A Phase Ib Study of TGFbi NK Cells and Isatuximab for Myeloma Relapsed/Refractory to BCMA Targeting Therapy
This phase I trial tests the side effects and best dose of TGFbi natural killer (NK) cells (TiNK) when given together with isatuximab for the treatment of patients with multiple myeloma that has come back after a period of improvement (relapsed) or that has not responded to treatment (refractory). NK cells are a type of white blood cell that are known to spontaneously attack cancer cells. TiNK are NK cells made in a laboratory to have a higher response to tumor cells. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as isatuximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Patients also receive standard treatment (cyclophosphamide and dexamethasone) on this trial. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the body's immune response. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Giving TiNK and isatuximab with standard treatment may be a safe and effective treatment for relapsed or refractory multiple myeloma.
• Patients 18 years of age or older with evidence of relapsed or refractory disease as defined by IMWG criteria and measurable disease as defined by any of the following:
‣ Serum M-protein ≥ 0.5 g/dl
⁃ Urine monoclonal protein ≥ 200 mg/24h
⁃ Involved free light chain (FLC) level ≥ 10mg/dl (≥ 100mg/l) and an abnormal serum free light chain ratio (\< 0.26, or \> 1.65)
• Patients must have had at least 3 prior lines of therapy including lenalidomide, proteasome inhibitor (PI), anti-CD38 or anti-SLAMF7 directed antibody, and BCMA-targeting therapy.
‣ Prior daratumumab or isatuximab is permitted but not in the immediate line prior to study entry
⁃ Prior autologous hematopoietic cell transplant is permitted
⁃ Prior allogeneic transplant is excluded
• Refractory (progressed on or within 60 days of treatment) to their last treatment
‣ If chimeric antigen receptor t cell (CAR-T) therapy was the immediately prior therapy, then the definition of refractory disease will not be limited to within 60 days
⁃ Patients must be off last treatment for at least 2 weeks by the beginning of treatment on this protocol
• Hemoglobin ≥ 7g/dL
• Absolute neutrophil count (ANC) ≥ 1000/µL
• Platelets ≥ 70,000/µL
‣ If plasma cell percentage on bone marrow biopsy core is \> 30%, platelet requirement will be adjusted to 50,000/µl
• Total bilirubin \< 2 mg/dL
• Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT)/ alkaline phosphatase \< 2.5 X the upper limit of normal (ULN)
• Calculated creatinine clearance of ≥ 30ml/min using Modification of Diet in Renal Disease (MDRD) formula
• Left ventricular ejection fraction ≥ 30%; baseline echocardiography (ECHO) is not required if ECHO was done within the preceding one year and patients do not have new signs/symptoms suggestive of heart failure
• No uncontrolled arrhythmias
• No New York Heart Association class III-IV heart failure
• 12-lead electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec
• Patients must provide informed consent
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of ≤ 2
• Fertility requirements:
‣ Women of child bearing potential (WOCBP) must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device \[IUD\], hormonal \[birth control pills, injections, hormonal patches, vaginal rings or implants\] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing and continue to 6 months after study treatment ending. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy.
⁃ Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy
⁃ A negative pregnancy test will be required for all WOCBP within 24 hours before starting treatment drugs
⁃ Breast feeding is not permitted
⁃ Male patients must agree to use an adequate method of contraception (latex or synthetic condom) for the duration of the study and up to 6 months after study treatment ending
⁃ Criteria also applies to azoospermic males
⁃ Males should refrain from sperm donation during this time and continue for 6 months after study treatment ending