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Nivolumab, Ixazomib, Cyclophosphamide, and Dexamethasone for the Treatment of Relapsed and Refractory Multiple Myeloma

Trial Status: Active

This phase II trial studies the side effects of nivolumab, ixazomib, cyclophosphamide, and dexamethasone and to see how well they work for the treatment of multiple myeloma that has come back (relapsed) and does not respond to treatment (refractory). Nivolumab is a type of antibody (a protein that attaches to other cells to fight off infection and disease) that attaches to and inhibits a protein called PD-1. PD-1 normally acts as a type of “off switch” that helps keep the T cells from attacking other cells in the body. Some cancer cells have large amounts of PD-L1 which binds to PD-1 and turns off the immune system. Nivolumab inhibits PD-1 and helps take the “brake” off the immune system, which may allow immune cells to then recognize and destroy cancer cells. Ixazomib is a type of inhibitor that blocks a protein in cells called a proteasome. Proteasomes are responsible for breaking down other proteins in cells when they need to be disposed of. By blocking the proteasome from working, a buildup of proteins will be created in cancer cells, which may lead to cancer cell death. Chemotherapy drugs, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Anti-inflammatory drugs, such as dexamethasone, lower the body’s immune response and are used with other drugs in the treatment of some types of cancer. Giving nivolumab and ixazomib with cyclophosphamide and dexamethasone may increase the activity of both ixazomib and nivolumab.

Inclusion Criteria

  • Previously treated relapsed and refractory multiple myeloma per International Myeloma Working Group consensus criteria
  • Patients must have received at least three prior lines of therapy, including an immunomodulatory drug (e.g. lenalidomide, pomalidomide), a proteasome inhibitor (e.g. bortezomib, carfilzomib), and anti-CD38 monoclonal antibody (e.g. daratumumab)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Measurable disease of multiple myeloma as defined by at least one of the following (IgD and IgA with monoclonal protein < 0.5 g/dL may be permitted after discussion with principal investigator [PI]): * Serum monoclonal protein >= 0.5 g/dL (or quantitative IgA >= 1000 mg/dL), or * >= 200 mg of monoclonal protein in the urine on 24-hour urine protein electrophoresis, and/or * Serum free light chain >= 100 mg/L (10 mg/dL) and abnormal serum free kappa to serum free kappa light chain ratio
  • Absolute neutrophil count (ANC) >= 1000/uL (performed within 21 days of initiation of protocol therapy unless otherwise specified). Granulocyte colony-stimulating factor (G-CSF) is not permitted within 14 days of screening
  • Platelet count >= 75,000/uL (performed within 21 days of initiation of protocol therapy unless otherwise specified). Platelet transfusions are not permitted within 7 days of screening
  • Hemoglobin >= 8 g/dL (performed within 21 days of initiation of protocol therapy unless otherwise specified). Red blood cell transfusions are permitted to meet eligibility criteria.
  • Calculated creatinine clearance of >= 30 mL/min according to Cockcroft-Gault equation (performed within 21 days of initiation of protocol therapy unless otherwise specified)
  • Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values < 3 x the institutional upper limit of normal (ULN) (performed within 21 days of initiation of protocol therapy unless otherwise specified)
  • Serum bilirubin values < 1.5 mg/dL (performed within 21 days of initiation of protocol therapy unless otherwise specified). Patients with elevated bilirubin due to Gilbert’s syndrome may be permitted with principal investigator (PI) approval
  • Able to swallow capsules whole (ixazomib capsules should not be crushed, dissolved or broken)
  • Women of childbearing potential (WOCBP) must agree to follow instructions for methods of contraception for the duration of study treatment with nivolumab and for five months after the last dose of study treatment. If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through five months after the last dose of study drug OR agree to practice true abstinence when it in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Women of child bearing potential are women who are not postmenopausal for at least one year and who are not surgically sterile
  • Males who are sexually active (even if surgically sterilized, i.e. vasectomy) with WOBCP must agree to follow instructions for methods of contraception for the duration of study treatment with nivolumab and 7 months after the last dose of study treatment. Agree to practice effective barrier contraception during the entire study treatment period and through 7 months after the last dose of study drug, OR agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
  • Patient has given voluntary, signed written informed consent before performance of any study-related procedure that is not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care

Exclusion Criteria

  • Prior therapy with ixazomib
  • Prior therapy with any anti-PD1 antibody (e.g. nivolumab, pembrolizumab) or anti-PDL1 antibody (e.g. atezolizumab, avelumab, durvalumab)
  • Participants who have had chemotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) or with monoclonal antibodies 3 weeks of cycle 1 day 1 (C1D1) or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. Patients may have received dexamethasone within 2 weeks prior to C1D1
  • Participation in other clinical trials, including those with other investigational agents, within five half-lives prior to C1D1and throughout the duration of this trial. Prior treatment with an investigational agent within five half lives prior to C1D1 may be permitted after discussion with the PI
  • Concomitant high-dose corticosteroid use except chronic steroids (maximum dose 10 mg/day prednisone equivalent) if they are being given for disorders other than myeloma, e.g. adrenal insufficiency, rheumatoid arthritis, etc.
  • Female patients who are lactating or have a positive serum pregnancy test during the screening period (within 21 days of C1D1)
  • Prior history of malignancies, other than multiple myeloma (MM), unless the patient has been free of the disease for >= 3 years. Exceptions include the following if the patient has undergone complete resection: * Basal or squamous cell carcinoma of the skin * Carcinoma in situ of the cervix * Ductal carcinoma in situ of the breast * Incidental histologic finding of prostate cancer (T1a or T1b)
  • Patients with another malignancy undergoing active treatment with the exception of non-melanoma skin cancer or in situ cervical cancer
  • Patients with plasma cell leukemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, or amyloidosis are excluded from this trial
  • Human immunodeficiency virus (HIV) infection
  • Active hepatitis B infection or active hepatitis C infection. Participants who have prior hepatitis C infection and who have received an antiviral treatment and show no detectable viral ribonucleic acid (RNA) for 6 months prior to screening are eligible
  • Peripheral neuropathy >= grade 2 despite supportive therapy
  • Prior allogeneic stem cell transplant within five years prior to study registration. Patients who have had an allogeneic stem cell transplant within five years prior to study registration may participate as long as there are no symptoms of graft versus host disease
  • Patient has a history of significant cardiovascular, neurological, endocrine, gastrointestinal, respiratory, or inflammatory illness that could preclude study participation, pose an undue medical hazard, or interfere with the interpretation of the study results, including, but not limited to, patients with congestive heart failure (New York Heart Association [NYHA] class 3 or 4); unstable angina; cardiac arrhythmia; recent (within the preceding 6 months) myocardial infarction or stroke; hypertension requiring > 2 medications for adequate control; diabetes mellitus with > 2 episodes of ketoacidosis in the preceding 12 months; or chronic obstructive pulmonary disease (COPD) requiring > 2 hospitalizations in the preceding 12 months
  • Autoimmune disease: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune pneumonitis, autoimmune vasculitis (e.g., Wegener’s granulomatosis) and motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre syndrome and myasthenia gravis). Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
  • Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension
  • Major surgery within 14 days prior to study registration
  • Central nervous system involvement
  • Infection requiring systemic antibiotic therapy or other serious infection within 14 days prior to study registration
  • Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John’s wort within 14 days prior to C1D1
  • Receipt of a live or attenuated vaccine within 30 days of C1D1
  • Any serious medical of psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol
  • Known allergy to any study medications, their analogs, or excipients in the various formulations of any agent

Massachusetts

Boston
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Andrew Jenho Yee
Danvers
Mass General / North Shore Cancer Center
Status: ACTIVE
Contact: Andrew Jenho Yee
Newton
Newton-Wellesley Hospital
Status: ACTIVE
Contact: Robb Scott Friedman

PRIMARY OBJECTIVES:

I. To evaluate the objective response rate of nivolumab in combination with ixazomib citrate (ixazomib), cyclophosphamide, and dexamethasone in patients with relapsed and refractory multiple myeloma.

II. To evaluate the safety profile of nivolumab in combination with ixazomib, cyclophosphamide, and dexamethasone.

SECONDARY OBJECTIVES:

I. To evaluate the progression free survival (PFS) of nivolumab in combination with ixazomib, cyclophosphamide, and dexamethasone.

II. To evaluate biomarkers that may correlate with response to nivolumab in combination with ixazomib, cyclophosphamide, and dexamethasone (exploratory).

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes on day 1, ixazomib citrate orally (PO) on days 1, 8, and 15, cyclophosphamide IV over 1 hour on days 1, 8, and 15, and dexamethasone PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression and unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Andrew Jenho Yee

  • Primary ID 19-283
  • Secondary IDs NCI-2020-02020
  • Clinicaltrials.gov ID NCT04119336