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

Lymphoma Clinical Trial

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01744223
• Other study ID #: BP-001
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: March 2013
• Est. completion date: October 2032

Study information

• Verified date: July 2022
• Source: Bellicum Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 36
• Est. completion date: October 2032
• Est. primary completion date: October 9, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Acute Myelogenous Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Lymphoma
• Myelodysplastic Syndromes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Biological:
• BPX-501 dose 1
Subjects will receive 2x10E5 donor T cells/kg genetically modified with BPZ-1001 retroviral vector containing the iCasp suicide gene (BPX-501) after stem cell transplant.

Drug:
• Rimiducid
Dimerizer drug administered by intravenous infusion in those subjects who develop GVHD after infusion of BPX-501 cells.

Biological:
• BPX-501 dose 2
Subjects will receive 5x10E5 donor T cells/kg genetically modified with BPZ-1001 retroviral vector containing the iCasp suicide gene (BPX-501) after stem cell transplant.
• BPX-501 dose 3
Subjects will receive 1x10E6 donor T cells/kg genetically modified with BPZ-1001 retroviral vector containing the iCasp suicide gene (BPX-501) after stem cell transplant.
• BPX-501 dose 4
Subjects will receive 3x10E6 donor T cells/kg genetically modified with BPZ-1001 retroviral vector containing the iCasp suicide gene (BPX-501) after stem cell transplant.

Procedure:
• SCT
all subjects will receive an alpha beta depleted donor transplant as part of treatment

Locations

Country	Name	City	State
United States	Emory University Winship Cancer Institute	Atlanta	Georgia
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	Baylor Sammons Cancer Center	Dallas	Texas
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Oregon Health & Science University	Portland	Oregon
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Bellicum Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	BPX-501 Safety	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)	24 months
Primary	Rimiducid Safety	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	24 months
Primary	MTD	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.	24 months
Primary	Immune Reconstitution	To assess immune reconstitution for each dose cohort	24 months
Secondary	Efficacy- NRM	Non-Relapse Mortality (NRM)	100, 180 days and 1 year
Secondary	Efficacy- DFS	Disease-free survival	24 months
Secondary	Efficacy- TRM	Transplant related mortality (TRM)	24 months
Secondary	Efficacy- Relapse	Incidence of Relapse	24 months
Secondary	Incidence of engraftment	Evaluation of neutrophil and platelet engraftment, kinetics of donor cell engraftment and graft failure	24 months
Secondary	GvHD	Incidence and severity of acute and chronic GvHD	24 months
Secondary	GvHD post Rimiducid Administration	Time to resolution of acute GvHD after administration of Rimiducid	24 months
Secondary	BPX-501 Safety Profile	Characterize the safety profile of BPX-501 including evaluation of high grade toxicity and infectious complications	24 months
Secondary	Pharmacokinetics of Rimiducid	Pharmacokinetic disposition of Rimiducid	24 months