Study of Gene Modified Donor T Cell Infusion in Patients With Recurrent Disease After Allogeneic Transplant

Study Overview
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Brief Summary
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A Phase I study of BPX-501 T cell infusion in adults with recurrent or minimal residual disease (MRD) hematologic malignancies post-allogeneic transplant. The treatment consists of increasing doses of BPX-501 T cell infusions to achieve a clinical response. Rimiducid will be investigated for the treatment of aGvHD after BPX-501 T cell infusion to determine a dose that can mitigate GvHD and preserve the graft versus leukemia effect.

Detailed Description
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Unmanipulated donor lymphocyte infusion (DLI) is used after stem cell transplantation to treat and prevent relapse, to prevent infections and to establish full donor chimerism. The addition of mature T cells which exhibit a broad repertoire of T cell immunity against viral and cancer antigens, might provide a clinical benefit. However, an expected side effect of the presence of mature T cells is the potential occurrence of acute graft-versus-host disease (aGVHD). BPX-501 contains genetically modified donor T cells that have an inducible safety switch iCasp9 suicide gene. Evidence has emerged that escalating DLI has achieved higher clinical response rate with lower GVHD occurrence. Optimization of DLI dose and schedule as well as strategies of donor T-cell manipulation may lead to the consistent ability to separate GVHD from GvL (graft-versus-leukemia) activity and improve the safety of DLI treatment.

Official Title
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A Phase I Study of Donor BPX-501 T Cell Infusion for Adults With Recurrent or Minimal Residual Disease Hematologic Malignancies Post-Allogeneic Transplant

Conditions
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Leukemia, Myelodysplastic Syndromes, Lymphoma, Multiple Myeloma, Hematologic Neoplasms

Intervention / Treatment
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* Biological: BPX-501
* Drug: Rimiducid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects aged >18yrs and < 65yrs Clinical diagnosis of one of the following adult hematological malignancies Leukemia Myelodysplastic Syndromes Lymphomas Multiple myeloma Other high-risk hematologic malignancies eligible for stem cell transplantation per institutional standard Life expectancy >10 weeks Evidence of recurrent disease that presents > 100 days or minimal residual disease (MRD) that presents > 30 days after one of the following: Matched related HSCT Mismatched related HSCT Signed patient informed consent; A minimum genotypic identical match of 4/8 is required, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, and HLA- DRB1 Performance status: Karnofsky score > 50% Subjects with adequate organ function as measured by: Bone marrow: > 25% donor T-cell chimerism ANC >1 x 10E9/L Cardiac: left ventricular ejection fraction at rest must be >45%. Hepatic: direct bilirubin ≤ 3 x upper limit of normal, or AST/ALT ≤ 5 x upper limit of normal Renal: creatinine ≤ 2x of ULN for age Pulmonary: FEV 1, FVC, DLCO (diffusion capacity) > 50% predicted (corrected for hemoglobin) Exclusion Criteria: ≥ Grade II acute GVHD or chronic extensive GVHD due to a previous allograft at time of screening; Active CNS involvement by malignant cells; Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings). The principal investigator is the final arbiter of this criterion; Positive HIV serology or viral RNA Pregnancy (positive serum βHCG test) or breast-feeding; Subjects of reproductive potential unwilling to use effective forms of birth control or abstinence for a year after transplantation; Bovine product allergy

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: BPX-501 and Rimiducid<br>All subjects will receive 3 cycles of BPX-501 T cell infusions at escalating dose levels (DL). DL1 on Day 0, DL2 on Days 30 and 60. The first dose of BPX-501 T cells will occur ≥30 days after hematopoietic stem cell transplant (HSCT). Two doses of Rimiducid ( 0.1 mg/kg and 0.4 mg/kg) will be investigated for the treatment of aGvHD after BPX-501 T cell infusion. | Biological: BPX-501<br>* Biological: T cells transduced with CaspaCIDe suicide gene<br>Drug: Rimiducid<br>* Rimiducid administered to treat GVHD<br>* Other names: AP1903;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BPX-501 Safety | To evaluate the safety of 2 stratified dose levels of BPX-501 T cell infusions based on patient-donor match in adult subjects with hematological malignancies | Month 24 | 
| Rimiducid Safety | evaluate the safety of the infusion of escalating doses of dimerizer drug rimiducid (AP1903) in subjects who develop acute GvHD after BPX-501 infusion | Month 24 | 
| GvHD | Assess incidence and severity of acute and chronic GvHD | Month 24 | 
| Rimiducid Activity | Determine the effect of Rimiducid on mitigating GvHD | Month 24 | 
| Rimiducid Efficacy | Assess time to resolution of GvHD after administration of Rimiducid | Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Measure overall survival, disease free survival and response rates after BPX-501 infusion | Month 24 | 
| Translational | Evaluate BPX-501 T cell function | Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adult leukemias and myelodysplasia, Adult lymphomas, Adult multiple myeloma, allogeneic stem cell transplant, donor lymphocyte infusion