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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Hematologic Malignancies
• Intervention / Treatment: Biological: BPX-501; Drug: AP1903

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).

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.

• Study Type: Interventional
• Phase: Phase 1

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BPX-501 and AP1903; Three cohorts, 3 patients each, will receive two infusions (at the same dose) of BPX-501. If needed to treat aGVHD, a single dose of AP1903 will be administered IV.	Biological: BPX-501; T cells transduced with CaspaCIDe suicide gene; Drug: AP1903; dimerizer drug administered to treat GVHD; Other Names: Rimiducid

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Bellicum Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: June 29, 2015
• First Submitted That Met QC Criteria: June 29, 2015
• First Posted (Estimate): July 1, 2015

Study Record Updates

• Last Update Posted (Actual): October 5, 2020
• Last Update Submitted That Met QC Criteria: October 1, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: acute myeloid leukemia; myelodysplastic syndrome; chronic myeloid leukemia; acute lymphoblastic leukemia; hodgkin lymphoma; non-hodgkin lymphoma
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms
• Other Study ID Numbers: BP-005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No