Study of Matched Unrelated Donor T Cell Infusion for Hematologic Malignancies After Allo-HSCT

Study Overview
=================
Brief Summary
-----------------
This is a Phase I, multicenter, open-label, non-randomized study of matched unrelated donor BPX-501 T cell infusion in adult subjects with hematological malignancies presenting with recurrent disease minimal residual disease (MRD) post-allogeneic transplant.

Detailed Description
-----------------
Un-manipulated donor lymphocyte infusion (DLI) is used after stem cell transplantation to treat and prevent relapse, to prevent infections and to establish full donor chimerism. The addition of mature T cells which exhibit a broad repertoire of T cell immunity against viral antigens, as well as against cancer antigens, might provide a clinical benefit. However, an expected side effect of the presence of mature T cells is the potential occurrence of acute graft-versus-host disease (aGvHD). The use of a suicide gene switch which would trigger the initiation of the apoptosis of the alloreactive T cells by the infusion of a drug would represent the potential optimal strategy for restoring early immunity with a built in safety switch against GvHD side effects. Evidence has emerged that low-dose DLI followed by dose escalation can achieve higher clinical response rate with lower GvHD occurrence. Optimization of DLI dose and schedule as well as strategies of donor T-cell manipulation may lead to the consistent ability to separate GvHD from graft-versus-tumor (GvT) activity and improve the safety of DLI treatment. Our strategy is to infuse escalating doses of manipulated T cells (from the same donor who provided the original hematopoietic stem cell graft) in adults and children with recurrent or minimal residual disease (MRD) hematologic malignancies post-allogeneic transplant to accelerate immune reconstitution thus improving graft versus leukemic effect while reducing the severity of GvHD.

Official Title
-----------------
A Phase I Study of Matched Unrelated Donor BPX-501 T Cell Infusion for Adults With Recurrent or Minimal Residual Disease Hematologic Malignancies Post-Allogeneic Transplant

Conditions
-----------------
Leukemia, Myelodysplastic Syndromes, Lymphomas, Multiple Myeloma, Other High-risk Hematological Malignancies

Intervention / Treatment
-----------------
* Biological: rivogenlecleucel
* Drug: Rimiducid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects aged ≥ 18 yrs and ≤ 65 yrs; Clinical diagnosis of one of the following hematological malignancies: Leukemia Myelodysplastic Syndromes Lymphomas Multiple Myeloma Other high-risk hematological malignancy eligible for stem cell transplantation per institutional standard; Recurrent disease that presents ≥100 days after, or minimal residual disease (MRD) that presents ≥ 30 days following a hematopoietic stem cell transplant (HSCT) using a matched unrelated donor located through the National Marrow Donor Program (NMDP); Life expectancy >10 weeks; Signed donor and patient/guardian informed consent; A 8/8 genotypic identical match as determined by high resolution typing for the following genetic loci: human leukocyte antigen (HLA)-A, HLA-B, HLA-C and HLA-DRB1; Performance status: Karnofsky score > 50%; Subjects with adequate organ function as measured by: Bone marrow: > 25% donor T-cell chimerism post-transplant Absolute neutrophil count (ANC) >1 x 109/L Cardiac: left ventricular ejection fraction (LVEF) at rest ≥ 45% Pulmonary: forced expiratory volume (FEV) 1, forced vital capacity (FVC), diffusion capacity of lunch for carbon monoxide (DLCO) ≥ 50% predicted (corrected for hemoglobin) Hepatic: direct bilirubin ≤ 3x upper limit of normal (ULN), or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5x ULN Renal: creatinine ≤ 2x of ULN for age. Exclusion Criteria: ≥ Grade II acute GVHD or chronic extensive GVHD due to a previous allograft at the time of screening; Active central nervous system (CNS) involvement with malignant cells (≤ 2 months prior to consenting); Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings); the principal investigator is the final arbiter of this criterion; Positive HIV serology or viral RNA; Pregnancy (positive serum β human chorionic gonadotropin [HCG] test) or breast-feeding; Fertile men or women unwilling to use effective forms of birth control or abstinence for one year after transplantation; 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rivogenlecleucel & Rimiducid<br>All subjects will receive 3 courses of rivogenlecleucel (BPX-501 T cells) infusions at 30 day intervals with 2 escalating dose levels (DL). DL1 on Day 0 and DL2 on Days 30 and 60. Escalating doses of rimiducid (AP1903) (0.1 mg/kg and 0.4 mg/kg) will be investigated for the treatment of aGvHD after rivogenlecleucel infusion. | Biological: rivogenlecleucel<br>* T cells transduced with iCasp safety switch<br>* Other names: BPX-501;Drug: Rimiducid<br>* administered to treat GVHD<br>* Other names: AP1903;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Number of adverse events after study drug (BPX-501 and/or rimiducid) administration as a measure of safety | 30 days after last dose of study drug (BPX-501 and/or rimiducid) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
BPX-501, Rimiducid, AP1903, Hematological malignancies, Hematologic diseases, Leukemias and Myelodysplastic Syndromes, Lymphomas, Multiple myeloma