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

Memorial Sloan Kettering Cancer Center (MSK)

Status and phase: Active, not recruiting; Phase 2

Conditions: Acute Myeloid Leukemia (AML); Myelodysplastic Syndromes (MDS); Acute Lymphoid Leukemia (ALL)

Treatments: Drug: Cyclophosphamide; Drug: Thiotepa; Drug: Busulfan; Drug: GCSF; Drug: Melphalan; Other: Personalized rATG (P-rATG); Radiation: Hyper fractionated total body irradiation; Drug: Fludarabine

Study type: Interventional

Funder types: Other

Identifiers

NCT04872595

21-193

Details and patient eligibility

About

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 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).

Enrollment: 59 patients

Sex: All

Ages: 4+ years old

Volunteers: No Healthy Volunteers

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 including research tests.

Donor Inclusion Criteria:

• Related or Unrelated Donors:

  °8/8 HLA 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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59 participants in 2 patient groups

P-rATG with total body irradiation, thiotepa, cyclophosphamide

Experimental group

Description:

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.

Treatment:

Radiation: Hyper fractionated total body irradiation

Other: Personalized rATG (P-rATG)

Drug: GCSF

Drug: Thiotepa

Drug: Cyclophosphamide

P-rATG with busulfan, melphalan and fludarabine

Experimental group

Description:

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

Treatment:

Drug: Fludarabine

Other: Personalized rATG (P-rATG)

Drug: Melphalan

Drug: GCSF

Drug: Busulfan