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12 Study Matches

Treatment of Cytomegalovirus (CMV) Infections With Viral-Specific T Cells

The present trial will consist of the treatment of 20 pediatric and adult Hematopoietic Stem Cell Transplantation (HSCT) recipients or immunocompromised participants diagnosed with opportunistic Cytomegalovirus (CMV) infections with virus-specific, antigen-selected T-cells. CMV-specific T-cells will be isolated from donor leukapheresis products using the CliniMACS® Prodigy. Prior studies on transfer of CMV specific T-cells have been shown to be safe and efficacious in the treatment of CMV infections. The main trial objective is to evaluate the feasibility and safety of CMV-specific T-cell transfer in adult and pediatric participants suffering from CMV infections or reactivation following HSCT or due to other immunocompromised states (e.g.; primary immunodeficiency, cytotoxic therapy). Participants will be followed for one year.
Kenneth Desantes, M.D.
All
1 Month and over
Phase 1
This study is NOT accepting healthy volunteers
NCT03798301
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Inclusion Criteria:
1. Adult or pediatric patient suffering from CMV reactivation/infections following HSCT or due to other immunocompromised states (e.g.; primary immunodeficiency, cytotoxic therapy).
• CMV reactivation/viremia defined as positive (>500 copies/ml) CMV qPCR and/or
• Presence of symptoms secondary to CMV infection or evidence of invasive CMV infection (e.g. pneumonitis, colitis) AND
• Patients must have ONE OF THE FOLLOWING CRITERIA:
• Absence of an improvement of viral load after ≥ 14 days of antiviral therapy with ganciclovir, valganciclovir or foscarnet (decrease by at least 1 log, i.e. 10-fold), or
• New, persistent and/or worsening CMV-related symptoms, signs and/or markers of end organ compromise while on antiviral therapy with ganciclovir, valganciclovir or foscarnet, or
• Have contraindications or experience adverse effects of antiviral therapy with ganciclovir, valganciclovir or foscarnet, or
• Known resistance to ganciclovir and/or foscarnet based on molecular testing. 2. Recipients of an allogeneic HSCT must be 28 days after stem cell infusion at the time of T-cell transfer. 3. Written informed consent given by patient or legal representative. 4. Minimum patient age 1 month. 5. Minimum weight 7 lbs. 6. Female patients of childbearing age with negative pregnancy tests. 7. Patient Karnofsky/Lansky Performance Status >30%. 8. Donor eligible based on FACT infectious screening requirements.
Exclusion Criteria:
1. Patient with acute GVHD > grade 2 or active moderate or severe chronic GVHD at time of T-cell transfer 2. Patient receiving steroids (>1.0 mg/kg body weight (BW) prednisone equivalent) at the time of T-cell transfer 3. Patient received allogeneic HSCT less than 28 days prior to T-cell transfer 4. Patient treated with donor lymphocyte infusion (DLI) within 28 days prior to T-cell transfer 5. Patient treated with Thymoglobulin (ATG), Alemtuzumab or T-cell immunosuppressive monoclonal antibodies within 28 days. 6. Patient with organ dysfunction or failure as determined by Karnofsky (patients >16 years) or Lansky (patients ≤16 years) score ≤30% (Appendix 5) 7. Patients with CMV retinitis 8. Concomitant enrollment in another clinical trial with endpoints interfering with this study 9. Any medical condition which could compromise participation in the study according to the investigator's assessment 10. Known HIV infection 11. Female patient who is pregnant or breast-feeding, or adult of reproductive potential not willing to use an effective method of birth control during study treatment. Note: Women of childbearing potential must have a negative serum pregnancy test at study entry. 12. Patients unwilling or unable to comply with the protocol or unable to give informed consent. Donor Eligibility: The original donor will be the first choice as source of T cells. If the original donor is not available for donation (such as NMDP donor, cord blood unit, or related donor not available) of peripheral mononuclear cells or does not meet all donor eligibility criteria (including donor selection criteria based on University of Wisconsin
•Madison Standard Operating Procedures for the selection of allogeneic donors), alternative related donors will be selected, with preference for those who have full HLA matching in 6/6 loci over those with partial HLA matching (≥ 3/6 HLA loci). 1. All donors must be ≥ 18 years old, available, CMV IgG positive, eligible and capable of undergoing a single standard 2 blood volume leukapheresis. If original HSCT donor is not available, CMV IgG negative or ineligible, a CMV IgG positive fully matched or haploidentical family donor will be used. 2. Related donors must be at least partially HLA compatible, matching with recipient in at least 3/6 HLA loci (HLA-A, HLA-B and HLA-DRB1 will be considered for this). 3. Donors must be CMV IgG seropositive. 4. Donors must show CMV T-cell activation after incubation with MACS GMP PepTivator Peptide Pools of CMV pp65 before undergoing leukapheresis. 5. Donor must meet the criteria for donor selection defined in the Standard Operating Procedures of the University of Wisconsin Hospitals and Clinics Stem Cell Transplant Program and in FACT standards.
Unknown Sites, CMV Infection, Cytomegalovirus Infections, CMV Viremia, Opportunistic Infections
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Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

This randomized phase III trial studies how well imatinib mesylate works in combination with two different chemotherapy regimens in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (ALL). Imatinib mesylate has been shown to improve outcomes in children and adolescents with Philadelphia chromosome positive (Ph+) ALL when given with strong chemotherapy, but the combination has many side effects. This trial is testing whether a different chemotherapy regimen may work as well as the stronger one but have fewer side effects when given with imatinib. The trial is also testing how well the combination of chemotherapy and imatinib works in another group of patients with a type of ALL that is similar to Ph+ ALL. This type of ALL is called "ABL-class fusion positive ALL", and because it is similar to Ph+ ALL, is thought it will respond well to the combination of agents used to treat Ph+ ALL.
Kenneth Desantes, M.D.
All
1 Year to 21 Years old
Phase 3
This study is NOT accepting healthy volunteers
NCT03007147
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Inclusion Criteria:

• For patients enrolled on APEC14B1 prior to enrollment on AALL1631, the required diagnostic bone marrow sample has been fulfilled
• For patients who have not previously enrolled on APEC14B1 prior to enrollment on AALL1631, a baseline diagnostic sample (or peripheral blood sample with blasts if marrow sample unavailable) must be available to develop an MRD probe
• In addition, laboratory reports detailing evidence of BCR-ABL1 fusion or ABL-class fusion must be submitted for rapid central review within 72 hours of study enrollment
• >= 1 year (365 days) and =< 21 years at ALL diagnosis
• Ph+ (BCR-ABL1 fusion): newly diagnosed de novo ALL (B-ALL or T-ALL) or mixed phenotypic acute leukemia (MPAL meeting 2016 World Health Organization [WHO] definition) with definitive evidence of BCR-ABL1 fusion by karyotype, fluorescence in situ hybridization (FISH) and/or molecular methodologies
• ABL-class fusion: newly diagnosed B-ALL with definitive evidence of ABL-class fusions. ABL-class fusions are defined as those involving the following genes: ABL1, ABL2, CSF1R, PDGFRB, PDGFRA. Methods of detection include fluorescence in-situ hybridization (FISH, e.g. using break-apart or colocalization signals probes), multiplex or singleplex reverse-transcription polymerase chain reaction (RT-PCR), whole transcriptome or panel-based ribonucleic acid (RNA)-sequencing (e.g. TruSight RNA Pan-Cancer Panel; Illumina, San Diego, CA, USA or similar)
• Ph+ patients must have previously started Induction therapy, which includes vincristine, a corticosteroid, pegaspargase, with or without anthracycline, and/or other standard cytotoxic chemotherapy
• Ph+ patients have not received more than 14 days of multiagent Induction therapy beginning with the first dose of vinCRIStine
• Ph+ patients may have started imatinib prior to study entry but have not received more than 14 days of imatinib
• ABL-class fusion patients must have previously completed the 4 or 5 weeks of multiagent Induction chemotherapy (Induction IA phase)
• ABL-class fusion patients may have started imatinib during Induction IA, at the same time of or after the first vinCRIStine dose
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2
• Direct bilirubin =< 2.0 mg/dL
• Shortening fraction of >= 27% by echocardiogram
• Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram
• Corrected QT interval, QTc < 480 msec
• Note: Repeat echocardiogram and electrocardiogram are not required if they were performed at or after initial ALL diagnosis, before study enrollment
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or serum creatinine within normal limits based on age/gender, as follows:
• 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
• 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
• 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
• 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
• 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
• >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
Exclusion Criteria:

• Known history of chronic myelogenous leukemia (CML)
• ALL developing after a previous cancer treated with cytotoxic chemotherapy
• Active, uncontrolled infection, or active systemic illness that requires ongoing vasopressor support or mechanical ventilation
• Down syndrome
• Pregnancy and breast feeding
• 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 treatment according to protocol
• Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart block
• Prior treatment with dasatinib, or any TKI other than imatinib
Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia, Mixed Phenotype Acute Leukemia, T Acute Lymphoblastic Leukemia, Lymphoid Leukemia, Leukemia, other, Leukemia
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Patients Treated for Chronic Granulomatous Disease (CGD) Since 1995

Chronic granulomatous disease (CGD) is an inherited immune system abnormality in which bone marrow transplantation (BMT) has been shown to be curative. However the risks of transplantation are high and not all patients with CGD may need to undergo this high risk procedure. This study will determine the long term medical condition and daily functioning of participants with CGD after a transplant and if possible, compare these results to participants who do not undergo a transplant.
Kenneth Desantes, M.D.
All
Not specified
NA
This study is NOT accepting healthy volunteers
NCT02082353
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Inclusion Criteria:

• Participant Inclusion Criteria (Part 1
•Longitudinal Analysis)
• CGD Patients Undergoing Transplant 1995 to Present with Birth Year In or After 1988 1. CGD Patients will be Defined by both Defective Neutrophil NADPH Oxidase Function and by Clinical History Consistent with CGD Patients must have both of: A functional assay demonstrating abnormal NADPH oxidase function (see A below); AND Clinical history consistent with CGD (see B below). ************************************************************************* Patients must have both "A" and "B": A. Function: Assays of NADPH Oxidase Function I. Dihydrorhodamine (DHR) Assay:
• Blood sample was obtained at a time when patient was clinically stable and not critically ill, with control samples performed simultaneously indicating a qualified assay; and
• Assay unequivocally demonstrates CGD with an stimulation index (SI) SI < 35 or equivalent. Assay report, including mean fluorescence intensity (MFI) from unstimulated and stimulated samples and gating strategy, must be de-identified and provided. OR II. Nitroblue Tetrazolium Oxidation Test (NBT): o Diagnostic of CGD (reported as reduced granulocyte oxidative response). Report must be de-identified and provided. AND B. Clinical History: One or More of the Following:
• Severe and/or recurrent infection (liver, perirectal or lung abscess; pneumonia; adenitis; or osteomyelitis) due to, for example, Staphylococcus aureus, Burkholderia sp, Serratia marcescens, non-albicans Candida sp, Aspergillus sp or other mold; or Nocardia sp or other deep tissue infection characteristic of CGD
• Sterile granulomatous disease in respiratory, gastrointestinal or urogenital tracts; or Crohn's disease-like colitis
• A family history consistent with either X-linked or autosomal recessive CGD In cases where either functional assay (A) or history (B) is equivocal, one or more of the following may be used to confirm a diagnosis of CGD: C. Absent or significantly reduced in expression or abnormal size of any of the 5 phox components (gp91 phox, p47 phox, p22 phox, p67phox, and p40phox) of NADPH oxidase, by either:
• Western blot
• Northern blot OR D. Mutation in a gene encoding one of the 5 phox components (gp91 phox, p47 phox, p22 phox, p67 phox, and p40 phox) of NADPH oxidase that is predictive of a decreased or absent oxidative burst. (Nonsense, frameshift, or previously described missense mutation associated with CGD). Molecular Diagnosis is Desirable In addition, molecular diagnosis (gene sequencing and expression analysis) of CGD is desirable and should be performed when possible. 2. Further Characterization of Oxidase Level, Longitudinal Study, Prospective Cohort Patients who are to undergo transplantation during the study period must be further characterized as oxidase-null or oxidase positive by level of oxidase production by either:
• DHR assay stimulation Index: where SI ≤ 2.5 will be classified as oxidase-null CGD. Those with SI > 2.5 will be classified as oxidase positive CGD. A single validated test that is accepted by the PID-CGD Review Panel is adequate, but testing on two occasions for validation is desirable. OR
• Ferricytochrome C reduction assay of granulocytes with O2 < 2.3 nmoles /106 cells/h classified as oxidase-null CGD. A single validated test that is accepted by the PID-CGD Review Panel is adequate, but testing on two occasions for validation is desirable. OR o Genetic sequencing reporting a mutation that is unequivocally associated to absent oxidase production. (e.g. null mutations) will be classified as oxidase-null CGD (See discussion in Appendix I for how family history, genotype and CGD mutation information will be applied to assigning patients lacking any quantitative oxidase activity measurements to residual oxidase-null or residual oxidase-positive groups). 3. Longitudinal Study, Retrospective Cohort Patients who have already been transplanted will be included regardless of whether further characterization by oxidase level (or genotype/mutation data) is possible or not.
• Non-Transplanted CGD Patients with Birth Year In or After 1988 A non-transplant (conventional therapy) group of CGD subjects will be enrolled in the longitudinal study. The non-transplant subjects will be selected from the potentially eligible (retrospective) patient cohort with diagnosis of CGD treated with conventional non-transplant therapy. Participating sites will enter their entire retrospective cohort of CGD patients having birth year in or after 1988 into the registration cohort for this protocol. Baseline for both non-transplant subjects and HCT subjects for the purpose of comparing survival will be the year of birth. However, for non-transplant subjects, many of the detailed analyses such as infection and autoimmune complication rates will be assessed in the year preceding the date of last contact.
• Participant Inclusion Criteria (Part 2
•Cross-Sectional Analysis) To participate in the Cross-Sectional Analysis, patients must have previously been enrolled into the Longitudinal Analysis of Protocol 6903. All transplanted subjects in the Cross-Sectional Analysis are surviving and shall have at least 3 years of follow-up post-transplant to be included. Non-transplanted CGD subjects will become eligible for consideration for the Cross-Sectional Analysis if they were eligible and enrolled in the retrospective cohort of the Longitudinal Analysis, and if/when they are > 3 years post-diagnosis of CGD. Provision of written informed consent will be required for inclusion in the Cross-Sectional Analysis.
Exclusion Criteria:

• Participant Exclusion Criteria (Longitudinal and Cross- Sectional Analyses)
• Presence of other primary immunodeficiency syndromes that do not meet the clinical and laboratory criteria for CGD.
• Rac2 Deficiency
• Myeloperoxidase Deficiency (MPO Deficiency)
• Glutathione deficiency
• Leukocyte adhesion deficiency syndrome
• Non-transplant subjects:
• The above exclusions pertain.
• In addition, non-transplant subjects will be excluded if the only assessment of oxidase function available is the nitroblue tetrazolium (NBT) test (a non-quantitative test).
Immunologic Deficiency Syndromes [C20], Other, Granulomatous Disease, Chronic
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Patients Treated for Wiskott-Aldrich Syndrome (WAS) Since 1990

Wiskott - Aldrich syndrome (WAS) is a rare serious medical condition that causes problems both with the immune system and with easy bruising and bleeding. The immune abnormalities cause patients with WAS to be very susceptible to infections. Depending on the specific type of primary immune deficiency diseases, there are effective treatments, including antibiotics, cellular therapy and gene therapy, but studies of large numbers of patients are needed to determine the full range of causes, natural history, or the best methods of treatment for long term success. This multicenter study combines retrospective, prospective and cross-sectional analyses of the transplant experiences for patients with WAS who have already received HCT since 1990, or who will undergo Hematopoietic cell transplant (HCT) during the study period. The retrospective and prospective portions of the study will address the impact of a number of pre and post-transplant factors on post-transplant disease correction and ultimate benefit from HCT and the cross-sectional portion of the study will assess the benefit of HCT 2 years post-HCT in consenting surviving patients.
Kenneth Desantes, M.D.
Male
Not specified
NA
This study is NOT accepting healthy volunteers
NCT02064933
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Inclusion Criteria:

• WAS participants will be defined as males who have: 1. thrombocytopenia (< 100K) AND EITHER molecular diagnosis of WAS OR reduced WASP expression; OR 2. thrombocytopenia (< 100K) AND positive family history consistent with WAS diagnosis; OR 3. chronic thrombocytopenia (< 100K for minimum of 3 months) AND low mean platelet volume (MPV below normal range for age) AND EITHER recurrent and/or severe infections requiring treatment and/or eczema OR lack of antibody response to polysaccharide antigens or low IgM.
• Longitudinal Analysis (Retrospective and Prospective) 1. Stratum A. Participants with WAS who have or will Receive HCT
• Participants with WAS who have received an HCT since January 1, 1990 2. Stratum B. Participants with WAS who have or will Receive Gene Transfer
• Participants in which the intention is to treat with gene transfer with autologous modified cells
• Cross-Sectional Analysis (Strata A and B) 1. Participants with WAS who are surviving and at least 2 years after the most recent HCT or gene therapy.
Exclusion Criteria:

• As this is a natural history study, for both the Longitudinal Analysis and the Cross-Sectional Analysis we will not exclude any patients due to race or age who fit the inclusion criteria.
Wiskott-Aldrich Syndrome, Immunologic Deficiency Syndromes [C20], Other
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LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis

The LCH-IV is an international, multicenter, prospective clinical study for pediatric Langerhans Cell Histiocytosis LCH (age < 18 years).
Margo Hoover-Regan
All
up to 18 Years old
Phase 2/Phase 3
This study is NOT accepting healthy volunteers
NCT02205762
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Inclusion Criteria:

• Stratum I
• Patients must be less than 18 years of age at the time of diagnosis.
• Patients must have histological verification of the diagnosis of Langerhans cell histiocytosis according to the criteria described in Section 6.1
• Signed informed consent form
• Stratum II
• Patients of Stratum I who have:
• Progressive disease (AD worse) in non-risk organs after 6 weeks (Initial Course
• AD intermediate or worse in non-risk organs or AD better in risk organs after 12 weeks (Initial Course 2)
• Disease progression (AD worse) in non-risk organs at any time during continuation treatment
• Active disease at the end of Stratum I treatment
• Disease reactivation in non-risk organs at any time after completion of Stratum I treatment
• Stratum III
• Patients from Stratum I who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after week 12 (after Initial Course 2).
• Presence of unequivocally severe organ dysfunction at the above mentioned evaluation points (hematological dysfunction, liver dysfunction, or both of them) as
• Hb <70 g/L (<7.0 g/dl) and/or transfusion dependency
• PLT <20 x109/L (20,000/μL) and/or transfusion dependency (both criteria have to be fulfilled) AND/OR
• Liver dysfunction (or digestive involvement with protein loss)
• Total protein <55 g/L or substitution dependency
• Albumin <25 g/L or substitution dependency (at least one of the two criteria to be fulfilled)
• Stratum IV
• Patients from Stratum I or Stratum III who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after week 12 (after Initial Course 2) of Stratum I OR
• AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or AD intermediate after the 4th 2-CdA/Ara-C course of Stratum III AND
• Presence of unequivocally severe organ dysfunction at the above mentioned evaluation points (hematological dysfunction, liver dysfunction, or both of them) as defined in Table XI (see Section 10.3.1).
• Informed consent: All patients or their legal guardians (if the patient is <18 years of age) must sign an Ethics or institutional Review Board approved consent form indicating their awareness of the investigational nature and the risks of this study. When appropriate, younger patients will be included in all discussions in order to obtain assent.
• Adequate organ function: Patients should have adequate hepatic, renal, cardiac and pulmonary function to undergo reduced intensity HCT based upon local institutional guidelines, or at a minimum meet requirements noted in eligibility checklist Appendix A-VIII_1. However, significant hepatic and pulmonary dysfunction, if secondary to underlying LCH disease activity, will not exclude patients from protocol enrollment and should be discussed with the National PI Coordinator and the Coordinating Principal Investigator.
• Stratum V
• All patients with verified diagnosis of LCH and MRI findings consistent with ND-CNSLCH irrespective of previous treatments (also those not registered to other Strata ofLCH-IV).
• Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion in the hypothalamus-pituitary axis). In patients with already established diagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, a biopsy of the lesion is not obligatory. In all other cases a biopsy of the lesion is needed for inclusion into the study
• Stratum VI -- Patients with newly diagnosed SS-LCH and localization other than "multifocal bone",isolated tumorous CNS lesion, or isolated "CNS-risk" lesion.
• Stratum VII -- All patients registered in LCH IV (regardless of treatment) as long as consent for longterm follow-up has not been withheld.
Exclusion Criteria:

• Stratum I
• Pregnancy (patients of child-bearing age must be appropriately tested before chemotherapy)
• LCH-related permanent consequences (e.g. vertebra plana, sclerosing cholangitis, lung fibrosis, etc.) in the absence of active disease
• Prior systemic therapy
• Stratum II
• Patients with progressive disease in risk organs
• Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis, etc.) without evidence of active LCH in the same organ or in any other locations
• No written consent of the patient or his/her parents or legal guardian
• Stratum III
• The presence of any of the following criteria will exclude the patient from the study:
• Isolated sclerosing cholangitis without evidence of active hepatic LCH as the only evidence of risk organ involvement.
• Inadequate renal function as defined by serum creatinine > 3x normal for age
• Stratum IV
• Pulmonary failure (requiring mechanical ventilation) not due to active LCH.
• Isolated liver sclerosis or pulmonary fibrosis, without active LCH.
• Uncontrolled active life-threatening infection.
• Decreased renal function with a GFR of less than 50ml/1.73m2/min.
• Pregnancy or active breast feeding
• Failure to provide signed informed consent
• Stratum VI
• Patients with SS-LCH who have an isolated tumorous CNS lesion (they are eligible for Stratum V),
• Patients with isolated "CNS-risk" or multifocal bone lesions (they are eligible for Stratum I, Group 2)
Langerhans Cell Histiocytosis, Liver, Lung, Bones and Joints, Other Skin, Brain and Nervous System, Other Endocrine System, Other Hematopoietic, Brain/Central Nervous System, Endocrine cancers, Hematologic cancers, other, Melanoma/Skin cancer, Sarcoma
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Rituximab With or Without Stem Cell Transplant in Treating Patients With Minimal Residual Disease-Negative Mantle Cell Lymphoma in First Complete Remission

This randomized phase III trial studies rituximab after stem cell transplant and to see how well it works compared with rituximab alone in treating patients with in minimal residual disease-negative mantle cell lymphoma in first complete remission. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Giving chemotherapy before a stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Giving rituximab with or without stem cell transplant may work better in treating patients with mantle cell lymphoma.
Vaishalee Kenkre, MD
All
18 Years to 70 Years old
Phase 3
This study is NOT accepting healthy volunteers
NCT03267433
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Inclusion Criteria:

• INCLUSION CRITERIA FOR SCREENING (STEP 0
•PREREGISTRATION)
• Patients must have histologically confirmed mantle cell lymphoma, with cyclin D1 by immunohistochemical stains and/or t(11;14) by cytogenetics or FISH. If patient has cyclin D1 negative mantle cell lymphoma with classical morphology and an expression profile (including SOX11+) that is otherwise indistinguishable from mantle cell lymphoma, communication with investigator is required for consideration of enrollment. The proliferation rate, using Ki-67 or MIB-1, should also be determined, but is not required until Step 1 registration. Patients may register to Step 0 without a documented Ki-67 index.
• Patients should be deemed to be potentially eligible and willing candidates for auto-HCT by the enrolling physician
• Patient may be receiving or have completed induction therapy within 60 days prior to preregistration to step 0; no more than 300 days may have passed between the first day of induction therapy and preregistration to step 0
• For patients who have completed induction therapy, restaging evaluation must show status of partial (PR) or complete response (CR); patients preregistered post-induction with evidence of clinical disease progression are not eligible for preregistration
• Up to two regimens of chemotherapy are allowed as long as a continuous response was ongoing throughout therapy
• NOTE: For example, a patient who started treatment with rituximab/bendamustine and was then switched to rituximab(R)-cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP) (due to insufficient response or excessive toxicity) would be counted as having received 2 regimens; however, R-CHOP alternating with R-dexamethasone, high-dose cytarabine, and cisplatin (DHAP) as a planned induction regimen would count as one regimen
• Patient does not have any documented history of central nervous system (CNS) involvement by mantle cell lymphoma; this includes no evidence of parenchymal brain, spinal cord, or cerebrospinal fluid involvement; radiculopathy symptoms from nerve root compression by lymphoma do not constitute CNS involvement
• Patient must have archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the original diagnostic biopsy available for submission to Adaptive Biotechnologies for ClonoSEQ ID molecular marker identification of unique clonal immunoglobulin deoxyribonucleic acid (DNA) sequence
• NOTE: Patients for whom the molecular marker is identified will have peripheral blood collected after completion of induction (patient?s disease status is PR or CR) and submitted to Adaptive Biotechnologies for minimal residual disease (MRD) assessment
• INCLUSION CRITERIA FOR TREATMENT ASSIGNMENT (STEP 1)
• Patients must have met eligibility criteria for the screening step
• Institution has received results from Adaptive Biotechnologies as defined by one of the following criteria:
• Patients are ?MRD Indeterminate?: ClonoSEQ ID molecular marker assessment did not identify any unique clonal immunoglobulin DNA sequence OR
• ClonoSEQ ID molecular marker assessment identified unique clonal immunoglobulin DNA sequence and MRD assessment is completed
• Patients must have completed induction therapy within 120 days prior to preregistration to step 0, AND no more than 300 days may have elapsed from the first dose of induction chemotherapy (cycle 1 [C1] day 1 [D1]) given, until the last day of induction chemotherapy administered; for those assigned to Arms A, C, or D, the date of transplant (?day 0?) must not be greater than 365 days after the first dose of induction chemotherapy (C1D1) given
• Patient must have received at least four (4) cycles of induction therapy
• Up to two regimens of chemotherapy are allowed as long as a continuous response was ongoing throughout therapy
• NOTE: For example, a patient who started treatment with rituximab/bendamustine and was then switched to R-CHOP (due to insufficient response or excessive toxicity) would be counted as having received 2 regimens; however, R-CHOP alternating with R-DHAP as a planned induction regimen would count as one regimen
• Patients must have achieved a radiologic complete or partial remission as defined by the Lugano criteria
• Patients must meet institutional eligibility requirements for stem cell transplant, including cardiac, renal, liver, and pulmonary requirements
• Patients have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Human immunodeficiency virus (HIV) positive patients are not excluded, but to enroll, must meet all of the below criteria:
• HIV is sensitive to antiretroviral therapy
• Must be willing to take effective antiretroviral therapy if indicated
• CD4 count at screening >= 300 cells/mm^3
• No history of acquired immune deficiency syndrome (AIDS)-defining conditions
• Patient must be disease-free >= 3 years of prior malignancies with the exception of adequately treated non-melanoma skin cancer, adequately treated in situ carcinoma, low grade prostate carcinoma (Gleason grade =< 6) managed with observation that has been stable for at least 6 months
• Women must not be pregnant or breast-feeding
• All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy
• A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study
CD20 Positive, Mantle Cell Lymphoma, Non-Hodgkin's Lymphoma, Lymphoma
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A Safety, Tolerability, and Efficacy Study of VX-880 in Participants With Type 1 Diabetes

This study will evaluate the safety, tolerability and efficacy of VX-880 infusion in participants with Type 1 diabetes mellitus (T1D) and impaired awareness of hypoglycemia (IAH) and severe hypoglycemia.
Jon Odorico, MD
All
18 Years to 65 Years old
Phase 1/Phase 2
This study is NOT accepting healthy volunteers
NCT04786262
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Key
Inclusion Criteria:

• Clinical history of T1D with > 5 years of duration
• At least two episodes of documented severe hypoglycemia in the 12 months prior to enrollment
• Stable diabetic treatment
• Consistent use of continuous glucose monitor (CGM) for at least 3 months before Screening and willingness to use CGM for the duration of the study Key
Exclusion Criteria:

• Prior islet cell transplant, organ transplant, or cell therapy Other protocol defined Inclusion/Exclusion criteria may apply
Diabetes Mellitus, Type 1, Impaired Hypoglycemic Awareness, Severe Hypoglycemia, Other specified diabetes mellitus, Other, Transplant
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CardiAMP Cell Therapy Chronic Myocardial Ischemia Trial (CardiAMP CMI)

Prospective, multi-center, 2:1 randomized (Treatment : Sham Control), sham-controlled, double-blinded trial to compare treatment using the CardiAMP cell therapy system to sham treatment Treatment Group: Subjects treated with aBMC using the CardiAMP cell therapy system Sham Control Group: Subjects treated with a Sham Treatment (no introduction of the Helix transendocardial delivery catheter, no administration of aBMC)
Amish Raval, MD
All
21 Years to 80 Years old
N/A
This study is NOT accepting healthy volunteers
NCT03455725
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Inclusion Criteria:
1. Male or female 21 to 80 years of age 2. Canadian Cardiovascular Society (CCS) class III or IV chronic refractory angina. 3. Lack of control of angina symptoms despite maximum tolerated doses of anti-angina drugs. 4. Evidence of inducible myocardial ischemia on baseline stress testing 5. Obstructive coronary disease unsuitable for conventional revascularization 6. Experience angina episodes at a minimum of 7 angina episodes per week (during a 4-week screening period). 7. Able to complete an exercise tolerance test on the treadmill 8. Left ventricular ejection fraction of greater than or equal to 40% as measured by echocardiography. 9. Qualification of a pre-procedure screening of bone-marrow aspiration Exclusion Criteria Other cardiac or vascular system or other health-related criteria which may be seen in a patient's history and physical examination.
Refractory Angina, Chronic Myocardial Ischemia, Chronic ischemic heart disease, Other, Heart & Vascular
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Study of Ravulizumab in Pediatric Participants With HSCT-TMA

This study will evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of ravulizumab administered by intravenous infusion to pediatric participants, from 1 month to < 18 years of age, with HSCT-TMA. The treatment period is 26 weeks, followed by a 26-week off-treatment follow-up period.
Kenneth Desantes, M.D.
All
1 Month to 17 Years old
Phase 3
This study is NOT accepting healthy volunteers
NCT04557735
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Inclusion Criteria:
1. 1 month of age up to < 18 years of age at the time of signing the informed consent. 2. Received HSCT within the past 6 months. 3. Diagnosis of TMA that persists despite initial management of any triggering condition. 4. Body weight ≥ 5 kilograms. 5. Female participants of childbearing potential and male participants with female partners of childbearing potential must use highly effective contraception starting at Screening and continuing until at least 8 months after the last dose of ravulizumab. 6. Participants must be vaccinated against meningococcal infections if clinically feasible, according to institutional guidelines for immune reconstitution after HSCT. Participants must be re-vaccinated against Haemophilus influenzae type b and Streptococcus pneumoniae if clinically feasible, according to institutional guidelines for immune reconstitution after HSCT. All participants should be administered coverage with prophylactic antibiotics according to institutional post-transplant infection prophylaxis guidances, including coverage against Neisseria meningitidis for at least 2 weeks after meningococcal vaccination. Participants who cannot receive meningococcal vaccine should receive antibiotic prophylaxis coverage against Neisseria meningitidis the entire Treatment Period and for 8 months following the final dose of ravulizumab.
Exclusion Criteria:
1. Known familial or acquired 'a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13' deficiency (activity < 5%). 2. Known Shiga toxin-related hemolytic uremic syndrome. 3. Positive direct Coombs test. 4. Diagnosis or suspicion of disseminated intravascular coagulation. 5. Known bone marrow/graft failure. 6. Diagnosis of veno-occlusive disease (VOD). 7. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody titer). 8. Unresolved meningococcal disease. 9. Presence of sepsis requiring vasopressor support. 10. Pregnancy or breastfeeding. 11. Hypersensitivity to murine proteins or to 1 of the excipients of Ravulizumab. 12. Previously or currently treated with a complement inhibitor.
Thrombotic Microangiopathy, Other Hematopoietic, Hematologic cancers, other
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A Study of a New Way to Treat Children and Young Adults With a Brain Tumor Called NGGCT

This phase II trial studies the best approach to combine chemotherapy and radiation therapy (RT) based on the patient's response to induction chemotherapy in patients with non-germinomatous germ cell tumors (NGGCT) that have not spread to other parts of the brain or body (localized). This study has 2 goals: 1) optimizing radiation for patients who respond well to induction chemotherapy to diminish spinal cord relapses, 2) utilizing higher dose chemotherapy followed by conventional RT in patients who did not respond to induction chemotherapy. Chemotherapy drugs, such as carboplatin, etoposide, ifosfamide, and thiotepa, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays or high-energy protons to kill tumor cells and shrink tumors. Studies have shown that patients with newly-diagnosed localized NGGCT, whose disease responds well to chemotherapy before receiving radiation therapy, are more likely to be free of the disease for a longer time than are patients for whom the chemotherapy does not efficiently eliminate or reduce the size of the tumor. The purpose of this study is to see how well the tumors respond to induction chemotherapy to decide what treatment to give next. Some patients will be given RT to the spine and a portion of the brain. Others will be given high dose chemotherapy and a stem cell transplant before RT to the whole brain and spine. Giving treatment based on the response to induction chemotherapy may lower the side effects of radiation in some patients and adjust the therapy to a more efficient one for other patients with localized NGGCT.
Kenneth Desantes, M.D.
All
3 Years to 29 Years old
Phase 2
This study is NOT accepting healthy volunteers
NCT04684368
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Inclusion Criteria:

• Patients must be >= 3 years and < 30 years at the time of study enrollment
• Patients must be newly diagnosed with localized primary CNS NGGCT of the suprasellar and/or pineal region by pathology and/or serum or cerebrospinal fluid (CSF) elevation of AFP above institutional normal or > 10 ng/mL or human chorionic gonadotropin (hCG) beta > 100 mIU/mL as confirmed by Rapid Central Marker Screening Review on APEC14B1-CNS. Suprasellar, pineal and bifocal tumors are included. (CSF tumor markers and cytology must be within 31 days prior to enrollment and start of protocol therapy [repeat if necessary]. Serum tumor markers, AFP and hCGbeta must be within 7 days prior to enrollment and start of protocol therapy [repeat if necessary]). Basal ganglia or other primary sites are excluded
• Patients with any of the following pathological elements are eligible: endodermal sinus (yolk sac), embryonal carcinoma, choriocarcinoma, malignant/immature teratoma and mixed germ cell tumor (GCT) (i.e., may include some pure germinoma) if malignant elements listed above are present. Patients with only mature teratoma are excluded. Patients with pure germinoma admixed with mature teratoma are excluded (would be eligible for pure germinoma protocols)
• Patients must have a cranial MRI with and without gadolinium at diagnosis/prior to enrollment. If surgical resection is performed, patients must have pre-operative and post operative brain MRI with and without gadolinium. The post operative brain MRI should be obtained within 72 hours of surgery. If patient has a biopsy only, post-operative brain MRI is recommended but not required (within 31 days prior to study enrollment and start of protocol therapy )
• Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment. Spine MRI with and without gadolinium is recommended (within 31 days prior to study enrollment and start of protocol therapy)
• Lumbar CSF must be obtained prior to study enrollment unless medically contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be obtained at the time of surgery, then it should be performed at least 10 days following surgery and prior to study enrollment. False positive cytology can occur within 10 days of surgery
• Patients must have RAPID CENTRAL TUMOR MARKER REVIEW CSF tumor markers obtained prior to enrollment unless medically contraindicated. Ventricular CSF obtained at the time of CSF diversion procedure (if performed) is acceptable for tumor markers but lumbar CSF is preferred. In case CSF diversion and biopsy/surgery are combined, CSF tumor markers should be collected first
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to enrollment)
• Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to enrollment)
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (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 based on age/gender as follows (within 7 days prior to enrollment):
• Age: Maximum serum creatinine (mg/dL)
• 3 to < 6 years: 0.8 (male), 0.8 (female)
• 6 to < 10 years: 1 (male), 1 (female)
• 10 to < 13 years: 1.2 (male), 1.2 (female)
• 13 to < 16 years: 1.5 (male), 1.4 (female)
• >= 16 years: male (1.7), 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment)
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
• Central nervous system function defined as:
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
• Patients must not be in status epilepticus, coma or assisted ventilation prior to study enrollment
• Protocol therapy must begin within 31 calendar days of definitive surgery or clinical diagnosis, whichever is later. If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery.
• 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
• NEUROCOGNITIVE FUNCTION AND QUALITY OF LIFE ASSESSMENT:
• English-, Spanish-, or French- speaking
• Note: Patients who speak a language other than English, Spanish, or French will be allowed to participate in ACNS2021 but will not complete the neurocognitive and quality of life assessments
• No known history of neurodevelopmental disorder prior to diagnosis of NGGCT (e.g., Down syndrome, fragile X, William syndrome, intellectual disability). Patients with NF1 will be allowed to participate
• Additional eligibility criteria for the COG Standardized Neuropsychological Battery only: must be at a site that has a psychologist to administer the battery
• Note: If not eligible for the COG Standardized Battery, patients should still complete the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2), Pediatric Quality of Life Inventory (PedsQL), Adaptive Behavior Assessment System Third Edition (ABAS-3), and Behavior Assessment System for Children, Third Edition (BASC-3) questionnaires
Exclusion Criteria:

• Patients with tumors located outside the ventricles (i.e., basal ganglia, thalamus)
• Patients with only mature teratoma and non-elevated markers upon tumor sampling at diagnosis
• Patients who have received any prior tumor-directed therapy for their diagnosis of NGGCT other than surgical intervention and corticosteroids
• Patients with metastatic disease (i.e., MRI evaluation, lumbar CSF cytology or intraoperative evidence of dissemination)
• Female patients who are pregnant, since fetal toxicities and teratogenic effects have been noted for several of the study drugs
• Note: Serum and urine pregnancy tests may be falsely positive due to HCGbeta-secreting germ cell tumors. Ensure the patient is not pregnant by institutional standards
• 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
Central Nervous System Nongerminomatous Germ Cell Tumor, Choriocarcinoma, Embryonal Carcinoma, Immature Teratoma, Malignant Teratoma, Mixed Germ Cell Tumor, Pineal Region Germ Cell Tumor, Pineal Region Immature Teratoma, Pineal Region Yolk Sac Tumor, Suprasellar Germ Cell Tumor, Brain and Nervous System, Brain/Central Nervous System
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A Trial Comparing Unrelated Donor BMT With IST for Pediatric and Young Adult Patients With Severe Aplastic Anemia (TransIT, BMT CTN 2202) (TransIT)

Severe Aplastic Anemia (SAA) is a rare condition in which the body stops producing enough new blood cells. SAA can be cured with immune suppressive therapy or a bone marrow transplant. Regular treatment for patients with aplastic anemia who have a matched sibling (brother or sister), or family donor is a bone marrow transplant. Patients without a matched family donor normally are treated with immune suppressive therapy (IST). Match unrelated donor (URD) bone marrow transplant (BMT) is used as a secondary treatment in patients who did not get better with IST, had their disease come back, or a new worse disease replaced it (like leukemia). This trial will compare time from randomization to failure of treatment or death from any cause of IST versus URD BMT when used as initial therapy to treat SAA. The trial will also assess whether health-related quality of life and early markers of fertility differ between those randomized to URD BMT or IST, as well as assess the presence of marrow failure-related genes and presence of gene mutations associated with MDS or leukemia and the change in gene signatures after treatment in both study arms. This study treatment does not include any investigational drugs. The medicines and procedures in this study are standard for treatment of SAA.
Kenneth Desantes, M.D.
All
0 Years to 25 Years old
Phase 3
This study is NOT accepting healthy volunteers
NCT05600426
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Inclusion Criteria:
To be eligible to participate in the randomized trial, an individual must meet all the following criteria: 1. Provision of signed and dated informed consent form for the randomized trial by patient and/or legal guardian. 2. Age ≤25 years old at time of randomized trial consent. 3. Confirmed diagnosis of idiopathic SAA, defined as: 1. Bone marrow cellularity <25%, or <30% hematopoietic cells. 2. Two of three of the following (in peripheral blood): neutrophils <0.5 x 10^9/L, platelets <20 x 10^9/L, absolute reticulocyte count <60 x 10^9/L or hemoglobin <8 g/dL. 4. No suitable fully matched related donor available (minimum 6/6 match for HLA-A and B at intermediate or high resolution and DRB1 at high resolution using DNA based typing). 5. At least 2 unrelated donors noted on NMDP search who are well matched (9/10 or 10/10 for HLA-A, B, C, DRB1, and DQB1 using high resolution). 6. In the treating physician's opinion, no obvious contraindications precluding them from BMT or IST.
Exclusion Criteria:
1. Presence of Inherited bone marrow failure syndromes (IBMFS). The diagnosis of Fanconi anemia must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow. Telomere length testing should be sent on all patients to exclude Dyskeratosis Congenita (DC), but if results are delayed or unavailable and there are no clinical manifestations of DC, patients may enroll. If patients have clinical characteristics suspicious for Shwachman-Diamond syndrome, this disorder should be excluded by pancreatic isoamylase testing or gene mutation analysis (note: pancreatic isoamylase testing is not useful in children <3). Other testing per center may be performed to exclude IBMFS. 2. Clonal cytogenetic abnormalities or Fluorescence In-Situ Hybridization (FISH) pattern consistent with pre- myelodysplastic syndrome (pre-MDS) or MDS on marrow examination. 3. Known severe allergy to ATG. 4. Prior allogeneic or autologous stem cell transplant. 5. Prior solid organ transplant. 6. Infection with human immunodeficiency virus (HIV). 7. Active Hepatitis B or C. This only needs to be excluded in patients where there is clinical suspicion of hepatitis (e.g., elevated LFTs). 8. Female patients who are pregnant or breast-feeding. 9. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. 10. Disease modifying treatment prior to study enrollment, including but not limited to use of androgens, eltrombopag, romiplostim, or immune suppression. Note: Supportive care measures such as G-CSF, blood transfusion support and antibiotics are allowable
Severe Aplastic Anemia, Other Hematopoietic, Hematologic cancers, other
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Mismatched Related Donor Versus Matched Unrelated Donor Stem Cell Transplantation for Children, Adolescents, and Young Adults With Acute Leukemia or Myelodysplastic Syndrome

This phase III trial compares hematopoietic (stem) cell transplantation (HCT) using mismatched related donors (haploidentical [haplo]) versus matched unrelated donors (MUD) in treating children, adolescents, and young adults with acute leukemia or myelodysplastic syndrome (MDS). HCT is considered standard of care treatment for patients with high-risk acute leukemia and MDS. In HCT, patients are given very high doses of chemotherapy and/or radiation therapy, which is intended to kill cancer cells that may be resistant to more standard doses of chemotherapy; unfortunately, this also destroys the normal cells in the bone marrow, including stem cells. After the treatment, patients must have a healthy supply of stem cells reintroduced or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. The healthy stem cells may come from the blood or bone marrow of a related or unrelated donor. If patients do not have a matched related donor, doctors do not know what the next best donor choice is. This trial may help researchers understand whether a haplo related donor or a MUD HCT for children with acute leukemia or MDS is better or if there is no difference at all.
Kenneth Desantes, M.D.
All
6 Months to 21 Years old
Phase 3
This study is NOT accepting healthy volunteers
NCT05457556
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Inclusion Criteria:

• PATIENT INCLUSION CRITERIA FOR ENROLLMENT:
• 6 months to < 22 years at enrollment
• Diagnosed with ALL, AML, or MDS or mixed phenotype acute leukemia (MPAL) for which an allogeneic hematopoietic stem cell transplant is indicated. Complete Remission (CR) status will not be confirmed at the time of enrollment. CR as defined in these sections is required to proceed with the actual HCT treatment plan
• Has not received a prior allogeneic hematopoietic stem cell transplant
• Does not have a suitable human leukocyte antigen (HLA)-matched sibling donor available for stem cell donation
• Has an eligible haploidentical related family donor based on at least intermediate resolution HLA typing
• Patients who also have an eligible 8/8 MUD adult donor based on confirmatory high resolution HLA typing are eligible for randomization to Arm A or Arm B.
• Patients who do not have an eligible MUD donor are eligible for enrollment to Arm C
• 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
• Co-Enrollment on other trials
• Patients will not be excluded from enrollment on this study if already enrolled on other protocols for treatment of high risk and/or relapsed ALL, AML, MPAL and MDS. This is including, but not limited to, COG AAML1831, COG AALL1821, the EndRAD Trial, as well as local institutional trials. We will collect information on all co-enrollments
• Patients will not be excluded from enrollment on this study if receiving immunotherapy prior to transplant as a way to achieve remission and bridge to transplant. This includes chimeric antigen receptor (CAR) T cell therapy and other immunotherapies
• PATIENT INCLUSION CRITERIA TO PROCEED TO HCT:
• Karnofsky Index or Lansky Play-Performance Scale >= 60 on pre-transplant evaluation. Karnofsky scores must be used for patients >= 16 years of age and Lansky scores for patients =< 16 years of age (within 4 weeks of starting therapy)
• A serum creatinine based on age/gender as follows: 6 months to < 1 year: 0.5 mg/dL (Male); 0.5 mg/dL (Female) 1. to < 2 years: 0.6 mg/dL (Male); 0.6 mg/dL (Female) 2. to < 6 years: 0.8 mg/dL (Male); 0.8 mg/dL (Female) 6 to < 10 years: 1 mg/dL (Male); 1 mg/dL (Female) 10 to < 13 years: 1.2 mg/dL (Male); 1.2 mg/dL (Female) 13 to < 16 years: 1.5 mg/dL (Male); 1.4 mg/dL (Female) >= 16 years: 1.7 mg/dL (Male); 1.4 mg/dL (Female)
• OR
• A 24 hour urine Creatinine clearance >= 60 mL/min/1.73 m^2
• OR
• A glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)
• Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility
• Serum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase [AST] or serum glutamate pyruvate transaminase (SGPT) aminotransferase [ALT] < 5 x upper limit of normal (ULN) for age
• Total bilirubin < 2.5 mg/dL, unless attributable to Gilbert's Syndrome
• Shortening fraction of >= 27% by echocardiogram or radionuclide scan (MUGA)
• OR
• Ejection fraction of >= 50% by echocardiogram or radionuclide scan (MUGA), choice of test according to local standard of care
• Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and corrected carbon monoxide diffusing capability (DLCO) must all be >= 50% of predicted by pulmonary function tests (PFTs).
• For children who are unable to perform for PFTs (e.g., due to age or developmental delay), the criteria are: no evidence of dyspnea at rest, oxygen (O2) saturation (Sat) > 92% on room air by pulse oximetry, not on supplemental O2 at rest, and not on supplemental O2 at rest
• MPAL in first complete remission (CR1) for whom transplant is indicated. Examples include those patients who are poorly responsive to ALL therapy (end of induction failure( IF-MPAL) to ALL induction (see IF-MPAL note below), end of induction MRD ≥ 5% or end-of-consolidation MRD > 0.01%), as well as patients treated with AML therapy
• IF-MPAL: additional criterion for Induction failure for MPAL ONLY as per ALL1732:
• An increasing number of circulating leukemia cells on 3 or more consecutive CBCs obtained at daily or longer intervals following day 8 of Induction therapy and prior to day 29 with confirmation by flow cytometry OR development of new sites of extramedullary disease, or other laboratory or clinical evidence of refractory disease or progression prior to the end of Induction evaluation (note that residual testicular disease at the end of Induction is an exception)
• MPAL in > second complete remission (CR2)
• ALL high-risk in CR1 for whom transplant is indicated. Examples include: induction failure, treatment failure as per minimal residual disease by flow cytometry > 0.01% after consolidation and not eligible for AALL1721 or AALL1721 not available/unwilling to enroll, hypodiploidy (< 44 chromosomes) with MRD+ > 0.01% after induction, persistent or recurrent cytogenetic or molecular evidence of disease during therapy requiring additional therapy after induction to achieve remission (e.g. persistent molecular BCR-ABL positivity), T cell ALL with persistent MRD > 0.01% after consolidation.
• ALL in CR2 for whom transplant is indicated. Examples include: B-cell: early (=< 36 months from initiation of therapy) bone marrow (BM) relapse, late BM relapse (>= 36 months) with MRD >= 0.1% by flow cytometry after first re-induction therapy; T or B-cell: early (< 18 months) isolated extramedullary (IEM), late (>= 18 months) IEM, end-Block 1 MRD >= 0.1%; T-cell or Philadelphia chromosome positive (Ph+): BM relapse at any time
• ALL in >= third complete remission (CR3)
• Patients treated with chimeric antigen receptor T-cells (CART) cells for whom transplant is indicated. Examples include: transplant for consolidation of CART, loss of CART persistence and/or B cell aplasia < 6 months from infusion or have other evidence (e.g., MRD+) that transplant is indicated to prevent relapse
• AML in CR1 for whom transplant is indicated. Examples include those deemed high risk for relapse as described in AAML1831:
• FLT3/ITD+ with allelic ratio > 0.1 without bZIP CEBPA, NPM1
• FLT3/ITD+ with allelic ratio > 0.1 with concurrent bZIP CEBPA or NPM1 and with evidence of residual AML (MRD >= 0.05%) at end of Induction
• Presence of RAM phenotype or unfavorable prognostic markers (other than FLT3/ITD) per cytogenetics, fluorescence in situ hybridization (FISH), next generation sequencing (NGS) results, regardless of favorable genetic markers, MRD status or FLT3/ITD mutation status
• AML without favorable or unfavorable cytogenetic or molecular features but with evidence of residual AML (MRD >= 0.05%) at end of Induction
• Presence of a non-ITD FLT3 activating mutation and positive MRD (>= 0.05%) at end of Induction 1 regardless of presence of favorable genetic markers.
• AML in >= CR2
• MDS with < 5% blasts by morphology and flow cytometry (if available) on the pre-transplant bone marrow evaluation
• Complete remission (CR) is defined as < 5% blasts by morphology and flow cytometry (if available) on the pre-transplant bone marrow evaluation with minimum sustained absolute neutrophil count (ANC) of 300 cells/microliter for 1 week or ANC > 500 cells/microliter. We will be collecting data from all approaches to MRD evaluation performed including NGS and polymerase chain reaction (PCR). It is strongly recommended that MPAL be evaluated using multidimensional flow cytometry and/or (KMT2Ar) qt PCR. It is strongly recommended that MPAL be evaluated using multidimensional flow cytometry and/or (KMT2Ar) qt PCR
• DONOR ELIGIBILITY CRITERIA:
• Matched Unrelated Donors: Unrelated donor candidates must be matched at high resolution at a minimum of 8/8 alleles (HLA-A, -B, -C, -DRB1). One-antigen HLA mismatches are not permitted. HLA matching of additional alleles is recommended according to National Marrow Donor Program (NMDP) guidelines, but will be at the discretion of local centers
• Haploidentical Matched Family Members:
• Minimum match level full haploidentical (at least 5/10; HLA-A, -B, -C, -DRB1, -DQB1 alleles). The following issues (in no particular order) should be considered in choosing a haploidentical donor:
• Absent or low patient donor-specific antibodies (DSA)
• Mean fluorescence intensity (MFI) of any anti-donor HLA antibody by solid phase immunoassay should be < 2000. Donors with higher levels are not eligible.
• If a screening assay against pooled HLA antigens is used, positive results must be followed with specificity testing using a single antigen assay. The MFI must be < 2000 unless the laboratory has validated higher threshold values for reactivity for HLA antigens (such as HLA-C, -DQ, and -DP), that may be enhanced in concentration on the single antigen assays. Donor anti- recipient antibodies are of unknown clinical significance and do not need to be sent or reported.
• Consult with Study Chair for the clinical significance of any recipient anti-donor HLA antibody.
• If centers are unable to perform this type of testing, please contact the Study Chair to make arrangements for testing.
• If killer immunoglobulin testing (KIR) is performed: KIR status by mismatch, KIR-B, or KIR content criteria can be used according to institutional guidelines.
• ABO compatibility (in order of priority):
• Compatible or minor ABO incompatibility
• Major ABO incompatibility
• CMV serostatus:
• For a CMV seronegative recipient: the priority is to use a CMV seronegative donor when feasible
• For a CMV seropositive recipient: the priority is to use a CMV seropositive donor when feasible
• Age: younger donors including siblings/half-siblings, and second degree relatives (aunts, uncles, cousins) are recommended, even if < 18 years
• Size and vascular access appropriate by center standard for peripheral blood stem cell (PBSC) collection if needed
• Haploidentical matched family members: screened by center health screens and found to be eligible
• Unrelated donors: meet eligibility criteria as defined by the NMDP or other unrelated donor registries. If the donor does not meet the registry eligibility criteria but an acceptable eligibility waiver is completed and signed per registry guidelines, the donor will be considered eligible for this study
• Human immunodeficiency virus (HIV) negative
• Not pregnant
• MUD donors and post-transplant cyclophosphamide haplo donors should be asked to provide BM. If donors refuse and other donors are not available, PBSC is allowed. TCR-alpha beta/CD19 depleted haplo donors must agree to donate PBSC
• Must give informed consent:
• Haploidentical matched family members: Institution standard of care donor consent and Protocol-specific Donor Consent for Optional Studies
• Unrelated donors: standard NMDP Unrelated Donor Consent
Exclusion Criteria:

• PATIENT EXCLUSION CRITERIA FOR ENROLLMENT:
• Patients with genetic disorders (generally marrow failure syndromes) prone to secondary AML/ALL/MPAL with known poor outcomes because of sensitivity to alkylator therapy and/or TBI are not eligible (Fanconi Anemia, Kostmann Syndrome, Dyskeratosis Congenita, etc). Patients with Downs syndrome because of increased toxicity with intensive conditioning regimens.
• Patients with any obvious contraindication to myeloablative HCT at the time of enrollment
• Female patients who are pregnant are ineligible as many of the medications used in this protocol could be harmful to unborn children and infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
• PATIENT EXCLUSION CRITERIA TO PROCEED TO HCT:
• Patients with uncontrolled fungal, bacterial, viral, or parasitic infections are excluded. Patients with history of fungal disease during chemotherapy may proceed if they have a significant response to antifungal therapy with no or minimal evidence of disease remaining by computed tomography (CT) evaluation
• Patients with active central nervous system (CNS) leukemia or any other active site of extramedullary disease at the time of initiation of the conditioning regimen are not permitted.
• Note: Those with prior history of CNS or extramedullary disease, but with no active disease at the time of pre-transplant workup, are eligible
• Pregnant or breastfeeding females are ineligible as many of the medications used in this protocol could be harmful to unborn children and infants
Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Mixed Phenotype Acute Leukemia, Myelodysplastic Syndrome, Myeloid and Monocytic Leukemia, Leukemia, other, Other Hematopoietic, Hematologic cancers, other, Leukemia
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