Clinical Trials /

Safety Study of Gene Modified Donor T-Cells in Adults With Advanced Hematologic Malignancies

NCT02487459

Description:

This is an open-label, non-randomized study to evaluate the safety of two planned infusions of BPX-501 T cells after partially mismatched, related (haploidentical) HSCT in adults with hematologic malignancies.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Myeloid Leukemia
  • Lymphoma
  • Myelodysplastic Syndromes
Recruiting Status:

Withdrawn

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety Study of Gene Modified Donor T-Cells in Adults With Advanced Hematologic Malignancies
  • Official Title: A Phase I/II Safety Study of Planned BPX-501 T Cell Infusion After Partially Mismatched, Related, HSCT in Adults With Advanced Hematologic Malignances at High Risk for Relapse

Clinical Trial IDs

  • ORG STUDY ID: BP-005
  • NCT ID: NCT02487459

Conditions

  • Hematologic Malignancies

Interventions

DrugSynonymsArms
BPX-501BPX-501 and AP1903
AP1903RimiducidBPX-501 and AP1903

Purpose

This is an open-label, non-randomized study to evaluate the safety of two planned infusions of BPX-501 T cells after partially mismatched, related (haploidentical) HSCT in adults with hematologic malignancies.

Detailed Description

      The objective is to evaluate the safety of two planned infusions of BPX-501 after partially
      mismatched, related HSCT with post-transplant cyclophosphamide and to evaluate the safety and
      efficacy of the treatment of dimerizer drug, rimiducid (AP1903), to subjects who received
      BPX-501 and have uncontrolled GvHD. Assuming no toxicity, enrollment will proceed
      sequentially for the initial 9 patients (following the 3+3 design), who will be followed for
      100 days, prior to enrolling the subsequent 31 patients. Toxicity may increase the number of
      initial group of patients). As multiple dose levels may be administered among the first 9 (or
      more) patients, toxicity will be assessed on the cohort with the maximum tolerated dose
      (MTD).

      Stopping Rules (for the Phase II portion of the study):

        -  >20% of patients experience Grade III or IV acute GVHD attributable to BPX-501 T cells
           and non-responsive to AP1903 infusions.

        -  Grade IV reactions related to infusion of BPX-501 or AP1903.

        -  Death related to BPX-501 or AP1903 infusions.

      The Medical Monitoring committee will review the data with the investigators and determine
      whether to proceed and or implement any changes to the protocol

      BPX-501 contains genetically modified donor T cells that have an inducible safety switch
      iCasp9 suicide gene. In the event of acute GvHD, administration of rimiducid dimerizes and
      activates caspase 9; this activates downstream caspases, obligating cellular apoptosis within
      24 hours.
    

Trial Arms

NameTypeDescriptionInterventions
BPX-501 and AP1903ExperimentalThree cohorts, 3 patients each, will receive two infusions (at the same dose) of BPX-501. If needed to treat aGVHD, a single dose of 40 mg of AP1903 will be administered IV.
  • AP1903

Eligibility Criteria

        Inclusion Criteria:

          1. Signed informed consent

          2. Patients with one of the life-threatening hematological malignancies:

               -  Acute lymphocytic leukemia (ALL) in CR1 with high-risk features including adverse
                  cytogenetics such as t(9;22), t(1;19), t(4;11), or MLL gene rearrangements;
                  greater than 1 cycle to achiever remission or with persistent MRD; ALL in second
                  or greater remission with or without MRD. Acute myeloid leukemia (AML) in CR1
                  with high-risk features defined as: Greater than 1 cycle of induction therapy
                  required to achieve remission; Preceding myelodysplastic syndrome (MDS) or
                  myeloproliferative disease; Presence of FLT3 mutations or internal tandem
                  duplications; FAB M6 or M7 classification; Adverse cytogenetics, -5, del 5q, -7,
                  del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, +8 [> 3 abnormalities];

               -  AML in second or greater remission, primary induction failure and patients with
                  relapsed disease;

               -  Advanced chronic myeloid leukemia (CML) who have progressed to blast phase or
                  accelerated phase and are in need of a transplant and do not have an HLA matched
                  donor;

               -  MDS with IPSS intermediate-2 or higher or therapy-related MDS.Hodgkin lymphoma or
                  Non-Hodgkin lymphoma (NHL): relapsed disease where remission duration is less
                  than 1 year, relapse after previous autologous transplant, or failure to achieve
                  CR with chemotherapy.

          3. Age ≥ 18 years and ≤ 65 years

          4. Deemed eligible for allogeneic stem cell transplantation

          5. Lack of suitable conventional donor (i.e. 8/8 related or unrelated donor) or presence
             of rapidly progressive disease not permitting time to identify an unrelated donor

          6. HLA typing will be performed at high resolution (allele level) for the HLA-A, -B, Cw,
             and DRBl loci

               -  A minimum genotypic identical haplotype match of 4/8 is required

               -  The donor and recipient must be identical, 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

          7. Subjects with adequate organs function as measured by:

               -  Cardiac: Left ventricular ejection fraction at rest must be >45%

               -  Pulmonary: FEV 1, FVC, DLCO (diffusion capacity) > 50% predicted (corrected for
                  hemoglobin); or O2 saturation > 92% on room air

               -  Hepatic: Direct bilirubin ≤ 3 x upper limit of normal (ULN), or AST/ALT ≤ 5 x ULN

               -  Renal: Serum creatinine within normal range for age or creatinine clearance, or
                  with a recommended GFR ≥ 50 mL/min/1.73m2

          8. Performance status: Karnofsky ≥ 80%

        Exclusion Criteria:

        Subjects meeting the following criteria are NOT eligible for the study:

          1. HLA 8/8 allele matched (HLA-A,-B,-Cw,-DRBl) related or unrelated donor able to donate;

          2. Autologous hematopoietic stem cell transplant ≤ 3 months prior to enrollment;

          3. Prior allogeneic transplantation;

          4. Active CNS involvement by malignant cells (less than 2 months from the conditioning);

          5. Current uncontrolled bacterial, viral or fungal infection (currently taking medication
             with evidence of progression of clinical symptoms or radiologic findings); the PI is
             the final arbiter of this criterion;

          6. Positive HIV serology or viral RNA (≥ Grade III per CTCAE criteria);

          7. Pregnancy (positive serum or urine βHCG test) or breast-feeding;

          8. Fertile men or women unwilling to use effective forms of birth control or abstinence
             for a year after transplantation;

          9. Bovine product allergy.

         10. Severe obesity (patient's weight is >/= 1.5x the donor weight).
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Adverse events
Time Frame:2 years
Safety Issue:
Description:Number of adverse events after BPX-501 as a measure of safety

Secondary Outcome Measures

Measure:Adverse events
Time Frame:48 hours
Safety Issue:
Description:Number of adverse events after AP1903 as a measure of safety

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Bellicum Pharmaceuticals

Trial Keywords

  • acute lymphoblastic leukemia
  • acute myeloid leukemia
  • chronic myeloid leukemia
  • myelodysplastic syndrome
  • non-hodgkin lymphoma
  • hodgkin lymphoma

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