A Phase 1/2, Open-Label, Dose Escalation and Confirmation Study of CAR-BCMA, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against BCMA in Subjects With Multiple Myeloma
This is an open label, abbreviated (3+3) dose escalation study in subjects with RRMM, followed by an extension phase at the selected safe dose. The dose escalation stage will involve recruitment of 3 RRMM patients for 'low' dose (6 x 106 CAR-T cells/kg) CAR-T therapy. After 14 days of follow-up for each of the 3 subjects, the DSC will determine whether the next subject can be recruited. After 14 days follow-up for the 3rd subject, DSC will review data for the 3rd subject and consider the data for the first 3 subjects. In the absence of dose limiting toxicities (DLTs), the DSC may recommend recruitment of 3 subjects to be treated with the 'high' dose (9x106 CAR-T cells/kg) CAR-T therapy, with similar staggering. In case of DLTs in one of the 3 low dose subjects, the DSC may recommend to recruit an additional 3 low dose subjects (6 in total). If there are no additional DLTs in these 3 patients the low dose may be recommended by the DSC for the extension stage. However, further DLTs may prompt the DSC to recommend to modify the protocol, or to stop the study. In case of DLTs in one of the first 3 high dose subjects, the DSC may recommend to recruit an additional 3 high dose subjects.If there are no additional DLTs in these 3 patients, the high dose may be recommended by the DSC for the study extension stage. However, further DLTs may prompt the DSC to recommend continuation to the extension stage with the low dose, or to modify the protocol, or to stop the study. After completion of two months follow-up for the 6th subject in the low or high dose cohort (as applicable), and review of all the data for all subjects, following DSC recommendations, the Stage 2 extension phase of the study may recruit additional subjects, up to a maximum of 75 subjects for Stages 1 and 2, combined. DSC will review study data during the extension stage follow-up after 5 years to determine if additional safety follow-up is required.
• Bone marrow plasma cells must be at least 10% of total bone marrow cells based on a bone marrow biopsy/aspiration performed within 30 days of the start of protocol treatment.
• Documented diagnosis of multiple myeloma according to IMWG diagnostic criteria.
• Subjects must have measurable MM as defined by at least one of the criteria below.
• One or more of these abnormalities defines measurable disease
‣ Serum M-protein equal or greater than 0.4 g/dl (10 g/l).
‣ Urine M-protein equal or greater than 200 mg/24 h.
‣ Serum free light chain (FLC) assay: involved FLC level greater or equal to10 mg/dl (100 mg/l) provided serum FLC ratio is abnormal.
‣ A biopsy-proven plasmacytoma
• Patients must have received at least 3 prior treatment regimens for multiple myeloma.
• Greater than or equal to 18 years of age.
• Able to understand and sign the Informed Consent Document.
• Clinical performance status of ECOG 0-2
• Subjects of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen.
• Women of child bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.
⁃ Seronegative for HIV- 1, 2 antibody.
⁃ Seronegative for hepatitis B surface antigen (HBsAg) or HBsAg positive with negative PCR for HBV nucleotides in blood. (Treatment to prevent HBV reactivation is standard in any case of seropositivity for HBV).
⁃ Seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then subjects must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
⁃ Syphilis negative.
⁃ Absolute neutrophil count greater than or equal to 500/mm3 without the support of filgrastim or other growth factors.
⁃ Platelet count greater than or equal to 30,000/mm3 without transfusion support
⁃ Hemoglobin greater than 8.0 g/dl.
⁃ Less than 5% plasma cells in the peripheral blood leukocytes
⁃ At least 14 days must have elapsed since any prior systemic therapy at the time the subject starts the cyclophosphamide and fludarabine conditioning regimen, and subjects' toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
⁃ Systemic anti-myeloma therapy including systemic corticosteroid therapy of greater than 5 mg/day of prednisone or equivalent dose of another corticosteroid are not allowed within 2 weeks prior to the required leukapheresis, within 2 weeks prior to CAR T-cell infusion, and for 30 days after the CAR T cell infusion, unless required for treatment of toxicity or other medical need.
⁃ Cardiac ejection fraction greater than or equal to 45% by echocardiography within 6 weeks of the start of the treatment protocol.