A Phase II Study of Nivolumab in Combination With Ixazomib, Cyclophosphamide, and Dexamethasone in Relapsed and Refractory Multiple Myeloma

Andrew Yee, MD2 sites in 1 country2 target enrollmentFebruary 14, 2020

Overview

Brief Summary

This research is being done to assess the effectiveness and safety of the combination of nivolumab with ixazomib, cyclophosphamide, and dexamethasone in relapsed and refractory multiple myeloma.

Detailed Description

This research study is a phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied. * The U.S. Food and Drug Administration (FDA) has not approved nivolumab for relapsed and refractory Multiple Myeloma but it has been approved for other uses. * The FDA has approved ixazomib and cyclophosphamide as treatment options for your disease. * 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 is a checkpoint protein on immune cells called T cells. It 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. The investigators' hope that nivolumab will inhibit the PD-1 protein, thus allowing your immune cells to recognize and destroy cancer cells. * Ixazomib is a type of inhibitor that blocks a protein in your cells called a proteasome. This protein is responsible for breaking down other proteins in your cells when they need to be disposed of. By blocking the proteasome from working, a buildup of proteins will be created in the cancer cells, which may lead to cell death. * The investigators hope that the combination of ixazomib and nivolumab with standard of care chemotherapy cyclophosphamide and dexamethasone will work together with ixazomib and nivolumab to treat multiple myeloma.

Registry

clinicaltrials.gov

Start Date

February 14, 2020

End Date

March 30, 2022

Last Updated

2 years ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

Andrew Yee, MD

Responsible Party

Sponsor Investigator

Principal Investigator

Andrew Yee, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

Inclusion Criteria

•Previously treated relapsed and refractory multiple myeloma per International Myeloma Working Group consensus criteria (Rajkumar et al., 2011).
•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 (see Appendix A).
•Age ≥ 18 years
•All laboratory assessments for eligibility should be performed within 21 days of initiation of protocol therapy unless otherwise specified.
•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 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
•ANC ≥ 1000/μL. G-CSF is not permitted within 14 days of screening.

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 or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) or with monoclonal antibodies 3 weeks of 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 C1D
•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 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

Arms & Interventions

Nivolumab and Ixazomib

- Participants will receive Nivolumab, Ixazomib, Cyclophosphamide, and Dexamethasone on a 28-day cycle. * Oral: * Ixazomib given weekly on days 1, 8, 15 * Dexamethasone given weekly during cycle * Infused: * Nivolumab given once per cycle * Cyclophosphamide given on days 1, 8, 15 during cycle

Intervention: Nivolumab

Nivolumab and Ixazomib

- Participants will receive Nivolumab, Ixazomib, Cyclophosphamide, and Dexamethasone on a 28-day cycle. * Oral: * Ixazomib given weekly on days 1, 8, 15 * Dexamethasone given weekly during cycle * Infused: * Nivolumab given once per cycle * Cyclophosphamide given on days 1, 8, 15 during cycle

Intervention: Ixazomib

Nivolumab and Ixazomib

- Participants will receive Nivolumab, Ixazomib, Cyclophosphamide, and Dexamethasone on a 28-day cycle. * Oral: * Ixazomib given weekly on days 1, 8, 15 * Dexamethasone given weekly during cycle * Infused: * Nivolumab given once per cycle * Cyclophosphamide given on days 1, 8, 15 during cycle

Intervention: Dexamethasone

Nivolumab and Ixazomib

- Participants will receive Nivolumab, Ixazomib, Cyclophosphamide, and Dexamethasone on a 28-day cycle. * Oral: * Ixazomib given weekly on days 1, 8, 15 * Dexamethasone given weekly during cycle * Infused: * Nivolumab given once per cycle * Cyclophosphamide given on days 1, 8, 15 during cycle

Intervention: Cyclophosphamide

Outcomes

Primary Outcomes

Objective Response Rate (ORR)

Time Frame: up to 8 months

ORR is defined as percentage of participants with complete response (CR) and partial response (PR) per International Myeloma Working Group (IMWG) criteria below. * CR = Negative immunofixation on serum and urine; disappearance of soft tissue plasmacytomas, and \<5% plasma cells in bone marrow * Stringent CR = Above definition plus normal FLC ration and absence of clonal cells in bone marrow by IHC or 2-4 color flow cytometry * PR = At least 50% reduction of serum M-protein and reduction in 24 urinary M-protein by at least 90% or to \<200 mg/24 h. If serum and urine M-protein unmeasurable, require at least 50% decrease in difference between involved and uninvolved FLC levels. If serum free light assay also unmeasurable, require at least 50% reduction in plasma cells, provided baseline was at least 30% * Very Good PR (VGPR) = Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or \>90% reduction in serum M-protein plus urine M-protein level \<100 mg/24 h