ≤6), or cervical carcinoma in situ. 4. Life expectancy of less than 3 months. 5. Participants with brain metastases are excluded, unless all of the following criteria are met:
• Central nervous system (CNS) lesions are asymptomatic, previously treated and no active therapy is required (i.e., no steroids for edema).
• Imaging demonstrates stability of disease 28 days from last treatment for CNS metastases. 6. Receipt of any organ transplantation, including autologous or allogeneic stem-cell transplantation. 7. Significant acute or chronic infections (including historic positive test for human immunodeficiency virus [HIV], or active or latent hepatitis B or active hepatitis C tested during the screening window). If HBsAg is negative and the anti-hepatitis B core antibody is positive, then hepatitis B viral DNA load must be undetectable. 8. Preexisting autoimmune disease (except for participants with vitiligo) needing treatment with systemic immunosuppressive agents for more than 28 days within the last 3 years, or clinically relevant immunodeficiencies (eg, dysgammaglobulinemia or congenital immunodeficiencies). Participants with a history of immune related endocrinopathies (e.g. hypothyroidism, type 1 diabetes mellitus [TIDM] and adrenal insufficiency) that are stable on hormone replacement therapy may be eligible for this study. 9. Participants with a known medical history that may place them at risk of known toxicities of EGFR-blockage.
• History of or ongoing keratitis, ulcerative keratitis, or corneal perforation,
• History of cardiopulmonary arrest unless this was caused by an acute, reversible etiology that is no longer present.
• History of or ongoing pulmonary fibrosis or interstitial lung disease. 10. Known severe hypersensitivity reactions to monoclonal antibodies (≥Grade 3 of the NCI-CTCAE v5.0), any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of partly controlled asthma). 11. Persisting toxicity related to prior therapy >Grade 1 NCI-CTCAE v5.0; however, alopecia ≤Grade 2, endocrinopathies ≤Grade 2, and sensory neuropathy ≤Grade 2 is acceptable. 12. Participants who have received an anti-PD-(L)1 as a previous line of therapy are eligible for the study, unless they have experienced either:
• a Grade 3 or 4 drug-related toxicity during and attributed to treatment with the anti-PD-(L)1.
• a Grade 2 drug-related toxicity that impacted either the lungs or the nervous system, caused by the administration of the anti-PD-(L)1. 13. Pregnancy or lactation in females during the study. 14. Known alcohol or drug abuse. 15. Serious cardiac illness or medical conditions, including but not limited to:
• History of New York Heart Association class III or IV heart failure or systolic dysfunction (left ventricular ejection fraction [LVEF] <55%).
• High-risk uncontrolled arrhythmias (eg, tachycardia with a heart rate >100/min at rest).
• Significant ventricular arrhythmia (ventricular tachycardia) or higher-grade atrioventricular (AV) block (eg, AV-block, second degree AV block Type 2 [Mobitz 2], or third-degree AV-block).
• Angina pectoris requiring anti-anginal medication.
• Clinically significant valvular heart disease.
• Evidence of transmural infarction on ECGs.
• Poorly controlled hypertension (defined as systolic >160 mm Hg or diastolic >100 mm Hg).
• Clinically relevant uncontrolled cardiac risk factors, clinically relevant pulmonary disease, or any clinically relevant medical condition in the opinion of the Investigator that may limit participation in this study.
• Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy. 16. All other significant diseases (eg, inflammatory bowel disease), which, in the opinion of the Investigator, might impair the participant's ability to participate. 17. Any psychiatric condition that would prohibit the understanding or rendering of informed consent. 18. Legal incapacity or limited legal capacity. 19. Incapable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

• Pathologically (histologically or cytologically) proven diagnosis of renal cell carcinoma prior to registration
• Node-positive unresectable (TxN1Mx) or metastatic (TxNxM1) based on the following diagnostic workup:
• History/physical examination within 45 days prior to registration
• CT/magnetic resonance imaging (MRI) of the chest/abdomen/pelvis within 45 days prior to registration
• Patients must have IMDC intermediate (1-2 factors) or poor risk disease (>= 3 factors)
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with measurable disease (node positive or metastatic) as defined by RECIST version 1.1 excluding the primary renal tumor
• Patient not recommended for or refused immediate cytoreductive nephrectomy
• Candidate for standard of care therapy with either immuno-oncology (IO)-IO or IO-VEGF combination regimen
• Primary renal tumor measuring 20 cm or less in anterior to posterior dimension only on axial imaging
• Age >= 18
• Karnofsky performance status >= 60 within 45 days prior to registration
• Hemoglobin >= 8 g/dL (transfusions are allowed) (within 45 days prior to registration)
• Platelet count >= 50,000/mm^3 (within 45 days prior to registration)
• Absolute neutrophil count (ANC) >= 1500/mm^3 (within 45 days prior to registration)
• Calculated (Calc.) creatinine clearance >= 30 mL/min (within 45 days prior to registration)
• For African American patients specifically whose renal function is not considered adequate by the formula above, an alternative formula that takes race into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula) should be used for calculating the related estimated glomerular filtration rate (GFR) with a correction factor for African American race creatinine clearance for trial eligibility, where GFR >= 30 mL/min/1.73m^2 will be considered adequate
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) (within 45 days prior to registration)
• Aspartate aminotransferase and alanine aminotransferase (AST and ALT) =< 3 x upper limit of normal (ULN) or < 5 x ULN if hepatic metastases present (within 45 days prior to registration)
• Patients with known human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Testing is not required for entry into protocol
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load
• The patient must agree to use a highly effective contraception, including men with vasectomies if they are having sex with a woman of childbearing potential or with a woman who is pregnant, while on study drug and for 6 months following the last dose of study drug. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
• Patients with planned treatment of all metastatic disease with definitive therapy including either surgery, ablative (non-palliative) doses of radiation, or intervention of some type (definitive interventional radiology techniques) to ALL metastatic sites rendering the patient without extra-renal measurable disease. Patients NOT planned for definitive treatment of all metastatic sites are eligible. Lesions radiated palliatively are not eligible for response assessment
• Patients with untreated or unstable brain metastases or cranial epidural disease
• Note: Patients who have been adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator are eligible. Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator
• Prior radiotherapy to the kidney that would result in overlap of radiation therapy fields treatment of the primary tumor
• Any systemic therapy for metastatic renal cell carcinoma (RCC) that was initiated > 90 days before registration, note that prior chemotherapy for a different cancer is allowed (completed > 3 years prior to registration)
• Severe, active comorbidity defined as follows:
• Active autoimmune disease requiring ongoing therapy including systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications daily. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
• History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies
• Active tuberculosis (purified protein derivative [PPD] response without active tuberculosis [TB] is allowed)
• Uncontrolled hypertension (systolic blood pressure [BP] > 190 mmHg or diastolic BP > 110 mmHg)
• Major surgery requiring hospital admission ≤ 28 days prior to registration.
• Any serious (requiring hospital stay or long-term rehab) non-healing wound, ulcer, or bone fracture within 45 days prior to registration
• Any arterial thrombotic (ST elevation myocardial infarction [STEMI], non-ST elevation myocardial infarction [NSTEMI], cerebrovascular accident [CVA], etc) events within 180 days prior to registration
• Active New York (NY) Heart Association class 3-4 heart failure symptoms
• Moderate or severe hepatic impairment (Child-Pugh B or C)
• Any history of untreated pulmonary embolism or deep venous thrombosis (DVT) within 180 days prior to registration. (Any asymptomatic or treated pulmonary embolism or asymptomatic treated deep venous thrombosis > 30 days prior to registration is allowed)
• Unstable cardiac arrhythmia within 180 days prior to registration
• History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel obstruction, or gastric outlet obstruction within 180 days prior to registration
• History of or active inflammatory bowel disease
• Malabsorption syndrome within 45 days prior to registration
• Pregnancy and individuals unwilling to discontinue nursing. For women of child bearing potential must have a negative pregnancy test =< 45 days prior to registration

• Patients must have developed their first or second distant brain relapse(s) at least 8 weeks after upfront SRS and within 21 days prior to randomization
• Distant brain relapse lesions to be treated must measure =< 3.0 cm in maximal extent and total volume of distant brain relapses to be treated must measure < 30 mL on the contrast-enhanced diagnostic magnetic resonance imaging (MRI) brain scan obtained within 21 days prior to randomization
• Distant brain relapse lesions must be diagnosed on MRI, which will include the following elements:
• REQUIRED MRI ELEMENTS
• Post gadolinium contrast-enhanced T1-weighted three-dimensional (3D) spoiled gradient (SPGR). Acceptable 3D SPGR sequences include magnetization-prepared 3D gradient recalled echo (GRE) rapid gradient echo (MP-RAGE), turbo field echo (TFE) MRI, BRAVO (brain volume imaging) or 3D fast FE (field echo). The T1-weighted 3D scan should use the smallest possible axial slice thickness, not to exceed 1.5 mm
• Pre-contrast T1 weighted imaging (3D imaging sequence strongly encouraged)
• A minimum of one axial T2 fluid attenuated inversion recovery (FLAIR) (preferred) or T2 sequence is required. This can be acquired as a 2D or 3D image. If 2D, the images should be obtained in the axial plane
• ADDITIONAL RECOMMENDATIONS
• Recommendation is that an axial T2 FLAIR (preferred) sequence be performed instead of a T2 sequence
• Recommendation is that that pre-contrast 3D T1 be performed with the same parameters as the post-contrast 3D T1
• Recommendation is that imaging be performed on a 3 Tesla (3T) MRI
• Recommendation is that the study participants be scanned on the same MRI instrument at each time point
• Recommendation is that if additional sequences are obtained, these should meet the criteria outlined in Kaufmann et al., 2020
• If additional sequences are obtained, total imaging time should not exceed 60 minutes
• Brain metastasis velocity (BMV) since upfront SRS must be >= 4 brain metastases/year
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
• Pathologically (histologically or cytologically) proven diagnosis of non-small cell lung cancer, melanoma, breast cancer, renal cell carcinoma, or gastrointestinal cancer within 10 years prior to randomization. If the original histologic proof of malignancy is greater than 10 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic metastasis or brain metastasis)
• Other histologies are not permitted
• History and physical examination within 28 days prior to randomization
• Karnofsky performance status of >= 70 within 28 days prior to randomization
• Calculated creatinine clearance (CrCl) >= 30 ml/min (within 28 days prior to randomization)
• Blood urea nitrogen (BUN) within 1.5 times the institutional upper limit of normal (ULN) (e.g., if the ULN is 20 mg/dL, then BUN up to 30 mg/dL is permitted) (within 28 days prior to randomization)
• Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to randomization
• Prior WBRT or prophylactic cranial irradiation
• Local relapse of metastasis previously treated with upfront SRS (i.e., relapse outside previously SRS-treated metastases is allowed)
• Brain metastases from primary germ cell tumor, small cell carcinoma, or lymphoma
• Definitive leptomeningeal metastasis
• Planned cytotoxic chemotherapy on the same day as SRS or HA-WBRT; concurrent immunotherapy is permitted
• Radiographic evidence of enlargement or other architectural distortion of the lateral ventricles, including placement of external ventricular drain or ventriculoperitoneal shunt
• Known history of demyelinating disease such as multiple sclerosis
• Inability to swallow pills
• Contraindication to MR imaging such as non-MR conditional implanted metal devices or unknown metallic foreign bodies, or contraindication to gadolinium contrast administration during MR imaging, such as anaphylactic allergy that cannot be adequately addressed with pre-contrast medications or acute kidney injury
• Contraindications to memantine, including:
• Allergy, including prior allergic reaction to memantine
• Intractable seizures on adequate anticonvulsive therapy-more than 1 seizure per month for the past 2 months
• Current use of N-methyl-D-aspartate (NMDA) agonist
• Current alcohol or drug abuse, which can exacerbate lethargy/dizziness with memantine
• Severe, active co-morbidity defined as follows:
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
• Transmural myocardial infarction within the last 6 months
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of randomization
• Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of randomization
• Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic disease
• Renal tubular acidosis or metabolic acidosis
• Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to randomization. Note also that HIV testing is not required for eligibility for this protocol
• Pregnant or lactating women, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the medication and radiation involved in this study has unknown effects on the unborn fetus

1. Age ≥ 18 years 2. E-STOP AKI 2.0 score in the top 10% of risk (historically from all hospitalized patients) within the last 12 hours. (First time across this 10% risk threshold during this hospital stay). 3. Admitted to an inpatient ward, intermediate, or ICU care at the University of Chicago Medical Center (UCMC) or University of Wisconsin Health (UWHealth). (No Emergency Department patients) 4. Patient or their legally authorized representative must be able to read, speak, and understand English, for the purposes of consenting. Otherwise, inclusion in this protocol will be done without regard to race, ethnic origin or gender 1. Voluntary refusal or missing written consent of the patient / legal representative. 2. Patients with a known history of end-stage renal disease on dialysis (including renal transplantation). 3. Patients without a measured serum creatinine value during their inpatient stay. 4. Patients with a creatinine >4.0 mg/dl at the time of admission or available in the EHR from the last 6 months 5. Patients with prior episode of KDIGO defined AKI during this same hospitalization- regardless of E-STOP AKI 2.0 score 6. Patients with prior renal consultation during their admission. 7. Patient with an E-STOP AKI 2.0 above the top 10% risk threshold more than 12 hours ago during this same hospital stay. 8. Incarcerated patients 9. Pregnant patients

1. Written informed consent is provided by patient or legally acceptable representative; 2. Age ≥ 18 years; 3. Patient populations: 1. In the Safety Run-in, patients with histologically or cytologically confirmed advanced or metastatic solid tumors who have disease progression after treatment with standard therapies for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment or refuse standard treatment will be enrolled in therapy 2. In Expansion Phase, patient must have urothelial or NSCLC, and have failed prior anti-PD-1 or anti-PD-L1 4. Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology 5. Eastern Cooperative Oncology Group performance status of 0 to 1 6. Life expectancy of ≥ 3 months 1. Positive urine pregnancy test within 72 hours prior to treatment. I 2. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks (or 5 half-lives, whichever is shorter) prior to treatment; 3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137), AND was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event; 4. Has received prior radiotherapy within 2 weeks of start of study treatment. 5. For patients with NSCLC: 1. Patients who have received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of trial treatment are excluded; 2. Patients with mutations (e.g., EGFR mutations or ALK gene rearrangements) will be excluded unless they have been previously treated with all specific targeted therapies. 6. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. 7. Has had an allogeneic tissue /solid organ transplant.

• At least 18 years of age.
• Histologically or cytologically confirmed advanced solid tumors
• Arm #1 (Monotherapy): HRAS-mutant and/or amplified tumors (any solid tumor type); HRAS overexpression (only for HNSCC tumors); KRAS and/or NRAS, and/or HRAS-mutant and/or amplified NSCLC or CRC; KRAS-mutant and/or amplified PDAC
• Arm #2 (Combination): Must have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic RCC with predominantly clear cell subtype
• Arm #3 (Combination): Must have KRAS G12C-mutant locally advanced or metastatic NSCLC and have received at least 1 prior systemic therapy for advanced or metastatic NSCLC
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• Karnofsky Performance Status of 70 or higher with no clinically significant deterioration over the previous 2 weeks.
• Acceptable liver, renal, endocrine, and hematologic function.
• Other protocol-defined inclusion criteria may apply.
• Ongoing treatment with certain anticancer agents.
• Prior treatment with an FTI or HRAS inhibitor.
• Major surgery, other than local procedures, within 28 days prior to Cycle 1 Day 1, without complete recovery.
• Spinal cord compression, leptomeningeal disease, or clinically active CNS metastases.
• Toxicity (excluding alopecia) from prior therapy that has not been completely resolved to baseline at the time of consent.
• Active or prior documented autoimmune or inflammatory disorders within the past 5 years prior to Cycle 1 Day 1 (with exceptions).
• Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy.
• Inability to swallow, impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the trial drugs.
• Inadequate cardiac and/or vascular function, including receipt of treatment for unstable angina, myocardial infarction, and/or cerebro-vascular attack within the prior 6 months, mean QTcF ≥470 ms, or Class II or greater congestive heart failure.
• Other invasive malignancy within 2 years.
• Other protocol-defined exclusion criteria may apply.

Key
• Life expectancy of ≥ 12 weeks
• Measurable or non-measurable disease for Dose Escalation; measurable disease using RECIST v1.1 is required for Dose Expansion
• Recovered from prior therapy to Grade ≤ 1 or return to baseline status (except for alopecia)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Patients with adequate bone marrow, kidney and liver function
• Last dose of previous anticancer therapy ≥ 4 weeks prior to first dose of NDI-101150; includes prior anti-PD-1 or anti-PD-L1 therapy, other anticancer therapy, radiotherapy, or surgical intervention
• For Dose Escalation Phase Only (Dose Escalation, Monotherapy and Combination Therapy): Histologically or cytologically confirmed advanced or metastatic solid tumors for whom no standard therapies are available or refractory to standard therapy
• For Dose Expansion Phase (Dose Expansion, Monotherapy and Combination Therapy): Willing to consent to required tumor biopsy(ies). Histologically or cytologically confirmed advanced or metastatic G/GEJ, NSCLC or RCC for which no standard therapy is available or are refractory to standard therapy Key
• Previous solid organ or hematopoietic cell transplant
• Central nervous system (CNS) malignant disease not previously treated, active leptomeningeal disease, uncontrolled symptomatic CNS involvement, or CNS malignant disease requiring steroid or other therapeutic intervention
• Prior anticancer therapy within 2-6 weeks of trial start (depending on nature of therapy).
• Clinically significant cardiovascular disease
• History of severe hypersensitivity reaction to treatment with monoclonal antibody(ies) (for combination therapy cohorts only)
• History of interstitial lung disease, idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of history of pneumonitis on chest computed tomography scan in the last 6 months
• Known additional malignancy that is active and/or in progression requiring treatment
• Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition, uncontrolled diabetes, thromboembolic event within the past 3 months) or any important medical or psychiatric illness or abnormal laboratory finding
• Unable to discontinue medications that are strong inducers or inhibitors of CYP3A4 and/or CYP2C8
• History of severe irAE that led to permanent discontinuation of prior immunotherapy
• History of recent Grade >/= 3 irAE or any Grade 4 life-threatening irAE, neurologic or ocular AE of any grade while receiving prior immunotherapy NOTE: Other protocol defined Inclusion and Exclusion criteria may apply.

Key
• Availability of tumor tissue (archived and fresh tumor biopsy, if medically feasible)
• Select advanced or metastatic solid tumor that is likely to express CLDN18.2 such as gastric/GEJ, pancreatic and esophageal cancer
• ≥ 18 years of age
• ECOG performance status (PS) 0 or 1 at Screening
• Progressed on or after standard therapy, or are intolerable for available standard therapy, or there is no available standard therapy
• Have at least one measurable extra-cranial lesion as defined by RECIST v1.1
• Adequate organ function
• Life expectancy > 12 weeks
• Ability to understand the nature of this study, comply with protocol requirements, and give written informed consent
• Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following study completion Key
• Pregnant or breastfeeding
• Symptomatic or untreated brain metastases
• Have previously received CLDN18.2 antibody drug conjugates (ADCs) or any ADC containing an auristatin payload (prior monoclonal antibody against CLDN18.2 may be eligible)
• Have peripheral neuropathy Grade ≥2
• Have history of non-infectious pneumonitis/interstitial lung disease
• Have diagnosis of another malignancy, or history of systemic treatment for invasive cancer within last 3 years. Note: Patients with Stage I cancer who have received definitive local treatment and are considered unlikely to recur are eligible. Diagnosis of non-melanoma skin cancer, carcinoma in situ of the cervix or breast, or noninvasive tumor does not affect eligibility
• Have active ocular surface disease at baseline (based on screening ophthalmic examination)
• Have serious concurrent illness or clinically relevant active bacterial, fungal or viral infection
• Have previous hypersensitivity to any known components of EO-3021 or history of severe infusion reaction or hypersensitivity (CTCAE Grade 3 or higher) with monoclonal antibody treatment
• Clinically significant cardiac disease, including but not limited to symptomatic congestive heart failure, unstable angina, acute myocardial infarction within 6 months of planned first dose, or unstable cardiac arrhythmia requiring therapy (including torsades de pointes)
• Have history of allogenic hematopoietic stem cell transplantation or solid organ transplantation with ongoing systemic immunosuppressive therapy
• Patients who are not appropriate candidates for participation in this clinical study for any other reason as deemed by the Investigator

1. Adult participants must be 18 years of age or older 2. Advanced or metastatic solid tumors excluding primary central nervous system (CNS) tumors 3. Have documented evidence of genetic alterations conferring homologous recombination deficiency 4. Participant must have progressed on at least one prior line of therapy in the advanced or metastatic setting that is considered an appropriate standard of care, or for which the participant has documented intolerance 1. Known primary CNS malignancy 2. Impairment of GI function or GI disease that may significantly alter the absorption of IDE161 3. Have active, uncontrolled infection 4. Clinically significant cardiac abnormalities 5. Major surgery within 4 weeks prior to enrollment 6. Radiation therapy within 2 weeks prior to enrollment 7. Systemic cytotoxic chemotherapy within 4 weeks prior to enrollment 8. Radioimmunotherapy within 6 weeks of enrollment 9. Treatment with a therapeutic antibody within 4 weeks prior to enrollment 10. Treatment with an anti-cancer small molecule within 5 half-lives (t1/2), or 2 weeks, whichever is shorter

• Alive (per medical record)
• Diagnosed with cancer in the past 3 years
• Received care from a participating oncology clinic in the past year
• Has a current tobacco use status
• Does not have a preferred language other than English (missing language preference will be included).
• Valid address that is not a correctional facility or residential treatment/care facility.
• No flag for patient cognitive impairment, activated health care power of attorney, or other health care agent (e.g., legally authorized representative) in the EHR. The following additional inclusion criteria must be met for inclusion in the CET
• Smoked combustible cigarettes in the past month.
• Able to speak and understand English.
• Willing to set a date to quit smoking in the next 60 days.
• Willing to receive smoking treatment information.
• Willing to complete study activities.
• No current suicidal ideation.
• Suicide attempt in the past year.
• Currently receiving treatment for bipolar disorder, schizophrenia, schizoaffective disorder, or psychotic disorder.
• Incarceration.
• Unable to provide informed consent to treatment (i.e., cannot answer questions about study procedures or risks after hearing about the study).

1. Male or female participants ≥18 years of age 2. Dose Escalation Phase (Part 1): 1. Participants must have a pathologically confirmed diagnosis of an advanced or metastatic solid tumor with a documented RAS, NF1, or RAF mutations. A molecular pathology report documenting mutational status of RAS, NF1, or RAF must be available. 2. Progressed despite standard therapies, and received at least 1 prior line of anticancer therapy.
• Participants with a documented mutation in BRAF V600E or V600K must have received approved treatments known to provide clinical benefit prior to study entry. 3. Participants enrolled in the DCC-3116 and sotorasib cohort (Cohort D) must have a KRAS G12C mutation. 3. Dose Expansion Phase (Part 2): 1. Cohort 1: Patients with Pancreatic Ductal Adenocarcinoma (PDAC).
• Pathologically confirmed PDAC with a documented mutation in KRAS.
• Received only 1 prior line of systemic therapy in the advanced or metastatic setting. 2. Cohort 2: Patients with Non-Small Cell Lung Cancer (NSCLC)
• Pathologically confirmed NSCLC with a documented mutation in KRAS, NRAS, NF1, or BRAF.
• Received at least 2 prior lines but no more than 4 prior lines of systemic therapy in the advanced or metastatic setting. 3. Cohort 3: Patients with Colorectal Cancer (CRC)
• Pathologically confirmed CRC with a documented mutation in KRAS, NRAS, NF1, or BRAF.
• Received at least 2 prior lines of systemic therapy in the advanced or metastatic setting. 4. Cohort 4: Patients with Melanoma
• Pathologically confirmed melanoma with a documented mutation in NRAS.
• Received at least 1 but not more than 2 prior lines of systemic therapy in the advanced or metastatic setting that included T-cell checkpoint inhibitor-based therapy.
• Have not received prior MEK inhibitor therapy. 5. Cohort 5: Patients with KRAS G12C mutant NSCLC
• Pathologically confirmed NSCLC with a documented mutation in KRAS G12C.
• Received at least 1 prior line but no more than 3 prior lines of systemic therapy in the advanced or metastatic setting.
• Have not received prior sotorasib or other KRAS G12C inhibitor therapy. 4. Must provide a fresh tumor biopsy from a primary or metastatic cancer lesion that can be biopsied with acceptable risk as determined by the Investigator, and an archival tumor tissue sample, if available. If a fresh tumor biopsy is not possible, then an archival tumor tissue sample must be provided. 5. Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 (Dose Escalation) or 0 to 1 (Dose Expansion) at Screening 6. Adequate organ function and bone marrow function. 7. If a female of childbearing potential must have a negative pregnancy test prior to enrollment and agree to follow the contraception requirements. 8. Male participants must agree to follow contraception requirements. 9. Must provide signed consent to participate in the study and is willing to comply with study-specific procedures. 1. Must not have received the following within the specified time periods prior to the first dose of study drug: 1. Prior therapies (anticancer or therapies given for other reasons) that are known strong or moderate inhibitors or inducers of CYP3A4 or P-gp including certain herbal medications (eg, St. John's Wort): 14 days or 5× the half-life of the medication (whichever is longer) 2. All other prior anticancer therapies or any therapy that is investigational for the participant's condition with a known safety and PK profile: 14 days or 5× the half-life of the medication (whichever is shorter) 3. Investigational therapies with unknown safety and PK profile: 28 days. If there is enough data on the investigational therapy to assess the risk for drug.-drug interactions and late toxicities of prior therapy as low, the Sponsor's Medical Monitor may approve a shorter washout of 14 days 4. Grapefruit or grapefruit juice: 14 days 2. Have not recovered from all toxicities from prior therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). 3. Presence or history of central nervous system (CNS) metastases or leptomeningeal disease, with some exceptions 4. New York Heart Association Class III or IV heart disease, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension, congestive heart failure, or myocardial infarction within 6 months prior to the first dose of study drug. 5. Prolongation of the QT interval corrected by Fridericia's formula (QTcF) based on repeated demonstration of QTcF >450 ms in males or >470 ms in females at screening, or history of long QT syndrome. 6. Left ventricular ejection fraction (LVEF) <50% at Screening 7. Systemic arterial thrombotic or embolic events 8. Systemic venous thrombotic events 9. Malabsorption syndrome 10. Bone disease that requires ongoing treatment or has required treatment. 11. Major surgery within 4 weeks of the first dose of study drug. All surgical wounds must be healed and free of infection or dehiscence before the first dose of the study drug. 12. Any other clinically significant comorbidities. 13. For participants receiving DCC-3116 and trametinib combination or DCC-3116 and binimetinib combination: previous treatment with trametinib or binimetinib that resulted in treatment discontinuation due to intolerability as a result of an adverse event (AE) that was considered related to trametinib or binimetinib. 14. For participants receiving DCC-3116 and sotorasib combination in Dose Escalation Part 1: previous treatment with sotorasib that resulted in treatment discontinuation due to intolerability as a result of an adverse event (AE) that was considered related to sotorasib. 15. For participants receiving DCC-3116 and sotorasib combination: Use of proton pump inhibitors (PPIs) and H2 receptor antagonists that cannot be discontinued 3 days prior to the start of study drug administration. 16. Known allergy or hypersensitivity to any component of the investigational drug products. 17. Known human immunodeficiency virus unless the following requirements are met: 1. CD4 count >350/µL 2. No AIDS-defining opportunistic infection in the last 12 months 3. Stable anti-retroviral regimen with medications that are not prohibited by the protocol for at least 4 weeks with HIV viral load less than 400 copies/mL prior to enrollment. 18. Known active hepatitis B, active hepatitis C infection or if the participant is taking medications that are prohibited per protocol. 19. If female, the participant is pregnant or lactating. 20. Ongoing participation in an interventional study. 21. For participants receiving DCC-3116 and binimetinib combination: Known Gilbert's syndrome

1. Subject (or legally authorized representative, where applicable) is willing and able to provide signed informed consent and can follow protocol requirements 2. Subject is ≥18 years of age at time of informed consent 3. Eastern Cooperative Oncology Group performance status of 0 or 1 4. Subject has documented evidence of a BRAF V600 mutation obtained from tumor tissue or liquid biopsy: (other protocol conditions may apply) 5. Subject must have received ≥1 prior line of SoC therapy for their unresectable locally advanced or metastatic disease with disease progression on or after last prior treatment. Prior regimens for these subjects vary by indication and investigational arm, but must have included the following: 1. Melanoma or NSCLC (Phase 1 and Phase 2 Arms A1 and B1): Prior receipt of a BRAF inhibitor and an immune checkpoint inhibitor (any sequence or combination). Prior (neo)adjuvant immunotherapy may be acceptable. 2. CRC: Receipt of a systemic chemotherapy-based regimen per SoC for unresectable locally advanced or metastatic disease, and previous treatment with BRAF inhibitor in combination with an EGFR monoclonal antibody. Subjects with documented MSI-H or dMMR CRC must have received prior immunotherapy. Subjects with MSS disease must have received at least 2 prior treatments. Subjects who received neo(adjuvant) chemotherapy regimens may be eligible. 3. ATC: Subjects must have received SoC therapy options including BRAF inhibitor if available and of benefit to the subject 4. Other BRAF V600 mutant solid tumors (non-CNS): Subjects must have received SoC therapy options per their Investigator's best judgment, including BRAF inhibitor if available and of benefit to the subject 6. Subject has measurable disease per RECIST v1.1 7. Adequate bone marrow, liver, renal, and cardiac function 8. A female subject may be eligible if not pregnant, planning a pregnancy, not breast feeding, a women of non-child bearing potential or a WOCBP willing to comply with protocol conditions relating to the use contraception, ova or blood donation and pregnancy testing prior to the first dose 9. A male subject must agree to comply with protocol conditions relating to the use of contraception, sperm and blood donation 10. Subject can safely swallow a tablet or pill Other protocol defined exclusion criteria may apply 1. Subject has had major surgery within 21 days prior to the planned first dose. Minor surgery is permitted within 21 days prior to enrollment 2. Subject with CNS involvement (primary tumor or metastatic disease), except if clinically stable, have no evidence of new or enlarging brain metastases and are on stable or tapering doses of steroids for at least 7 days prior to first dose. Subjects with untreated brain metastases may be eligible to enter without prior radiation therapy. 3. Subject with known malignancy other than trial indication that is progressing or has required treatment within the past 3 years, except for conditions that have undergone potentially curative therapy 4. Subject with history of thromboembolic or cerebrovascular events ≤6 months as defined in the protocol 5. Subject with impaired cardiac function or clinically significant cardiac disease, as defined in the protocol 6. Subject with history of uncontrolled diabetes mellitus (only for subjects who will receive CFT1946 + trametinib) 7. Subject with history or current evidence of retinal vein occlusion (RVO), chorioretinopathy, or current risk factors for RVO (only for subjects who will receive CFT1946 + trametinib) 8. Subject has received live, attenuated vaccine within 28 days prior to first dose administration 9. Subject has history of pneumonitis or interstitial lung disease 10. Subject has history of uveitis 11. Subject has known human immunodeficiency virus (HIV) infection (with exceptions) 12. Subject has history of or known HBV or active HCV infection 13. Subject has concurrent administration of strong CYP3A4/5 inhibitors and inducers, including any herbal medications/supplements 14. Subject has presence of Grade ≥2 toxicity due to prior cancer therapy, excepting alopecia and hypothyroidism requiring thyroid replacement therapy 15. Subject has initiation or receipt of the following ≤7 days prior to first dose administration: Hematopoietic colony-stimulating growth factors, transfusion of packed red blood cells (pRBC), and transfusion of platelets 16. Subject is pregnant, breastfeeding, or expecting to conceive or father children any time during the study Other protocol defined exclusion criteria may apply