A Modified Dose of Rabbit Anti-thymocyte Globulin (rATG) in Children and Adults Receiving Treatment to Help Prepare Their Bodies for a Bone Marrow Transplant

Overview

The purpose of this study is to see if conditioning regimens that include personalized rabbit ATG (P-rATG) help the immune system recover sooner and decrease the chances of transplant-related side effects. Participants in this study will be children and adults who have acute leukemia or myelodysplastic syndrome (MDS), and they will receive a standard conditioning regimen to prepare the body for an allogeneic hematopoietic cell transplant (allo-HCT). The conditioning regimen will include r-ATG, one of two combinations of chemotherapy, and possibly total body irradiation (TBI).

Full Title of Study: “Phase 2 Study of Personalized r-ATG Dosing to Improve Survival Through Enhanced Immune Reconstitution in Pediatric and Adult Patients Undergoing Ex-vivo CD34-Selected Allogeneic-HCT (PRAISE-IR)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 2024

Interventions

  • Other: Personalized rATG (P-rATG)
    • P-rATG days (always starting on Day -12 to -10)
  • Radiation: Hyper fractionated total body irradiation
    • (1375 – 1500cGy*) Day -9 to -6 *TBI dose in 125cGy fractions (with lung shielding) and total dose to be determined by treating physician/radiation oncology and is based off age, stage of disease, and anesthesia requirements.
  • Drug: Thiotepa
    • (5mg/kg/day x 2 day) Day -5 to -4
  • Drug: Cyclophosphamide
    • (60mg/kg/day x 2 days) Day -3 to -2
  • Drug: GCSF
    • Day +7
  • Drug: Busulfan
    • Day -9 to -7 doses 2-3 to be adjusted per PK for target cumulative exposure of 65 mg*h/L
  • Drug: Melphalan
    • (70mg/m2/day x 2 days) Day -6 to -5
  • Drug: Fludarabine
    • (25mg/m2/day x 5 days) Day -6 to -2

Arms, Groups and Cohorts

  • Experimental: P-rATG with total body irradiation, thiotepa, cyclophosphamide
    • P-rATG days (always starting on Day -12 to -10) Hyper fractionated total body irradiation (1375 – 1500cGy*) Day -9 to -6 Thiotepa (5mg/kg/day x 2 day) Day -5 to -4 Cyclophosphamide (60mg/kg/day x 2 days) Day -3 to -2 GCSF Day +7 *TBI dose in 125cGy fractions (with lung shielding) and total dose to be determined by treating physician/radiation oncology and is based off age, stage of disease, and anesthesia requirements.
  • Experimental: P-rATG with busulfan, melphalan and fludarabine
    • P-rATG days (Appendix A – always starting on Day -12 to -10) Busulfan -Day -9 to -7 Initial dose per table in Appendix B; doses 2-3 to be adjusted per PK for target cumulative exposure of 65 mg*h/L Melphalan (70mg/m2/day x 2 days) Day -6 to -5 Fludarabine (25mg/m2/day x 5 days) Day -6 to -2 GCSF Day +7

Clinical Trial Outcome Measures

Primary Measures

  • proportion of patients who achieve CD4+IR
    • Time Frame: within 100 days of HCT
    • is defined at CD4+ > 50u/L at two consecutive measures within 100 days post allo-HCT.

Secondary Measures

  • Overall Survival (OS)
    • Time Frame: 2 years
    • The duration of time between HCT and death due to any cause.

Participating in This Clinical Trial

Inclusion Criteria

  • Patients receiving first peripheral blood mobilized ex-vivo CD34-selected T cell depleted allo-HCT for the following hematologic malignant conditions: – Acute myeloid leukemia (AML) with intermediate or high-risk features in CR1 or Relapse AML in ≥ CR2. – Must have MRD <5% (flow cytometry, molecular and/or cytogenetics accepted). – Acute leukemias of ambiguous lineage in ≥ CR1. – Must have MRD <5% (flow cytometry, molecular and/or cytogenetics accepted). – Acute lymphoid leukemia (ALL) in CR1 with clinical, flow cytometric, or molecular features indicating a high risk for relapse, or ALL in ≥ CR2. – Adult Patients – recommended but not required to be MRDnegative (by flow cytometry, molecular and/or cytogenetics). – Pediatric Patients – Must be MRD-negative by flow cytometry, molecular and/or cytogenetics. – Myelodysplastic syndromes (MDS) with least one of the following: – Revised International Prognostic Scoring System risk score of intermediate or higher at the time of transplant evaluation. – Life-threatening cytopenia. – Karyotype or genomic changes that indicate high risk for progression to acute myelogenous leukemia, including abnormalities of chromosome 7 or 3, mutations of TP53, or complex or monosomal karyotype. – Therapy related disease or disease evolving from other malignant processes. – Able to tolerate cytoreduction – Patients age: – Regimen A: 4 – 60 years – Regimen B – no age restriction – Adequate organ function is required, defined as follows: – Hepatic: Serum bilirubin ≤ 2 mg/dL, unless benign congenital hyperbilirubinemia. Patients with hyperbilirubinemia related to paroxysmal nocturnal hemoglobinuria or other hemolytic disorders are eligible with PI approval. – Hepatic: AST, ALT, and alkaline phosphatase < 2.5 times the upper limit of normal unless thought to be disease-related. – Renal: serum creatinine <1.5x normal for age. If serum creatinine is outside the normal range, then CrCl > 50 mL/min/1.73m2 (calculated or estimated) or GFR (mL/min/1.72m2) >30% of predicted normal for age. – Normal GFR by Age – 1 week 40.6 + / – 14.8 – 2 – 8 weeks 65.8 + / – 24.8 °> 8 weeks 95.7 +/- 21.7 – 2 – 12 years 133 +/- 27 – 13 – 21 years (males) 140 +/- 30 – 13 – 21 years (females) 126.0 + / – 22.0 – Cardiac: LVEF ≥ 50% by MUGA or resting echocardiogram. – Pulmonary: Pulmonary function testing (FEV1 and corrected DLCO) ≥ 50% predicted (pediatric patients unable to complete PFTs will need oxygen saturation as recorded by pulse oximetry of ≥92% on room air). – Adequate performance status: – Age ≥ 16 years: ECOG ≤ 1 or Karnofsky 70% – Age < 16 years: Lansky 70% – Each patient must be willing to participate as a research subject and must sign an informed consent form or legal guardian with assent as appropriate. Exclusion Criteria:

  • Patients with active extramedullary disease. – Patients with active central nervous system malignancy. – Uncontrolled infection at the time of allo-HCT. – Patients who have undergone previous allo-HCT. – Patient seropositivity for HIV I/II and/or HTLV I/II. – Females who are pregnant or breastfeeding. – Patients unwilling to use contraception during the study period. – Patient or parent or guardian unable to give informed consent or unable to comply with the treatment protocol. Donor Inclusion Criteria:

  • Related Donors: °8/8 or 7/8 HLA matched at A, B, C, and DRB1 loci, as tested by DNA analysis. – Unrelated Donors: °8/8 or 7/8 matched at A, B, C, and DRB1 loci, as tested by DNA analysis. – Able to provide informed consent for the donation process per institutional standards. – Meet standard criteria for donor collection (e.g. National Marrow Donor Program Guidelines or collecting center guidelines as approved by treating physician). – Provide GSCF mobilized peripheral blood stem cells

Gender Eligibility: All

Minimum Age: 4 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Memorial Sloan Kettering Cancer Center
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Kevin Curran, MD, Principal Investigator, Memorial Sloan Kettering Cancer Center
  • Overall Contact(s)
    • Kevin Curran, MD, 1-833-675-5437, currank@mskcc.org

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