Carfilzomib, Pomalidomide, and Dexamethasone in Treating Patients with Relapsed or Refractory Multiple Myeloma
- Relapsed and relapsed/refractory multiple myeloma requiring systemic therapy
- All subjects must have failed 1+ prior treatment, one of which must include lenalidomide therapy * Patients requiring second (2nd) line of therapy must meet criteria of lenalidomide-refractory disease defined as a history of progression on or within 60 days of completion of a regimen of a minimum of 2 cycles containing full or maximally tolerated dose of lenalidomide ** Patients progressing on lenalidomide maintenance in the first line of therapy will be eligible provided that they have received at least 2 cycles of lenalidomide at established standard maintenance dosing schedule; maintenance dosing and schedule must be documented and approved by lead principal investigator prior to enrollment * For patients requiring third (3rd) or higher line of therapy, history of treatment with lenalidomide is required but lenalidomide-refractory status is not * In addition, subjects also refractory to pomalidomide, carfilzomib, or bortezomib are permitted limited to 10 subjects per group
- Measurable disease, as indicated by one or more of the following: * Serum myeloma protein (M-protein) >= 0.5 g/dL * Urine M-protein >= 200 mg/24 hours * If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable * Involved serum free light chains >= 10 mg/dL provided that free light chain ratio is abnormal
- Life expectancy of more than 3 months
- Eastern Cooperative Oncology Group (ECOG) performance status 0–2
- Bilirubin < 1.5 times the upper limit of normal (ULN)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times ULN
- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
- Hemoglobin >= 8 g/dL
- Platelet count >= 75 x 10^9/L; subjects may receive red blood cells (RBC) transfusions or platelet transfusions, if clinically indicated in accordance with institutional guidelines; however, screening platelet count should be independent of platelet transfusions for at least 2 weeks
- Calculated or measured creatinine clearance of >= 30 mL/minute calculated using the Cockcroft and Gault formula
- Written informed consent in accordance with federal, local, and institutional guidelines
- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days and again within 24 hours prior to starting cycle 1 of pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking pomalidomide. FCBP must also agree to ongoing pregnancy testing; the contraceptive requirement for carfilzomib in females of childbearing potential is at least 30 days after the last dose; carfilzomib is prohibited in breast-feeding women; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; all subjects must be counseled on day 1 of each cycle (or at a minimum of every 28 days) and at drug discontinuation about pregnancy precautions and risks of fetal exposure
- Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy
- Male subjects must use contraception while on carfilzomib and for at least 90 days after the last dose of carfilzomib; male subjects must refrain from donating sperm for at least 90 days after the last dose of carfilzomib
- Male subjects must agree to inform his physician if he has had unprotected sexual contact with a female who can become pregnant or if he thinks for any reason that his sexual partner may be pregnant
- Male subjects must agree not to donate semen or sperm while taking pomalidomide and/or carfilzomib until at least 90 days after the last pomalidomide/carfilzomib dose
- Subjects must agree to adhere to all study requirements, visit schedule, outpatient treatment, required concomitant medications, and laboratory monitoring
- All study participants must be registered into the mandatory POMALYST (pomalidomide) Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the POMALYST REMS program; for subjects enrolled outside of the United States, Pomalidomide counseling but be completed by a designated counselor
- Subjects for whom there is the prospect of stem cell transplantation in the next 6 months in the treatment plan are excluded (including subjects for whom the PdC regimen is being considered as pre-transplant cytoreduction)
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
- Plasma cell leukemia
- Waldenstrom’s macroglobulinemia or immunoglobulin M (IgM) myeloma
- Radiotherapy to multiple sites or immunotherapy within 3 weeks before start of protocol treatment (localized radiotherapy to a single site at least 1 week before start is permissible)
- Participation in an investigational therapeutic study within 3 weeks or within 5 drug half-lives (t1/2) prior to first dose, whichever time is greater
- Subjects known to be refractory to any proteasome inhibitor other than bortezomib or carfilzomib, including but not limited to MLN9708, CEP-18770, ONX 0912, and SalmosporamideA; refractory will be defined as a history of progression on or within 60 days after completing a regimen containing the proteasome inhibitor for a minimum of 2 cycles at either approved or considered effective or best tolerated doses
- Pregnant or lactating females
- History of allergy to mannitol or prior hypersensitivity to thalidomide, lenalidomide or pomalidomide
- Major surgery within 3 weeks prior to first dose, prior peripheral stem cell transplant within 12 weeks of study enrollment
- Subject has received anti-cancer chemotherapy, immunotherapy, hormonal (with the exception of hormones for thyroid conditions or estrogen replacement therapy [ERT], or any investigational therapy) within 21 days of enrollment
- Myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
- Uncontrolled hypertension or diabetes
- Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
- Known or suspected human immunodeficiency (HIV) infection, known HIV seropositivity
- Active hepatitis A, B, or C infection * Daratumumab cohort: Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, 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
- Non-hematologic malignancy within the past 3 years except adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix or breast, prostate cancer < Gleason grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone
- Any clinically significant medical disease or condition that, in the investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent
- Significant neuropathy (grades 3-4, or grade 2 with pain) at the time of the first dose and/or within 14 days before enrollment
- Patients with contraindications to any of the required concomitant drugs or supportive treatments, including hypersensitivity to anticoagulation and antiplatelet options, antiviral drugs; for example, patients with a prior history of thrombotic disease who also have a contraindication to full anticoagulation including warfarin or low molecular weight heparin, would be excluded
- Subjects in whom the required program of PO and IV fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment
- Subjects with known or suspected amyloidosis of any organ
- Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis
- Prior exposure to daratumumab
I. To determine the maximally tolerated dose (MTD) of carfilzomib when administered in combination with pomalidomide and dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma.
II. To determine the efficacy of the combination regimen at the MTD as measured by partial response (PR) response rate defined as per International Myeloma Working Group (IMWG) criteria.
III. To determine the efficacy and tolerability of pomalidomide, dexamethasone, and carfilzomib (PdC) + daratumumab combination therapy.
I. To determine the best stringent complete response (sCR)/CR/near complete response (nCR) and >= very good partial response (VGPR) rates.
II. To estimate the time on study (TOS), duration of response (DOR), time to progression (TTP), progression-free survival (PFS), and overall survival (OS) distributions.
III. To further define the toxicity at the MTD.
I. To perform an analysis of a subset of patients who are refractory to pomalidomide, carfilzomib, or the combination of lenalidomide, bortezomib, and dexamethasone (RVD).
II. To evaluate the status of minimal residual disease (MRD) in patient who achieve sCR, CR or nCR.
III. To evaluate prognostic markers and markers of response to PdC in patients refractory to lenalidomide by analyzing pre-treatment clinical covariates and pre-treatment plasma cell profiles by proteomics and gene expression profiling (GEP).
OUTLINE: This is a phase I, dose-escalation study of carfilzomib followed by phase II study. Patients are assigned to 1 of 2 cohorts.
COHORT I: Patients receive pomalidomide orally (PO) once daily (QD) on days 1-21, dexamethasone PO or intravenously (IV) on days 1, 8, 15, and 22, and carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15 and 16 (days 1, 2, 15, and 16 of cycles 9 and beyond). Treatment repeats every 28 days for at least 8 cycles in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease may continue to receive treatment as maintenance therapy in the absence of disease progression or unacceptable toxicity. (Enrollment for this cohort has concluded).
COHORT II: Patients receive pomalidomide PO QD on days 1-21, dexamethasone PO or IV on days 1, 2, 8, 9, 15, 16, 22, and 23 of cycles 1-2, days 1, 2, 8, 15, 16, and 22 of cycles 3-6, and days 1, 2, 8, 15, and 22 of cycles 7 and beyond, and carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16 (days 1, 2, 15, and 16 of cycles 9 and beyond). Patients also receive daratumumab IV on days 1, 2, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, and day 1 of cycles 7 and beyond. Treatment repeats every 28 days for at least 8 cycles in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease may continue to receive treatment as maintenance therapy in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 28 days and then every 3 months for up to 2 years.
Trial Phase Phase I/II
Trial Type Treatment
University of Chicago Comprehensive Cancer Center
Andrzej J. Jakubowiak
- Primary ID IRB12-1088
- Secondary IDs NCI-2012-01168
- Clinicaltrials.gov ID NCT01665794