Relapsed Refractory Multiple Myeloma (RRMM)
Conditions
Keywords
Relapsed Refractory Multiple Myeloma (RRMM), Prior therapy, Triple class exposed RRMM
Brief summary
This is a phase 1 study to find the recommended dose and schedule of mezigdomide and talquetamab in relapsed and refractory multiple myeloma (RRMM), and to test the effects of the drugs on cancer. Cohort A will receive talquetamab + dexamethasone, then mezigdomide + talquetamab,+ dexamethasone. After Cohort A, Cohort B will evaluate mezigdomide + dexamethasone followed by step-up dosing of talquetamab (mezigdomide + talquetamab,+ dexamethasone).
Detailed description
This phase 1 open-label study will determine the recommended dose and schedule of mezigdomide and talquetamab in triple class exposed relapsed and refractory multiple myeloma. This study aims to enroll 25 participants including Cohorts A and B, and will follow a dose escalation schedule. Treatment is until progression or withdrawal of consent. The U.S. Food and Drug Administration (FDA) has not approved the combination of drugs mezigdomide, talquetamab, and dexamethasone as treatment for any disease. The FDA has not approved mezigdomide as a treatment for any disease. The FDA has approved talquetamab for the treatment of relapsed refractory multiple myeloma in patients who have already received 4 prior lines of therapy. Dexamethasone is approved by the FDA to treat multiple diseases including multiple myeloma.
Interventions
DRUGTalquetamab
Talquetamab is injected under the skin (subcutaneously injected) by trained medical staff. During first cycle of talquetamab, the dose of talquetamab will increase until the goal dose (treatment dose) is reached (pre-determined dose escalation).
DRUGMezigdomide
Administered orally once per day (days 1-21 of applicable 28-day cycles; Days 1-7 of the 7-day Cohort B pre-phase cycle).
DRUGDexamethasone
Administered orally once per day, at the schedule outlined in the Arm Descriptions.
Sponsors
Celgene Corporation
Janssen Research and Development LLC
Massachusetts General Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant has given voluntary signed written informed consent before performance of any study-related procedure that is not part of normal medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to their future medical care. * Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (see Appendix). * Age ≥ 18 years * Measurable disease of multiple myeloma as defined by at least one of the following: * Serum monoclonal protein ≥ 0.5 g/dL. Patients with IgD disease and lower amounts of monoclonal protein may be permitted to enroll with PI approval * ≥ 200 mg of monoclonal protein in the urine on 24-hour urine protein electrophoresis * Serum free light chain (FLC) ≥ 100 mg/L (10 mg/dL) and abnormal serum free light chain ratio * Previously treated relapsed and refractory multiple myeloma: * Patients must have received at least three prior lines of therapy; * Prior therapy including an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody (either in separate regimens or within the same regimen); and * Disease progression on, or within 60 days of completion of last therapy. * ANC ≥ 1000/μL. G-CSF is not permitted within 14 days of screening. * Platelet count ≥ 50,000/µL. Platelet transfusion and thrombopoietin receptor agonists are not permitted within 7 days of screening. * Hemoglobin ≥ 8 g/dL. Red blood cell transfusions are permitted to meet eligibility criteria. * Calculated creatinine clearance of ≥ 30 mL/min by Modified Diet in Renal Disease (MDRD) formula or Cockcroft-Gault formula * Serum bilirubin values \< 1.5 x ULN. Isolated bilirubin x 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%. Patients with elevated bilirubin due to Gilbert's syndrome may be permitted with PI approval (e.g. total bilirubin \<3 mg/dL and normal direct bilirubin); and * Serum aspartate transaminase (ALT) and aspartate transaminase (AST) values \< 2.5 × the upper limit of normal (ULN) of the institutional laboratory reference range. * Must be able to comply with thromboembolism prophylaxis with e.g. acetylsalicylic acid (ASA), apixaban, rivaroxaban, lower molecular weight heparin, or equivalent. * Females of childbearing potential (FCBP) must: * Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. The subject must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact. * Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use and be able to comply with two reliable forms of contraception as defined by the Pregnancy Prevention Plan. * Male subjects must follow the mezigdomide Pregnancy Prevention Plan (see Appendix). * Agree to follow the lifestyle considerations in Section 3.4 regarding blood donation, hospitalization and being in proximity to the hospital, and driving or operating heavy machinery.
Exclusion criteria
* Participants who have had myeloma therapy or investigational drug within 2 weeks prior to start of treatment or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. * Participants who are receiving any investigational agents. * Prior therapy with mezigdomide or iberdomide. * Prior therapy with anti-GPRC5D therapy (e.g. talquetamab). * Prior therapy with bispecific antibody therapy within three months * Prior therapy with gene-modified adoptive cell therapy (e.g. CAR T-cells, NK cells) within three months * Plasmapheresis within seven days prior to start of study treatment. * Primary refractory disease. * Concomitant high dose corticosteroids. Low dose corticosteroids (maximum dose prednisone 10 mg/day or equivalent) are permitted if given for disorders other than myeloma, e.g. adrenal insufficiency, rheumatoid arthritis, etc.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Dose | Day 1 of treatment through 30 days post last-dose (treatment is until disease progression or withdrawal; estimated to be 1 year from Day 1 of treatment) | To determine the recommended dose and schedule of mezigdomide and talquetamab in triple class exposed, relapsed and refractory multiple myeloma (RRMM), the dose level where 2 of 6 participants experience a DLT is considered the maximum tolerated dose. The dose level below this will be considered a recommended phase 2 dose. Or if dose level 2 is reached (mezigdomide 1 mg po for 21 out of 28 days) and there are ≤1 DLTs out of 6 participants, then dose level 2 will be considered the recommended phase 2 dose. Data from the secondary outcomes (frequency of adverse events, serious adverse events, and dose-limiting toxicities) will be used for this outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of serious adverse events | Day 1 of treatment through 30 days post last-dose (treatment is until disease progression or withdrawal; estimated to be 1 year from Day 1 of treatment) | Assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, the frequency of serious AEs will be tabulated by cohort and dose. |
| Frequency of dose-limiting toxicities (DLT) | Day 1 of treatment through 30 days post last-dose (treatment is until disease progression or withdrawal; estimated to be 1 year from Day 1 of treatment) | Unacceptable toxicity will be defined as grade 3-4 CRS, grade 3-4 ICANS, and grade 4, treatment-related, non-hematologic adverse events. Assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 when applicable. The frequency and type of DLTs will be tabulated by cohort and dose. |
| Frequency of adverse events | Day 1 of treatment through 30 days post last-dose (treatment is until disease progression or withdrawal; estimated to be 1 year from Day 1 of treatment) | Assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, the frequency of AEs will be tabulated by cohort and dose. |
| Progression Free Survival (PFS) | Day 1 of treatment through 2 years post last-dose (estimated total time to be 3 years; treatment is until disease progression or withdrawal) | Progression-free survival (PFS) is defined as the time from start of treatment to disease progression or death from any cause. Patients who have not progressed or died are censored at the date last known progression-free. Response will be according to IMWG criteria. PFS will be determined from first dose of study drug, according to Kaplan-Meier methodology. |
| Overall Survival (OS) | Day 1 of treatment through 2 years post last-dose (estimated total time to be 3 years; treatment is until disease progression or withdrawal) | Overall survival (OS) is defined as the time from start of treatment to death due to any cause or censored at date last known alive. Response will be according to IMWG criteria. OS will be determined from first dose of study drug, according to Kaplan-Meier methodology. |
| Overall response rate (ORR) | Day 1 of treatment through 2 years post last-dose (estimated total time to be 3 years; treatment is until disease progression or withdrawal) | Response rate will be according to IMWG criteria. Overall response rate is rate of patients achieving partial response or better. |
Countries
United States
Contacts
Primary ContactAndrew J. Yee, MD
Outcome results
None listed