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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

Primary Purpose

Acute Myeloid Leukemia (AML), Acute Lymphoid Leukemia (ALL), Myelodysplastic Syndromes (MDS)

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Personalized rATG (P-rATG)
Hyper fractionated total body irradiation
Thiotepa
Cyclophosphamide
GCSF
Busulfan
Melphalan
Fludarabine
Sponsored by
Memorial Sloan Kettering Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia (AML) focused on measuring personalized rabbit ATG (P-rATG), ex-vivo CD34+ T cell depleted, total body irradiation, thiotepa, cyclophosphamide, busulfan, melphalan, fludarabine, 21-193

Eligibility Criteria

4 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Memorial Sloan Kettering Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

P-rATG with total body irradiation, thiotepa, cyclophosphamide

P-rATG with busulfan, melphalan and fludarabine

Arm 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.

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Overall Survival (OS)
The duration of time between HCT and death due to any cause.

Full Information

First Posted
April 30, 2021
Last Updated
August 31, 2023
Sponsor
Memorial Sloan Kettering Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT04872595
Brief Title
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
Official Title
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
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 30, 2021 (Actual)
Primary Completion Date
April 2024 (Anticipated)
Study Completion Date
April 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Memorial Sloan Kettering Cancer Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes

5. Study Description

Brief Summary
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia (AML), Acute Lymphoid Leukemia (ALL), Myelodysplastic Syndromes (MDS)
Keywords
personalized rabbit ATG (P-rATG), ex-vivo CD34+ T cell depleted, total body irradiation, thiotepa, cyclophosphamide, busulfan, melphalan, fludarabine, 21-193

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
This phase 2 study is to assess the effects of personalized rabbit ATG (P-rATG) dosing on CD4+ immune reconstitution (CD4+IR) based on a pharmacokinetic/pharmacodynamic (PK/PD) model in patients with hematologic malignancies undergoing peripheral blood mobilized, ex-vivo CD34+ T cell depleted, allogeneic, hematopoietic cell transplantation (CD34+/TCD allo-HCT)1.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
56 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
P-rATG with total body irradiation, thiotepa, cyclophosphamide
Arm Type
Experimental
Arm 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.
Arm Title
P-rATG with busulfan, melphalan and fludarabine
Arm Type
Experimental
Arm 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
Intervention Type
Other
Intervention Name(s)
Personalized rATG (P-rATG)
Intervention Description
P-rATG days (always starting on Day -12 to -10)
Intervention Type
Radiation
Intervention Name(s)
Hyper fractionated total body irradiation
Intervention Description
(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.
Intervention Type
Drug
Intervention Name(s)
Thiotepa
Intervention Description
(5mg/kg/day x 2 day) Day -5 to -4
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
(60mg/kg/day x 2 days) Day -3 to -2
Intervention Type
Drug
Intervention Name(s)
GCSF
Intervention Description
Day +7
Intervention Type
Drug
Intervention Name(s)
Busulfan
Intervention Description
Day -9 to -7 doses 2-3 to be adjusted per PK for target cumulative exposure of 65 mg*h/L
Intervention Type
Drug
Intervention Name(s)
Melphalan
Intervention Description
(70mg/m2/day x 2 days) Day -6 to -5
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Description
(25mg/m2/day x 5 days) Day -6 to -2
Primary Outcome Measure Information:
Title
proportion of patients who achieve CD4+IR
Description
is defined at CD4+ > 50u/L at two consecutive measures within 100 days post allo-HCT.
Time Frame
within 100 days of HCT
Secondary Outcome Measure Information:
Title
Overall Survival (OS)
Description
The duration of time between HCT and death due to any cause.
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kevin Curran, MD
Phone
1-833-675-5437
Email
currank@mskcc.org
First Name & Middle Initial & Last Name or Official Title & Degree
Michael Scordo, MD
Phone
646-608-3771
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kevin Curran, MD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kevin Curran, MD
Phone
833-675-5437
First Name & Middle Initial & Last Name & Degree
Michael Scordo, MD
Phone
646-608-3771
First Name & Middle Initial & Last Name & Degree
Kevin Curran, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made following one year after publication and for up to 36 months later. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.
Links:
URL
http://www.mskcc.org/mskcc/html/44.cfm
Description
Memorial Sloan Kettering Cancer Center

Learn more about this trial

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

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