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

Study Overview
=================
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.

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)

Conditions
-----------------
Myelodysplastic Syndromes, Acute Lymphoblastic Leukemia, Acute Myelogenous Leukemia, Lymphoma

Intervention / Treatment
-----------------
* Biological: BPX-501 dose 1
* Drug: Rimiducid
* Biological: BPX-501 dose 2
* Biological: BPX-501 dose 3
* Biological: BPX-501 dose 4
* Procedure: SCT


Participation Criteria
=================
Eligibility Criteria
-----------------
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: Cardiac: Left ventricular ejection fraction at rest must be ≥ 45% Hepatic: Bilirubin ≤ 2.5 mg/dL and ALT, AST and Alkaline Phosphatase < 5 x ULN Renal: Serum creatinine within normal range for age or creatinine clearance, or with a recommended GFR ≥ 50 mL/min/1.73m2 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SCT, BPX-501 dose 1, Rimiducid if needed<br>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. | Biological: BPX-501 dose 1<br>* 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.<br>* Other names: rivogenlecleucel;Drug: Rimiducid<br>* Dimerizer drug administered by intravenous infusion in those subjects who develop GVHD after infusion of BPX-501 cells.<br>* Other names: AP1903;Procedure: SCT<br>* all subjects will receive an alpha beta depleted donor transplant as part of treatment<br>|
| Experimental: SCT, BPX-501 dose 2, Rimiducid if needed<br>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. | Drug: Rimiducid<br>* Dimerizer drug administered by intravenous infusion in those subjects who develop GVHD after infusion of BPX-501 cells.<br>* Other names: AP1903;Biological: BPX-501 dose 2<br>* 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.<br>* Other names: rivogenlecleucel;Procedure: SCT<br>* all subjects will receive an alpha beta depleted donor transplant as part of treatment<br>|
| Experimental: SCT, BPX-501 dose 3, Rimiducid if needed<br>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. | Drug: Rimiducid<br>* Dimerizer drug administered by intravenous infusion in those subjects who develop GVHD after infusion of BPX-501 cells.<br>* Other names: AP1903;Biological: BPX-501 dose 3<br>* 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.<br>* Other names: rivogenlecleucel;Procedure: SCT<br>* all subjects will receive an alpha beta depleted donor transplant as part of treatment<br>|
| Experimental: SCT, BPX-501 dose 4, Rimiducid if needed<br>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. | Drug: Rimiducid<br>* Dimerizer drug administered by intravenous infusion in those subjects who develop GVHD after infusion of BPX-501 cells.<br>* Other names: AP1903;Biological: BPX-501 dose 4<br>* 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.<br>* Other names: rivogenlecleucel;Procedure: SCT<br>* all subjects will receive an alpha beta depleted donor transplant as part of treatment<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| Immune Reconstitution | To assess immune reconstitution for each dose cohort | 24 months | 

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
iCaspase9, iCasp9, Inducible Caspase, AP1903, Dimerizer drug, T depleted, Suicide gene, CD-34 selection, haplotransplantation, Graft versus host disease, Allogenic transplantation