IRB Study Number 24-423
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
Phase 1 Part 1:
• To assess the safety and maximum tolerated dose (MTD) of P-BCMA-ALLO1 based on dose limiting toxicities (DLT).
Phase 1 Part 2:
• To assess the safety and tolerability of P-BCMA-ALLO1 when administered as a fixed dose of cells.
Phase 1b:
• To evaluate the anti-myeloma effect of cell dose and study arm to guide selection of Recommended Phase 2 Dose (RP2D)
Secondary Objectives
Phase 1 Part 1/Phase 1 Part 2/Phase 1b
• To evaluate the safety of P-BCMA-ALLO1
• To evaluate the anti-myeloma effect of P-BCMA-ALLO1
Inclusion Criteria
Must have signed written, informed consent.
Males or females, ≥ 18 years of age.
Must have a confirmed diagnosis of active MM as defined by the IMWG criteria at initial diagnosis (Kumar 2016, Rajkumar 2014).
Must have measurable MM as defined by at least 1 of the following criteria:
• Serum M-protein ≥ 1.0 g/dL (10 g/L)
• Urine M-protein ≥ 200 mg/24 h
• Serum free light chain (FLC) assay: involved FLC level greater or equal to 10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal
• Bone marrow plasma cells > 30% of total bone marrow cells
- Must have relapsed / refractory MM as defined by the following:
• Received at least 3 prior lines of therapy, which must have contained a proteasome inhibitor, IMiD, and anti-CD38 therapy OR
• Received at least 2 prior lines of therapy with disease refractory to all 3 classes of agents: proteasome inhibitor, IMiD and anti-CD38 therapy, with refractoriness defined as progression on or within 60 days of their last treatment in each line.
Must be willing to practice birth control from the time of Screening and throughout the first year of the study after P-BCMA-ALLO1 administration (both males and females of childbearing potential).
Must have a negative serum pregnancy test at Screening and a negative urine pregnancy test within 3 days prior to initiating the LD therapy regimen (females of childbearing potential).
Must be at least 90 days since autologous stem cell transplant, if performed.
Must have adequate vital organ function, defined as follows:
• Serum creatinine ≤ 1.5 mg/dL and estimated creatinine clearance ≥ 30 mL/min as calculated using the Cockcroft-Gault formula and not dialysis-dependent.
• Adequate hematologic function, including:
o Absolute neutrophil count ≥ 1000/μL in the absence of growth factor support (granulocyte colony stimulating factor [G-CSF] within 7 days or peg-G-CSF within 14 days prior to P-BCMA-ALLO1 administration)
o Platelet count ≥ 50,000/μL in the absence of transfusion support (platelet transfusion within 7 days prior to P-BCMA-ALLO1 administration)
o Hemoglobin ≥ 8 g/dL in the absence of transfusion support (red blood cell [RBC] or whole blood within 7 days prior to P-BCMA-ALLO1 administration)
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) ≤ 3 × the upper limit of normal (ULN) and total bilirubin ≤ 2.0 mg/dL (unless there is a molecularly documented history of Gilbert’s syndrome).
• Left ventricular ejection fraction (LVEF) ≥ 45%. LVEF assessment must have been performed within 4 weeks of enrollment.
Must have recovered from toxicities due to prior therapies, with the exception of peripheral neuropathy, to Grade ≤ 2 according to the NCI CTCAE v5.0 criteria or to the subject’s prior baseline.
Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Exclusion Criteria
Is pregnant or lactating.
Has inadequate venous access.
Has active hemolytic anemia, plasma cell leukemia, Waldenstrom’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), disseminated intravascular coagulation, leukostasis, or amyloidosis.
Has an active second malignancy (not disease-free for at least 5 years) in addition to MM, excluding low-risk neoplasms such as non-metastatic basal cell or squamous cell skin carcinoma.
Has active autoimmune disease, such as psoriasis, multiple sclerosis, lupus, rheumatoid arthritis, etc. (the medical monitor will determine if a disease is active and autoimmune).
Has a history of significant CNS disease, such as stroke, epilepsy, etc. (the medical monitor will determine if significant).
Has an active systemic infection (e.g., causing fevers or requiring antimicrobial treatment).
Has a history of hepatitis B, hepatitis C virus, human immunodeficiency virus (HIV), or human T-lymphotropic virus (HTLV) infection, or any immunodeficiency syndrome. Subjects with a history of treated hepatitis C can be enrolled if negative by hepatitis C PCR on multiple occasions and with medical monitor approval.
Is positive for cytomegalovirus (CMV) by PCR, CMV immunoglobulin M (IgM) antibody, or Coronavirus disease 2019 (COVID-19) by PCR.
Has New York Heart Association (NYHA) Class III or IV heart failure, unstable angina, or a history of myocardial infarction or significant arrhythmia (e.g., atrial fibrillation, sustained [> 30 seconds] ventricular tachyarrhythmias, etc.).
Has any psychiatric or medical disorder (e.g., cardiovascular, endocrine, renal, gastrointestinal, genitourinary, immunodeficiency or pulmonary disorder not otherwise specified) that would, in the opinion of the investigator or medical monitor, preclude safe participation in and/or adherence to the protocol (including medical conditions or laboratory findings that indicate a significant probability of not qualifying for or being unable to undergo, conditioning LD therapy and/or CAR-T cell administration).
Has received prior allogeneic cellular therapy or gene therapy. Subject may have received autologous CAR-T therapy or stem cells in association with an anti-myeloma treatment. Must be at least 90 days from autologous stem cell transplant or autologous CAR-T therapy, if performed. Prior P-BCMA-ALLO1 allowed for subjects approved by medical monitor for retreatment as part of P-BCMA-ALLO1-001 study.
Has received anti-cancer medications within 2 weeks of the time of initiating conditioning LD therapy.
Has received monoclonal antibody therapy within 4 weeks of initiating conditioning LD therapy.
Has received immunosuppressive medications within 2 weeks of the time of administration of P-BCMA-ALLO1, and/or expected to require them while on study (the medical monitor will determine if a medication is considered immunosuppressive).
Has received systemic corticosteroid therapy ≥ 5 mg/day of prednisone or equivalent dose of another corticosteroid within 1 week or 5 half-lives (whichever is shorter) of the administration of P-BCMA-ALLO1 or is expected to require it during the course of the study. (Topical and inhaled steroids are permitted. Systemic corticosteroids are contraindicated after receiving P-BCMA-ALLO1 cells outside of study-specific guidance).
Has CNS metastases or symptomatic CNS involvement (including leptomeningeal carcinomatosis, cranial neuropathies or mass lesions and spinal cord compression) of their myeloma.
Has a history of severe immediate hypersensitivity reaction to any of the agents used in this study.
Has a history of having undergone allogeneic stem cell transplantation, or any other allogeneic or xenogeneic transplant, or has undergone autologous transplantation within 90 days. Subjects with a prior history of allogeneic stem cell transplant for multiple myeloma may be enrolled if they are not on immunosuppressive medications and with medical monitor approval.
Rituximab arms (Arms R, RS, RP1, RP1.5, and RP2) Only:
a. Has received a live vaccine within the last 28 days of the first administration of rituximab.
b. Has known anaphylaxis or immunoglobulin E (IgE) mediated hypersensitivity to murine proteins or sensitivity to rituximab or any component of rituximab.
c. Has experienced any severe toxicity with rituximab.
- Has received radiation within 1 week of initiating conditioning LD therapy.
Additional Phase 1b exclusion criterion:
- For BCMA naïve cohorts, prior exposure to BCMA targeted therapies.
