Safety Study of Gene Modified Donor T-cells Following Partially Mismatched Stem Cell Transplant

Phase 1

Active, not recruiting

Conditions: Acute Myelogenous Leukemia
Acute Lymphoblastic Leukemia
Lymphoma
Myelodysplastic Syndromes

Interventions: Biological: BPX-501 dose 1
Biological: BPX-501 dose 2
Biological: BPX-501 dose 4
Biological: BPX-501 dose 3
Drug: Rimiducid
Procedure: SCT

Registration Number: NCT01744223

Lead Sponsor: Bellicum Pharmaceuticals

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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 36

Inclusion Criteria

Signed informed consent
Age ≥ 18 years and ≤ 65 years
Deemed eligible for allogeneic stem cell transplantation
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
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
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
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
Performance status: Karnofsky score ≥60%.
Patient with hematologic malignancy not responding to /or not eligible for conventional therapy and are approved by Sponsor

Exclusion Criteria

HLA 8/8 allele matched (HLA-A,-B,-Cw,-DRBl) related or unrelated donor able to donate.
Autologous hematopoietic stem cell transplant < 3 months prior to enrollment.
Pregnancy or breast-feeding.
Evidence of HIV infection or known HIV positive serology.
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.
Non-hematologic malignancy within prior three (3) years, with the exception of squamous cell or basal cell skin carcinoma.
Prior allogeneic hematopoietic stem cell transplant.
Subjects with a history of primary idiopathic myelofibrosis.
Bovine product allergy.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
SCT, BPX-501 dose 1, Rimiducid if needed	BPX-501 dose 1	2x10E5 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant. Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.
SCT, BPX-501 dose 1, Rimiducid if needed	SCT	2x10E5 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant. Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.
SCT, BPX-501 dose 2, Rimiducid if needed	BPX-501 dose 2	5x10E5 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant. Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.
SCT, BPX-501 dose 2, Rimiducid if needed	SCT	5x10E5 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant. Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.
SCT, BPX-501 dose 4, Rimiducid if needed	BPX-501 dose 4	3x10E6 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant . Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.
SCT, BPX-501 dose 3, Rimiducid if needed	BPX-501 dose 3	1x10E6 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant. Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.
SCT, BPX-501 dose 3, Rimiducid if needed	SCT	1x10E6 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant. Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.
SCT, BPX-501 dose 4, Rimiducid if needed	SCT	3x10E6 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant . Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.
SCT, BPX-501 dose 1, Rimiducid if needed	Rimiducid	2x10E5 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant. Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.
SCT, BPX-501 dose 2, Rimiducid if needed	Rimiducid	5x10E5 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant. Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.
SCT, BPX-501 dose 3, Rimiducid if needed	Rimiducid	1x10E6 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant. Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.
SCT, BPX-501 dose 4, Rimiducid if needed	Rimiducid	3x10E6 BPX-501 (rivogenlecleucel) cells per kg infused after TCR alpha beta depleted donor stem cell transplant . Rimiducid: Dimerizer drug administered by intravenous infusion in those subjects with acute GVHD with no response to steroids and/or other aGVHD medications or worsening in stage or grade of aGVHD after 48 hours. Subjects with chronic GvHD who do not respond to steroids/systemic therapies within 7 days, or there is a worsening in cGVHD, patients may then receive rimiducid.

Primary Outcome Measures

Name	Time	Method
Rimiducid Safety	24 months	To evaluate the safety of the infusion of the rimiducid in subjects who received BPX-501 and have developed visceral or steroid refractory graft-versus-host-disease
MTD	24 months	To determine the maximum dose of BPX-501 (up to 3x106 cells/kg) that results in an adjusted cumulative incidence by Day 100 of no more than 45% Grade II - IV aGVHD and / or no more than 17% Grade III -IV aGVHD.
Immune Reconstitution	24 months	To assess immune reconstitution for each dose cohort
BPX-501 Safety	24 months	To evaluate the safety of infusion of each of 4 dose cohorts of BPX-501 (2x105, 5x105, 1x106 and 3x106 cells/kg) after transplantation of partially mismatched T cell depleted hematopoietic stem cell transplant (HSCT)

Secondary Outcome Measures

Name	Time	Method
Efficacy- NRM	100, 180 days and 1 year	Non-Relapse Mortality (NRM)
Efficacy- DFS	24 months	Disease-free survival
Efficacy- TRM	24 months	Transplant related mortality (TRM)
Efficacy- Relapse	24 months	Incidence of Relapse
Incidence of engraftment	24 months	Evaluation of neutrophil and platelet engraftment, kinetics of donor cell engraftment and graft failure
GvHD	24 months	Incidence and severity of acute and chronic GvHD
GvHD post Rimiducid Administration	24 months	Time to resolution of acute GvHD after administration of Rimiducid
BPX-501 Safety Profile	24 months	Characterize the safety profile of BPX-501 including evaluation of high grade toxicity and infectious complications
Pharmacokinetics of Rimiducid	24 months	Pharmacokinetic disposition of Rimiducid

Trial Locations

Locations (8): Oregon Health & Science University
🇺🇸
Portland, Oregon, United States
Fred Hutchinson Cancer Research Center
🇺🇸
Seattle, Washington, United States
Emory University Winship Cancer Institute
🇺🇸
Atlanta, Georgia, United States
University Hospitals of Cleveland
🇺🇸
Cleveland, Ohio, United States
Baylor Sammons Cancer Center
🇺🇸
Dallas, Texas, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
UT Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States