Clinical trial NCT01744223: Safety Study of Gene Modified Donor T-cells Following Partially Mismatched Stem Cell Transplant
Official title: A Phase 1/2 Dose Escalation Study Evaluating Safety and Feasibility of BPX-501 T Cells After Partially Mismatched, Related, T Cell-Depleted HSCT (Hematopoietic Stem Cell Transplant)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Acute Lymphoblastic Leukemia
Acute Myelogenous Leukemia
Lymphoma
Myelodysplastic Syndromes
Keywords: iCaspase9
iCasp9
Inducible Caspase
AP1903
Dimerizer drug
T depleted
Suicide gene
CD-34 selection
haplotransplantation
Graft versus host disease
Allogenic transplantation
Lead sponsor: Bellicum Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2012-12-06
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study will evaluate patients with blood cell cancers who are going to have an allogeneic (donor) blood stem cell transplant from a partially matched relative. The research study will test whether immune cells, called T cells, which come from the donor relative and are specially grown in the laboratory and then given back to the patient along with the stem cell transplant (T cell addback), can help the immune system recover faster after the transplant. As a safety measure, these T cells have been "programmed" with a "self-destruct switch" so that if, after they have been given to the patient, the T cells start to react against the tissues (called "graft versus host" disease, GVHD), the T cells can be destroyed.

Detailed description: This is a Phase1/2 dose escalation study evaluating the safety and feasibility of BPX-501 infused after partially mismatched, related (haploidentical), T cell-depleted HSCT. The purpose of this clinical trial is to determine whether BPX-501 infusion can facilitate engraftment, enhance immune reconstitution and potentially improve the graft versus leukemia (GVL) effect, with the potential for reducing the severity and duration of severe acute graft versus host disease (GvHD). The trial will evaluate the treatment of GvHD by the infusion of dimerizer drug (Rimiducid) in those subjects who present with GvHD that does not adequately respond to standard of care therapy.

Eligibility criteria: Inclusion Criteria:

1. Signed informed consent
2. Age ≥ 18 years and ≤ 65 years
3. Deemed eligible for allogeneic stem cell transplantation
4. 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
5. HLA typing will be performed at high resolution (allele level) for the HLA-A, -B, Cw, and DRBl, and loci

   * A minimum genotypic identical 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
6. Subjects with adequate organ functions as measured by:

   1. Cardiac: Left ventricular ejection fraction at rest must be ≥ 45%
   2. Hepatic: Bilirubin ≤ 2.5 mg/dL and ALT, AST and Alkaline Phosphatase \< 5 x ULN
   3. Renal: Serum creatinine within normal range for age or creatinine clearance, or with a recommended GFR ≥ 50 mL/min/1.73m2
   4. Pulmonary: FEV 1, FVC and DLCO (diffusion capacity) ≥ 50% predicted (corrected for hemoglobin); or O2 saturation \> 92% on room air
7. Clinical diagnosis of one of the following:

   a. Acute Leukemia (includes T lymphoblastic lymphoma) in 2nd or subsequent complete remission (CR) i. Acute Lymphoblastic Leukemia (ALL) in 2nd or subsequent CR. ALL shall be morphologic remission at the time of transplant. Morphologic remission is defined that subjects with normal neutrophil and platelet counts, less than 5% blast cells in a bone marrow (BM) smear and no extramedullary disease ii. Acute Myeloid Leukemia (AML) in 2nd or subsequent CR with or without persistent minimal residual disease b. High-risk ALL in 1st CR (including features such as those in i-iii) i. Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), MLL rearrangements ii. Subjects over 30 years of age, or iii. Time to complete remission was greater than 4 weeks. c. High-risk AML in 1st CR (including features such as those listed in i-vii) i. Greater than 1 cycle of induction therapy required to achieve remission ii. Preceding myelodysplastic syndrome (MDS) iii. Presence of FLT3 abnormalities iv. FAB M6 or M7 leukemia v. Adverse cytogenetics for overall survival such as those associated with MDS vi. Complex karyotype (\>3 abnormalities), or vii. Any of the following: inv(3) or t(3;3), t(6;9), t(6;11), + 8 \[alone or with other abnormalities except for t(8;21), t(9;11), inv(16) or t(16;16)\], t(l1;19)(q23;p13.1) d. High risk Myelodysplastic Syndrome e. Non-Hodgkin's Lymphoma relapsed after autologous transplantation f. Non-Hodgkin's Lymphoma with insufficient autologous hematopoietic stem cells to undergo autologous transplantation g. CML i. in first chronic phase that has not attained at least a complete cytogenetic remission after exposure to at least 3 tyrosine kinase inhibitors ii. in accelerated phase that has not attained at least a complete cytogenetic remission iii. in second chronic phase
8. Performance status: Karnofsky score ≥60%.
9. Patient with hematologic malignancy not responding to /or not eligible for conventional therapy and are approved by Sponsor

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. Pregnancy or breast-feeding.
4. Evidence of HIV infection or known HIV positive serology.
5. Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings). The treating physician will make final determination.
6. Non-hematologic malignancy within prior three (3) years, with the exception of squamous cell or basal cell skin carcinoma.
7. Prior allogeneic hematopoietic stem cell transplant.
8. Subjects with a history of primary idiopathic myelofibrosis.
9. Bovine product allergy.

Primary outcomes:
measure: BPX-501 Safety
timeFrame: 24 months
measure: Rimiducid Safety
timeFrame: 24 months
measure: MTD
timeFrame: 24 months
measure: Immune Reconstitution
timeFrame: 24 months
Secondary outcomes:
measure: Efficacy- NRM
timeFrame: 100, 180 days and 1 year
measure: Efficacy- DFS
timeFrame: 24 months
measure: Efficacy- TRM
timeFrame: 24 months
measure: Efficacy- Relapse
timeFrame: 24 months
measure: Incidence of engraftment
timeFrame: 24 months
measure: GvHD
timeFrame: 24 months
measure: GvHD post Rimiducid Administration
timeFrame: 24 months
measure: BPX-501 Safety Profile
timeFrame: 24 months
measure: Pharmacokinetics of Rimiducid
timeFrame: 24 months
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University Winship Cancer Institute
state: Georgia
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Dallas
country: United States
facility: Baylor Sammons Cancer Center
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: Bellicum Pharmaceuticals, Inc.
name: Bellicum Pharmaceuticals
role: STUDY_DIRECTOR
References: