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

Leukemia, Myelocytic, Acute Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00201240
• Other study ID #: BMTCTN0303
• Secondary ID: U01HL069254U01HL
• Status: Completed
• Phase: Phase 2
• Start date: June 2005
• Est. completion date: December 2013

Study information

• Verified date: August 2017
• Source: National Heart, Lung, and Blood Institute (NHLBI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: December 2013
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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)

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelocytic, Acute
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Biological:
• CD34+ selection with CliniMACS device
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

Locations

Country	Name	City	State
United States	Dana Farber Cancer Institute/Brigham & Women's Hospital	Boston	Massachusetts
United States	University Hospitals of Cleveland/Case Western	Cleveland	Ohio
United States	Ohio State/Arthur G. James Cancer Hospital	Columbus	Ohio
United States	City of Hope National Medical Center	Duarte	California
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	University of Pennsylvania Cancer Center	Philadelphia	Pennsylvania
United States	University of California, San Francisco	San Francisco	California

Sponsors (3)

Lead Sponsor	Collaborator
National Heart, Lung, and Blood Institute (NHLBI)	Blood and Marrow Transplant Clinical Trials Network, National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Devine SM, Carter S, Soiffer RJ, Pasquini MC, Hari PN, Stein A, Lazarus HM, Linker C, Stadtmauer EA, Alyea EP 3rd, Keever-Taylor CA, O'Reilly RJ. Low risk of chronic graft-versus-host disease and relapse associated with T cell-depleted peripheral blood st — View Citation

Keever-Taylor CA, Devine SM, Soiffer RJ, Mendizabal A, Carter S, Pasquini MC, Hari PN, Stein A, Lazarus HM, Linker C, Goldstein SC, Stadtmauer EA, O'Reilly RJ. Characteristics of CliniMACS® System CD34-enriched T cell-depleted grafts in a multicenter tria — View Citation

Pasquini MC, Devine S, Mendizabal A, Baden LR, Wingard JR, Lazarus HM, Appelbaum FR, Keever-Taylor CA, Horowitz MM, Carter S, O'Reilly RJ, Soiffer RJ. Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-versus-host — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Acute Graft Versus Host Disease (GVHD)	Incidence and severity of acute GVHD will be graded according to the BMT CTN MOP.	Day 100
Secondary	Chronic Graft Versus Host Disease (GVHD)	Incidence and severity of chronic GVHD will be scored according to the BMT CTN MOP.	Year 2
Secondary	Transplant Related Mortality	Death occurring in a patient in continuing complete remission.	Months 12, 24, and 36
Secondary	Determination of Infusional Toxicity		28 day
Secondary	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
Secondary	Overall Survival	Overall survival is defined as time from transplant to death or last follow-up.	Months 12 and 36
Secondary	CD34+ and CD3+ Cell Doses	Total CD34+ and CD3+ cell doses will be calculated based on results of flow cytometric analysis.	Day 0
Secondary	Post-transplant Lymphoproliferative Disorder (PTLD)	PTLD is defined as increased Epstein Barr Virus viremia requiring clinical intervention.	Year 2

External Links

•   Blood and Marrow Transplant Clinical Trials Network Website