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

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ClinicalTrials.gov Identifier: NCT02743611
Recruitment Status : Recruiting
First Posted : April 19, 2016
Last Update Posted : September 24, 2018
Sponsor:
Information provided by (Responsible Party):
Bellicum Pharmaceuticals

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Myelodysplastic Syndrome Uveal Melanoma Biological: BPX-701 Drug: Rimiducid Phase 1 Phase 2

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).


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 116 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description: Open Label
Primary Purpose: Treatment
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
Actual Study Start Date : April 14, 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: BPX-701 and Rimiducid (AP1903)

BPX-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

Biological: BPX-701
TCR modified T cells

Drug: Rimiducid
dimerizer that activates a molecular safety switch to induce apoptosis in BPX-701 TCR modified T cells
Other Name: AP1903




Primary Outcome Measures :
  1. 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 ]
    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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02743611


Contacts
Contact: Paul Wooddard, MD (832) 384-1100 pwoodard@bellicum.com

Locations
United States, Colorado
Colorado Blood Cancer Institute Not yet recruiting
Denver, Colorado, United States, 80218
Contact    720-754-4890      
Principal Investigator: Michael B Maris, MD         
United States, Michigan
Barbara Ann Karmanos Cancer Institute Not yet recruiting
Detroit, Michigan, United States, 48201
United States, Oregon
Oregon Health & Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Rachel Cook, MD    503-494-7386    coora@ohsu.edu   
United States, Tennessee
Tennessee Oncology Not yet recruiting
Nashville, Tennessee, United States, 37203
Contact: William Donnellan, MD1    615-329-7274    wdonnellan@tnonc.com   
United States, Texas
Texas Transplant Institute Not yet recruiting
San Antonio, Texas, United States, 78229
Contact: Paul Shaughnessy, MD    210-575-7278      
Sponsors and Collaborators
Bellicum Pharmaceuticals
Investigators
Principal Investigator: Rachel Cook, MD Oregon Health and Science University

Responsible Party: Bellicum Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02743611     History of Changes
Other Study ID Numbers: BP-011
First Posted: April 19, 2016    Key Record Dates
Last Update Posted: September 24, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Bellicum Pharmaceuticals:
BPX-701
AP1903
Rimiducid
AML
MDS
Relapsed AML
uveal melanoma

Additional relevant MeSH terms:
Melanoma
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Uveal Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Leukemia, Myeloid
Leukemia
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Eye Neoplasms
Neoplasms by Site
Eye Diseases
Uveal Diseases