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Daratumumab, Carfilzomib, Pomalidomide, and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma

Trial Status: Active

This phase II trial studies the side effects of daratumumab and how well it works in combination with carfilzomib, pomalidomide, and dexamethasone in treating patients with multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Daratumumab is a type of antibody (a protein that attaches to other cells to fight off infection) that works by attaching to the CD38 molecule which is expressed in multiple myeloma cells. By attaching to the CD38 molecule, daratumumab may cause cell death. Carfilzomib is a type of inhibitor that works by inhibiting (blocking) multiple myeloma cells from breaking down proteins within the cells. This may cause a buildup of proteins within multiple myeloma cells, which may lead to cell death. Pomalidomide is an immunomodulatory drug (it affects the immune system) that works by affecting the growth signals that keep cancer cells alive. Dexamethasone is a corticosteroid (a type of steroid) that may kill cancer cells. Giving daratumumab in combination with carfilzomib, pomalidomide, and dexamethasone may kill more cancer cells in patients with multiple myeloma.

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of any study-related procedure that is not part of normal medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to their future medical care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
  • 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 principal investigator (PI) approval * >= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis * Serum free light chain >= 100 mg/L (10 mg/dL) and abnormal serum free kappa to serum free kappa light chain ratio
  • Previously treated relapsed and refractory multiple myeloma * Patients must have received at least one prior line of therapy; * Prior therapy must include at least 2 cycles of lenalidomide and at least 2 cycles of a proteasome inhibitor (either in separate regimens or within the same regimen); and * Disease progression on or within 60 days of completion of last therapy
  • Absolute neutrophil count (ANC) >= 1000/uL (performed within 14 days prior to the date of registration). Granulocyte colony-stimulating factor (G-CSF) is not permitted within 14 days of screening. Patients with ANC < 1000/uL can be considered for screening on a case by case basis with additional monitoring, after discussion with and approval from the PI
  • Platelet count >= 50,000/uL (performed within 14 days prior to the date of registration). Platelet transfusion is not permitted within 7 days of screening
  • Hemoglobin >= 8 g/dL (performed within 14 days prior to the date of registration). Red blood cell transfusions are permitted to meet eligibility criteria
  • Calculated creatinine clearance of >= 30 mL/min by Cockcroft-Gault equation (performed within 14 days prior to the date of registration)
  • Serum bilirubin values < 2 mg/dL (performed within 14 days prior to the date of registration)
  • Serum alanine transaminase (ALT) and/or aspartate transaminase (AST) values < 2.5 x the upper limit of normal (ULN) of the institutional laboratory reference range (performed within 14 days prior to the date of registration). 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)
  • Must be able to take acetylsalicylic acid (aspirin [ASA]) daily as prophylactic anticoagulation. Patients intolerant to ASA may use low molecular weight heparin, apixaban, rivaroxaban, or equivalent
  • All study participants must be registered into the mandatory pomalidomide (Pomalyst) Risk Evaluation and Mitigation Strategy (REMS) program and be willing and able to comply with the requirements of the Pomalyst REMS program
  • Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Pomalyst REMS program
  • A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control e.g. either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study and for 3 months after receiving the last dose of study drug
  • Able to swallow capsules whole (pomalidomide capsules cannot be crushed, dissolved or broken)

Exclusion Criteria

  • Participants who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to study registration 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 study registration
  • Participants who are receiving any other investigational agents
  • Last line of therapy with the combination of carfilzomib, pomalidomide, and dexamethasone. Note: prior treatment with daratumumab or other anti-CD38 therapy is permitted. Prior treatment with carfilzomib or pomalidomide is permitted (as different lines of treatment but not in the same combination)
  • Concomitant high dose corticosteroids. Low dose corticosteroids (maximum dose 10 mg/day prednisone equivalent) is permitted if given for disorders other than myeloma, e.g. adrenal insufficiency, rheumatoid arthritis, etc.
  • Pregnancy or lactation or planned lactation (breastfeeding)
  • Prior history of malignancies, other than multiple myeloma (MM), unless the patient has completed definitive treatment and has been free of the disease for >= 3 years. Patients who are free of disease < 3 years may enroll after discussion with and approval of the PI. Exceptions include the following (i.e. the following are eligible to participate): * 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) managed with surveillance
  • Patients with plasma cell leukemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, or amyloidosis are excluded from this trial
  • Seropositive for human immunodeficiency virus (HIV) infection
  • Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]; see exception below). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded. Exception: subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
  • Seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)
  • Peripheral neuropathy >= grade 2 despite supportive therapy
  • Hypersensitivity to daratumumab, thalidomide, lenalidomide, pomalidomide, carfilzomib, or dexamethasone (such as Stevens-Johnson syndrome). Rash to immunomodulatory drug that can be medically managed is allowable
  • Allogeneic stem cell transplant < 12 months prior to initiation of study treatment and who have not discontinued immunosuppressive treatment for at least four weeks prior to initiation of study treatment and who are currently dependent on such treatment. Patients may also not have active graft versus (v.) host disease (GVHD)
  • 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
  • Known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second < 60% of predicted normal), known moderate or severe persistent asthma within 2 years prior to study registration (intermittent asthma is allowed). Patient with known or suspected COPD or asthma must have an FEV1 test within 28 days prior to study registration
  • Major surgery within 2 weeks prior to cycle 1 day 1 (C1D1)
  • Patient has any other medical, psychiatric, or social condition that would preclude participation in the study, pose an undue medical hazard, interfere with the conduct of the study, or interfere with interpretation of the study results
  • Toxicity from previous anticancer therapy must resolve to baseline levels or to grade =< 1, except for alopecia and peripheral neuropathy

Massachusetts

Boston
Beth Israel Deaconess Medical Center
Status: ACTIVE
Contact: Jacalyn M. Rosenblatt
Brigham and Women's Hospital
Status: ACTIVE
Contact: Omar Nadeem
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Omar Nadeem
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Andrew Jenho Yee

PRIMARY OBJECTIVES:

I. To evaluate the objective response rate of daratumumab in combination with weekly carfilzomib, pomalidomide, and dexamethasone in relapsed and refractory multiple myeloma.

II. To evaluate the safety profile of daratumumab in combination with weekly carfilzomib, pomalidomide, and dexamethasone in relapsed and refractory multiple myeloma.

SECONDARY OBJECTIVES:

I. To evaluate the progression free survival (PFS) of daratumumab in combination with weekly carfilzomib, pomalidomide, and dexamethasone in relapsed and refractory multiple myeloma.

II. To study clonal evolution, clonal heterogeneity, and correlate with response. (exploratory)

OUTLINE:

Patient receive daratumumab intravenously (IV) on days 1, 2, 8, 15, and 22 of cycle 1, days 1, 8, 15, 22 of cycle 2, days 1 and 15 of cycles 3-6, and day 1 of subsequent cycles. Patients also receive carfilzomib IV over 30 minutes on days 1, 8, and 15, pomalidomide orally (PO) once daily (QD) on days 1-21, and dexamethasone PO QD on days 1, 2, 8, 9, 15, 16, 22, and 23. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months until 5 years from time of study enrollment.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Andrew Jenho Yee

  • Primary ID 19-379
  • Secondary IDs NCI-2020-02126
  • Clinicaltrials.gov ID NCT04176718