Acute Myeloid Leukemia T Cell Depletion to Improve Transplants in Adults With Acute Myeloid Leukemia (BMT CTN 0303)

Study Overview
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Brief Summary
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This study is a single arm Phase II, multicenter trial. It is designed to determine whether the anticipated endpoints for a T cell depleted transplant arm of a planned prospective randomized trial comparing T cell depleted and unmodified hematopoietic allografts are likely to be achieved in a multicenter study conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN or Network). The study population is patients with acute myeloid leukemia (AML) in first or second morphologic complete remission. The enrollment is 45 patients. Based on published results of unmodified transplants from HLA-matched siblings applied to patients with AML in first or second morphologic complete remission, a significant improvement in results with a graft modified as specified in this protocol would be expected if disease-free survival (DFS) at 6 months was greater than 75%, the true incidence of transplant-related mortality at 1 year was less than 30%, and the DFS rate at 2 years was greater 70% for patients transplanted in first remission and less than 60% for patients transplanted in second remission. Additional secondary endpoints include the following: graft failure rate and incidences of acute grade II-IV and chronic graft-versus-host disease (GVHD). Additionally, the trial will have target specific doses of CD34+ progenitors and CD3+ T cells to be obtained following fractionation with the CliniMACS system. Based on the results of this trial, a Phase III trial comparing T cell depleted peripheral blood stem cell transplants (PBSCT) with unmanipulated bone marrow or unmanipulated PBSCT will be designed.

Detailed Description
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BACKGROUND: Allogeneic hematopoietic cell transplantation is an accepted therapy for AML. Transplants of unmodified HLA-matched related bone marrow or peripheral blood stem cells following conditioning with total body irradiation (TBI) and cyclophosphamide or VP-16 or busulfan and cyclophosphamide have led to sustained DFS rates of 45-60% for adults transplanted in first complete remission (CR1) and 40-53% for patients transplanted in second complete remission (CR2). In several single center and multicenter cooperative group prospective trials comparing HLA-matched allogeneic transplants to chemotherapy in the treatment of AML in CR1, DFS rates for the transplant arm were almost invariably superior; however, these advantages were statistically significant in only a minority of the cooperative group studies conducted. In each study, the risk of relapse was significantly lower for patients receiving allogeneic transplants. However, this advantage was counterbalanced by transplant-related mortality, principally reflecting infections complicating GVHD and its treatment. DESIGN NARRATIVE: Despite increased risks of infection, development of effective T cell depletion (TCD) techniques for prevention of GVHD and tolerable modifications of regimens for pre-transplant cytoreduction that secure consistent engraftment offer the potential for significant decreases in transplant-related mortality. Furthermore, the use of TCD transplants in the treatment of patients with AML is not associated with substantial increases in the incidence of relapse. Several single center trials indicate highly encouraging long-term results, particularly for patients with AML in CR1 or CR2. Although the number of cases in each single center series is limited, the consistency of the results suggests that the use of an effective technique for TCD together with an adequate cytoreductive regimen might yield transplant results superior to those achieved with unmodified grafts.

Official Title
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A Phase 2 Single Arm Trial of HLA-Matched Transplants, CD34+ Enriched, T-Cell Depleted Peripheral Blood Stem Cells Isolated by CliniMACS System in the Treatment of Patients With AML in 1st or 2nd Morphologic Complete Remission (BMTCTN0303)

Conditions
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Leukemia, Myelocytic, Acute

Intervention / Treatment
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* Biological: CD34+ selection with CliniMACS device


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with AML with or without prior history of myelodysplastic syndrome based on the World Health Organization criteria at the following stages: First morphologic complete remission (CR) Second morphologic CR If prior history of central nervous system (CNS) involvement, no evidence of active CNS leukemia during the pre-transplant evaluation (no evidence of leukemic blasts in cerebrospinal fluid) First or second CR was achieved after no more than two cycles of induction (or re-induction for patients in second CR) chemotherapy No more than 6 months elapsed from documentation of CR to transplant for patients in first CR, or 3 months for patients in second CR. A 6/6 HLA antigen (A, B, DRB1)-compatible sibling donor; the match may be determined at serologic level for HLA-A and HLA-B loci; DRB1 must be matched at least at low-resolution using DNA typing techniques; HLA-C will be typed at the serologic level, but not included in the match algorithm Karnofsky performance status greater than 70% Life expectancy greater than 8 weeks Diffusing capacity of the lung for carbon monoxide (DLCO) of at least 40% (corrected for hemoglobin) with no symptomatic pulmonary disease Left ventricular ejection fraction (LVEF) by Multi Gated Acquisition Scan (MUGA) or echocardiogram greater than 40% Serum creatinine greater than 2 mg/dL, bilirubin greater than 2 mg/dL, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at least 3 times the upper limit of normal at time of enrollment Willingness of both the patient and the donor to participate Exclusion Criteria: M3-AML (acute promyelocytic leukemia) in first CR Acute leukemia following blast transformation of prior chronic myelogenous leukemia (CML) or other myeloproliferative disease M4Eo-AML with inv 16 in first CR AML with t(8;21) in first CR Participation in other clinical trials that involve investigational drugs or devices except with permission from the Medical Monitor Evidence of active Hepatitis B or C infection or evidence of cirrhosis HIV positive Uncontrolled diabetes mellitus If proven or probable invasive fungal infection, infection must be controlled; patients may be on prophylactic anti-fungal agents, but are not permitted to be on anti-fungal agents for therapeutic purposes (i.e., active treatment for disease) Uncontrolled viral or bacterial infection (currently taking medication without clinical improvement) Documented allergy to iron dextran or murine proteins Pregnant or breastfeeding; women of childbearing age must avoid becoming pregnant while in the study Prior autologous or allogeneic hematopoietic stem cell transplantation (HSCT)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CD34+ selection with CliniMACS device<br>T cell depletion using Miltenyi device | Biological: CD34+ selection with CliniMACS device<br>* CD34+ cell selection will be performed according to procedures given in the CliniMACS Users Operating Manual and institutional Standard Operating Procedures (SOPs) in place and validated at the study sites. CliniMACS (Miltenyi device) to target CD34+ >5 x 10*6/kg and CD3+ < 1 x 10*5/kg<br>* Other names: T Cell Depletion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of Disease-free Survival (DFS) at 6 Months Post-transplant (Death or Relapse Will be Considered Events for This Endpoint) | The primary analysis will consist of estimating the 6-month DFS (from day of enrollment) probability based on the Kaplan-Meier product limit estimator. The 6-month DFS probability and confidence interval will be calculated. All registered patients will be considered for this analysis. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Leukemia Relapse | To assess the incidence of acute leukemia relapse from day of transplant, a cumulative incidence curve will be computed along with a 95% confidence interval. Death prior to relapse will be considered as a competing risk. | Months 12 and 36 | 
| Neutrophil Engraftment | Time to neutrophil engraftment is measured by determining the first of three consecutive measurements of absolute neutrophil count ≥ 500/uL following conditioning regimen induced nadir, starting from Day 0. | 28 day | 
| Platelet Engraftment | Time to platelet engraftment is measured by determining the first of three consecutive measurements of platelet count ≥ 20,000/uL without platelet transfusion support for seven days, starting from Day 0. | 6 Months | 
| Graft Failure | Primary graft failure is defined as the failure to achieve an ANC > 500 cells/µL by Day +30. Secondary graft failure is defined as initial neutrophil engraftment followed by subsequent decline in neutrophil counts < 500 cells/µL, unresponsive to growth factor therapy. | Day 100 | 
| Acute Graft Versus Host Disease (GVHD) | Incidence and severity of acute GVHD will be graded according to the BMT CTN MOP. | Day 100 | 
| Chronic Graft Versus Host Disease (GVHD) | Incidence and severity of chronic GVHD will be scored according to the BMT CTN MOP. | Year 2 | 
| Transplant Related Mortality | Death occurring in a patient in continuing complete remission. | Months 12, 24, and 36 | 
| Determination of Infusional Toxicity |  | 28 day | 
| Disease-free Survival (DFS) | DFS is defined as the minimum time interval of times to relapse/recurrence, to death or to the last follow-up, from the time of transplant. | Months 6, 12, and 36 | 
| Overall Survival | Overall survival is defined as time from transplant to death or last follow-up. | Months 12 and 36 | 
| CD34+ and CD3+ Cell Doses | Total CD34+ and CD3+ cell doses will be calculated based on results of flow cytometric analysis. | Day 0 | 
| Post-transplant Lymphoproliferative Disorder (PTLD) | PTLD is defined as increased Epstein Barr Virus viremia requiring clinical intervention. | Year 2 |