Clinical Trials /

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

NCT02743611

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Refractory Anemia with Excess Blasts-1
  • Refractory Anemia with Excess Blasts-2
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dose Finding Study Evaluating Safety in Patients With Relapsed AML, Previously Treated MDS or Metastatic Uveal Melanoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: BP-011
  • NCT ID: NCT02743611

Conditions

  • Acute Myeloid Leukemia
  • Myelodysplastic Syndrome
  • Uveal Melanoma

Interventions

DrugSynonymsArms
BPX-701BPX-701 and Rimiducid (AP1903)
RimiducidAP1903BPX-701 and Rimiducid (AP1903)

Purpose

This study will evaluate patients with relapsed AML, previously treated MDS or metastatic uveal melanoma who will have autologous immune cells, called T cells, collected via apheresis. The T cells will be reinfused according to a dose-finding schedule after the patient has been identified as having adequate lymphopenia to provide for homeostatic expansion of the adoptively transferred, engineered T cell therapeutic product. As a safety measure, these T cells have been programmed with a self-destruct switch to remove gene-modified T cells in response to uncontrollable treatment-emergent toxicity.

Detailed Description

      A Phase 1/2, multicenter, open-label, non-randomized study of the feasibility, safety, and
      clinical activity of BPX-701, a genetically modified autologous T cell product incorporating
      an HLA-A2.01-restricted PRAME-directed T cell receptor (TCR) and an inducible caspase-9
      (iCasp9) safety switch, when administered to subjects with relapsed AML (Arm 1), previously
      treated MDS (Arm 1) or metastatic uveal melanoma (Arm 2). Arms 1 and 2 will be conducted in
      parallel. For each Arm, the study will be comprised of multiple parts, beginning initially
      with Part 1 (Phase 1).

      Part 1 is a Cell Dose Escalation phase to identify the recommended BPX-701 cell dose for
      expansion (RDE) using a 3+3 dose escalation Parts 2 and 3 comprise a Dose Expansion phase to
      further assess safety, pharmacodynamics (including BPX-701 T cell persistence and response to
      rimiducid as applicable), and clinical activity of BPX-701 T cells administered at the RDE.

      The opening of Part 3 is dependent upon antitumor activity observed in Part 2. Within each
      Arm, subjects will be monitored for clinical activity to enable early stopping for futility
      if sufficient antitumor activity is not demonstrated. For each Arm, the maximum planned
      enrollment in dose expansion is 40 subjects (Parts 2 and 3 combined).
    

Trial Arms

NameTypeDescriptionInterventions
BPX-701 and Rimiducid (AP1903)ExperimentalBPX-701: autologous T cells genetically modified to express αβ T cell receptor reacting with PRAME peptide/human leukocyte antigen (HLA)-A2.01 and containing an inducible safety switch Rimiducid (AP1903): administered to induce apoptosis of the BPX-701 T cells in the event of toxicity
  • Rimiducid

Eligibility Criteria

        Inclusion Criteria

          1. Each subject (or their legally acceptable representative) must sign and date an
             informed consent form approved by the institutional review board/ethics committee, as
             appropriate, indicating that he/she understands the purpose of and procedures required
             for the study and are willing to comply. Consent is to be obtained prior to the
             performance of any study-specific procedures or tests that are not part of the
             standard of care for the subject's disease.

          2. Arm 1:

               -  MDS not responding to hypomethylation therapy or recurrence after initial
                  response; or,

               -  AML with disease relapse following first complete remission with intermediate or
                  adverse genetics according to the ELN criteria (Dohner 2017) - Subjects with a
                  prior treatment history of stem cell transplant must be >100 days post-transplant
                  with no evidence of active GvHD and not requiring systemic immunomodulatory or
                  immunosuppressive therapy defined as >10mg prednisone or equivalent per day and
                  active use of a calcineurin inhibitor

             Arm 2:

               -  Histologically or cytologically confirmed diagnosis of metastatic uveal melanoma

               -  Measurable disease (at least one target lesion) per RECIST v1.1 (Eisenhauer 2009)

               -  Adequate bone marrow function defined as:

                    -  Absolute neutrophil count ≥1,000/µL

                    -  Platelets ≥75,000/µL

          3. HLA-A2.01 positive by local assessment

          4. Documented positive myeloid blast or tumor expression of PRAME as determined by
             central testing of an available, representative bone marrow aspirate (fresh sample) or
             tissue specimen (formalin-fixed paraffin-embedded tissue, either from an archived
             sample or fresh biopsy) for Arm 1 and Arm 2, respectively

          5. Absolute lymphocyte count ≥200/μL

          6. Age ≥18 years

          7. Life expectancy >12 weeks

          8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

          9. Subjects must have adequate venous access for apheresis or agree to use of a central
             line for apheresis collection

         10. Subject has adequate organ function:

               -  Cardiac: Left ventricular ejection fraction at rest must be ≥lower limit of
                  institutional normal

               -  Coagulation: International normalized ratio ≤1.5

               -  Hepatic:

               -  Direct bilirubin ≤2x upper limit of normal (ULN), or ≤3x if due to Gilbert's
                  disease

               -  Aspartate aminotransferase and alanine aminotransferase ≤3 x ULN, or ≤5 x ULN if
                  liver metastases are present

               -  Renal: Creatinine ≤1.5 x ULN

         11. Before planned BPX-701 T cell infusion, as well as during the study, a female subject
             must be either:

               -  Not of childbearing potential defined as:

                    1. Premenarchal,

                    2. Postmenopausal (>45 years of age with amenorrhea ≥12 months),

                    3. Permanently sterilized,

                    4. Otherwise incapable of pregnancy; or,

               -  Of childbearing potential and agrees to use 2 highly effective methods of birth
                  control for at least 12 months after lymphodepletion

        Exclusion Criteria

          1. Arm 1:

               -  Diagnosis of Acute Promyelocytic Leukemia

               -  Primary refractory AML

               -  Uncontrolled disseminated intravascular coagulation

               -  Symptomatic or untreated central nervous system involvement by malignant cells

               -  Peripheral blast count ≥20,000/μL

          2. Arm 2:

               -  Symptomatic, untreated or actively progressing central nervous system metastases.
                  Subjects with prior brain metastases treated at least 2 weeks prior to the
                  planned BPX-701 T cell infusion who are clinically stable and do not require
                  chronic corticosteroid treatment are allowed

               -  History of leptomeningeal disease

          3. Ongoing toxicities related to prior anticancer therapy that have not resolved to Grade
             ≤1. Current unresolved Grade ≥2 non-hematologic toxicity may be allowed following
             discussion with and approval by the sponsor

          4. Participation in any investigational drug study within 4 weeks prior to the planned
             BPX-701 T cell infusion

          5. Chemotherapy (excluding hydroxyurea), targeted therapy, or radiotherapy (excluding
             palliative radiation) within 2 weeks, hydroxyurea within 1 week, or immunotherapy
             within 4 weeks prior to BPX-701 T cell infusion, other than salvage/lymphodepletion
             chemotherapy

          6. Active autoimmune disease requiring immunosuppressive therapy. Subjects with vitiligo;
             type I diabetes; hypothyroidism, adrenal insufficiency, or hypophysitis only requiring
             hormone replacement; psoriasis not requiring systemic treatment or conditions not
             expected to recur; or history of Hashimoto's Thyroiditis on stable dose of thyroid
             hormone replacement therapy should not be excluded

          7. Impaired cardiac function or clinically significant cardiac disease, including any of
             the following:

               -  Symptomatic congestive heart failure requiring treatment;

               -  Clinically significant cardiac arrhythmia;

               -  Uncontrolled hypertension;

               -  Acute myocardial infarction or unstable angina pectoris within 3 months prior to
                  BPX-701 T cell infusion; or,

               -  Marked limitation of physical activity due to symptoms, or unable to carry on any
                  physical activity without discomfort (i.e., New York Heart Association Functional
                  Class III-IV)

          8. Major surgical procedure, other than for diagnosis, within 4 weeks prior to BPX-701 T
             cell infusion, or anticipation of the need for a major surgical procedure during the
             study

          9. Received a vaccine containing live virus within 4 weeks prior to the planned BPX-701 T
             cell infusion. Seasonal flu vaccines that do not contain live virus are permitted

         10. Treatment with systemic chronic steroid therapy (prednisone >10mg daily or equivalent)
             within 7 days or 7 half-lives, whichever is shorter, prior to the planned apheresis
             date (See Appendix 6 on half-lives of common corticosteroids). Local steroid therapies
             (e.g., otic, ophthalmic, intra-articular or inhaled medications) are acceptable

         11. Uncontrolled intercurrent illness including but not limited to poorly controlled
             hypertension or diabetes, or any medical condition determined by the investigator to
             be a risk for enrolling on the protocol

         12. Uncontrolled infection requiring systemic therapy. Prior oral or IV antibiotics
             antifungals or antiviral medications must be discontinued at least 2 weeks prior to
             BPX-701 T cell infusion except for use of prophylactic antimicrobial agents

         13. Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a
             positive hepatitis B surface antigen (HBsAg) test during Screening. Subjects with a
             past or resolved HBV infection, defined as having a negative HBsAg test and a positive
             total hepatitis B core antibody (HBcAb) test at screening are eligible for the study
             if HBV DNA test is negative. If a patient has a negative HBsAg test and a positive
             total HBcAb test at screening, an HBV DNA test should be performed

         14. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody
             test followed by a positive HCV RNA test during Screening. The HCV RNA test will be
             performed only for patients who have a positive HCV test

         15. History of human immunodeficiency virus (HIV), or positive HIV test during Screening
             (unless not permitted by local regulations)

         16. Subject is a woman of child-bearing potential is pregnant (positive serum β-human
             chorionic gonadotropin test at Baseline), planning to become pregnant within 12 months
             after lymphodepletion or is breastfeeding

         17. Subject is a man who plans to father a child within 12 months after lymphodepletion

         18. Known bovine product allergy

         19. Malignant disease other than that being treated in this study. Exceptions to this
             exclusion are:

               -  Malignancies that were treated curatively and have not recurred within 2 years
                  prior to Screening

               -  Completely resected basal cell and squamous cell skin cancers

               -  Any malignancy considered to be indolent and that has never required therapy
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) and/or recommended expansion dose of BPX-701 measured by dose limiting toxicities (DLTs)
Time Frame:30 days post-treatment infusion
Safety Issue:
Description:To assess the safety and tolerability as defined by dose-limiting toxicities (DLTs) of BPX-701 T cells administered to patients expressing the HLA- A2.01 allele with relapsed AML, MDS or metastatic uveal melanoma

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Bellicum Pharmaceuticals

Trial Keywords

  • BPX-701
  • AP1903
  • Rimiducid
  • AML
  • MDS
  • Relapsed AML
  • uveal melanoma

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