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
Study Details
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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. |
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
|
| 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 |
Other: Personalized rATG (P-rATG)
P-rATG days (always starting on Day -12 to -10)
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
|
Outcome Measures
Primary Outcome Measures
- proportion of patients who achieve CD4+IR [within 100 days of HCT]
is defined at CD4+ > 50u/L at two consecutive measures within 100 days post allo-HCT.
Secondary Outcome Measures
- Overall Survival (OS) [2 years]
The duration of time between HCT and death due to any cause.
Eligibility Criteria
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 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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
Sponsors and Collaborators
- Memorial Sloan Kettering Cancer Center
Investigators
- Principal Investigator: Kevin Curran, MD, Memorial Sloan Kettering Cancer Center
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 21-193