Safety & Activity of Controllable PRAME-TCR Therapy in Previously Treated AML/MDS or Metastatic Uveal Melanoma

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and activity of BPX-701 in participants with relapsed AML, previously treated MDS, or metastatic uveal melanoma expressing high levels of PReferentially expressed Antigen in MElanoma (PRAME). Participants' T cells are modified to recognize and target the PRAME tumor marker on cancer cells.

Detailed Description
-----------------
The goal of this study is to characterize the safety, feasibility, and clinical activity of BPX-701, a genetically modified autologous T cell product incorporating an HLA-A2-restricted PRAME-directed TCR and a rimiducid-inducible safety switch, when administered to subjects with relapsed AML, previously treated MDS, or metastatic uveal melanoma. The study will be comprised of multiple parts: Part 1 (Phase 1): Cell dose escalation to identify the maximum dose of BPX-701 T cells (escalating doses from 1.25 x 10E6 cells/kg up to 5.0 x 10E6 cells/kg to be explored) Parts 2 and 3 (Phase 2): Dose expansion to assess the safety, pharmacodynamics (including BPX-701 T cell persistence and response to rimiducid as applicable), and clinical activity at the recommended dose identified in Part 1 During Parts 1, 2, or 3, rimiducid may be administered following BPX-701 T cell infusion in response to uncontrollable, treatment-emergent toxicity

Official Title
-----------------
A Phase 1/2 Dose-Finding Study to Evaluate the Safety, Feasibility, and Activity of BPX-701, a Controllable PRAME T-Cell Receptor Therapy, in HLA-A2+ Subjects With AML, Previously Treated MDS, or Metastatic Uveal Melanoma

Conditions
-----------------
Acute Myeloid Leukemia, Myelodysplastic Syndrome, Uveal Melanoma

Intervention / Treatment
-----------------
* Biological: BPX-701
* Drug: Rimiducid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Signed informed consent Participants in Arm 1: MDS not responding to hypomethylation therapy or recurrence after initial response AML with disease relapse following first complete remission with intermediate or adverse genetics according to the European Leukemia Net criteria. AML participants with prior stem cell transplant must be >100 days post-transplant with no evidence of active graft-versus-host disease and not requiring systemic immunomodulatory or immunosuppressive therapy (>10mg prednisone daily or treatment with a calcineurin inhibitor) Participants in Arm 2: Metastatic uveal melanoma with a radiographically measurable tumor, absolute neutrophil count >/=1000/uL, and platelets >/=75,000/uL HLA-A2.01 positive by local testing Tumor with positive PRAME expression by central testing Age >/= 18 years Participant has a life expectancy >12 weeks and is able to carry out daily life activities without difficulty (Eastern Cooperative Oncology Group performance status 0 or 1). Participant has adequate venous access for apheresis or agrees to use of a central line for blood collection. Participant does not have significant side effects from previous anticancer treatment. Adequate organ function including absolute lymphocyte count >/=200/uL. Sexually active participants must use medically acceptable methods of contraception for at least 1 year after study treatment. Exclusion Criteria Participants with AML must not have: Acute promyelocytic leukemia, Primary refractory disease, Uncontrolled disseminated intravascular coagulation, Signs or symptoms of cancer cells in the brain or nervous system, Peripheral blast count >/=20,000/uL Participants with uveal melanoma must not have an untreated brain tumor Participant has a history of major surgery or treatment with other cancer therapy within 2-4 weeks (1 week for hydroxyurea) before study treatment. Participant has an active, autoimmune disease that requires immunosuppressive therapy. Exceptions are vitiligo, type I diabetes, certain cases of hypothyroidism and psoriasis, or Hashimoto's thyroiditis on a stable dose of thyroid replacement therapy History of clinically significant heart problems. Current severe, uncontrolled systemic disease including an ongoing, active infection requiring treatment with antibiotics within 2 weeks before study treatment. Participant is currently pregnant or breastfeeding. Participant requires chronic, systemic steroid therapy. Participant is positive for Hepatitis B, Hepatitis C, HIV, syphilis, West Nile virus, or Chagas disease. Participant has side effects from earlier cancer treatment that have not resolved

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 Does Escalation<br>Participants with relapsed AML or previously treated MDS will receive an intravenous infusion of BPX-701. Dose escalation of BPX-701 will continue until the recommended cell dose level is reached. Rimiducid may be administered in response to treatment-related toxicity. | Biological: BPX-701<br>* autologous T cells genetically modified to express the αβ TCR reacting with PRAME peptide/HLA-A2.01 (PRAME TCR) and an inducible safety switch<br>Drug: Rimiducid<br>* dimerizer infusion to activate the safety switch and induce apoptosis of the BPX-701 T cells in the event of toxicity<br>* Other names: AP1903;|
| Experimental: Arm 2 Dose Escalation<br>Participants with metastatic uveal melanoma will receive an intravenous infusion of BPX-701. Dose escalation of BPX-701 will continue until the recommended cell dose level is reached. Rimiducid may be administered in response to treatment-related toxicity. | Biological: BPX-701<br>* autologous T cells genetically modified to express the αβ TCR reacting with PRAME peptide/HLA-A2.01 (PRAME TCR) and an inducible safety switch<br>Drug: Rimiducid<br>* dimerizer infusion to activate the safety switch and induce apoptosis of the BPX-701 T cells in the event of toxicity<br>* Other names: AP1903;|
| Experimental: Arm 1 Part 2 Dose Expansion<br>Participants with relapsed AML or previously treated MDS will receive an intravenous infusion of BPX-701 at the recommended cell dose level. Rimiducid may be administered in response to treatment-related toxicity. | Biological: BPX-701<br>* autologous T cells genetically modified to express the αβ TCR reacting with PRAME peptide/HLA-A2.01 (PRAME TCR) and an inducible safety switch<br>Drug: Rimiducid<br>* dimerizer infusion to activate the safety switch and induce apoptosis of the BPX-701 T cells in the event of toxicity<br>* Other names: AP1903;|
| Experimental: Arm 2 Part 2 Dose Expansion<br>Participants with metastatic uveal melanoma will receive an intravenous infusion of BPX-701 at the recommended cell dose level. Rimiducid may be administered in response to treatment-related toxicity. | Biological: BPX-701<br>* autologous T cells genetically modified to express the αβ TCR reacting with PRAME peptide/HLA-A2.01 (PRAME TCR) and an inducible safety switch<br>Drug: Rimiducid<br>* dimerizer infusion to activate the safety switch and induce apoptosis of the BPX-701 T cells in the event of toxicity<br>* Other names: AP1903;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 Arm 1: Dose-limiting Toxicity | Incidence of dose limiting-toxicity (DLT) | 28 days after BPX-701 infusion | 
| Part 1 Arm 1: Treatment-emergent Adverse Events (AEs) and Serious AEs (SAEs) | Number of participants with AEs and SAEs assessed for severity using CTCAE | 15 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
BPX-701, AP1903, rimiducid, AML, MDS, relapsed AML, uveal melanoma, PRAME