Details
Description
Inclusion Criteria
Exclusion Criteria
Details
Title A Multicenter, Randomized, Open-label, Phase 2 Study of Carfilzomib With or Without ARRY-520 in Patients With Advanced Multiple Myeloma
IRB ARRY1A13
CC 14-258
Hospital Main Campus
Phase Phase 2
Disease Multiple Myeloma
Drug ARRY-520, Carfilzomib
Description
Primary Objective- Estimate the PFS of patients treated with carfilzomib + ARRY-520 and of patients treated with single-agent carfilzomib
- Evaluate additional measures of efficacy in patients treated with carfilzomib + ARRY-520 and in patients treated with single-agent carfilzomib
- Assess the safety of carfilzomib + ARRY-520 treatment and single-agent carfilzomib treatment
- Assess the PK of ARRY-520, carfilzomib and carfilzomib-M14 (a morpholino-hPhe metabolite of carfilzomib) in patients treated with carfilzomib + ARRY-520
- Following crossover from single-agent carfilzomib, estimate the ORR in patients treated with carfilzomib + ARRY-520 and assess the safety of carfilzomib + ARRY-520 treatment
- Assess the effect of CYP2C19 genotype on ARRY-520 exposure in patients treated with carfilzomib + ARRY-520
- Evaluate patient levels of AAG at Baseline and changes in AAG levels during the treatment period
- Assess the concentration of unbound ARRY-520
Inclusion Criteria
- Provide a personally signed and dated informed consent form prior to initiation of any study-related procedures that are not considered standard of care.
- Male or female ≥ 18 years of age at time of informed consent.
- Patients with confirmed multiple myeloma whose treatment history must include all of the following:
- Received at least 2 prior treatment regimens, including bortezomib and an IMiD (e.g., lenalidomide, thalidomide, pomalidomide). Induction therapy and stem cell transplant +/- maintenance are to be considered as a single regimen.
- Refractory disease, defined as either failure to achieve an MR or better during the last myeloma therapy, or documented disease progression during or within 60 days of completing the last myeloma therapy.
- Measurable multiple myeloma disease, defined as meeting at least 1 of the following criteria within 14 days prior to randomization:
- A monoclonal Ig (M-protein) concentration on serum protein electrophoresis (SPEP) of ≥ 0.5 g/dL.
- Measurable urinary light chain secretion by quantitative analysis using urine protein electrophoresis (UPEP) of ≥ 200 mg/24 hours.
- Involved serum free light chain (FLC) level ≥ 10 mg/dL, provided the serum FLC ratio is abnormal.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 within 14 days prior to randomization.
- Adequate hematology laboratory values within 14 days prior to randomization:
- Neutrophils ≥ 1.5 x 109/L without growth factor support (defined as no growth factor administration for at least 14 days prior to observation). If the bone marrow contains 50% plasma cells, a neutrophil count of ≥ 1.0 x 109/L is allowed.
- Platelets ≥ 50 x 109/L.
- Adequate hepatic and renal function laboratory values within 14 days prior to randomization:
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 x the upper limit of normal (ULN).
- Total bilirubin ≤ 1.5 mg/dL.
- Calculated (Cockcroft and Gault formula) or measured creatinine clearance ≥ 25 mL/min.
- Left ventricular ejection fraction (LVEF) ≥ 40% within 28 days prior to randomization, evaluated by 2-D transthoracic echocardiogram (ECHO) or, if ECHO is not available, by multi-gated acquisition (MUGA) scan.
- If patient is female and of childbearing potential, she must have a negative serum beta human chorionic gonadotropin (β-HCG) test within 14 days prior to randomization and consent to ongoing pregnancy testing during the course of the study.
- Male patients must agree to use an effective method of contraception per institutional standard through 90 days after the last administration of study drug and female patients of childbearing potential must agree to use an effective method of contraception per institutional standard through 30 days after the last administration of study drug.
- Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
Exclusion Criteria
- Prior treatment with carfilzomib.
- Prior treatment with ARRY-520 or any other KSP inhibitor.
- Past or current plasma cell leukemia (> 2 x 109/L circulating plasma cells and plasma cells accounting for ≥ 20% by standard white blood cell [WBC] differential).
- Primary amyloidosis (amyloidosis associated with multiple myeloma is allowed).
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes).
- Ongoing Grade 3 or Grade 4 peripheral neuropathy (per National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Version 4.03), or Grade 2 peripheral neuropathy with pain despite appropriate interventions, within the 28 days prior to randomization.
- Autologous or allogeneic stem cell or bone marrow transplant within 3 months prior to randomization.
- Concomitant malignancies or previous malignancies (other than multiple myeloma) with less than a 2-year disease-free interval at the time of randomization. Patients with adequately resected basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or Stage 1 prostate cancer are eligible irrespective of the time of diagnosis.
- Use of an investigational agent that is not expected to be cleared by the time of randomization or that has demonstrated prolonged side effects. Patients must have recovered from the side effects to a Grade 0 or Grade 1 (except alopecia [any grade is allowed] and neuropathy [see exclusion criterion #6]).
- Monoclonal antibody treatment for multiple myeloma within 28 days prior to randomization.
- Cytotoxic therapy within 21 days prior to randomization.
- Proteasome inhibitor therapy within 14 days prior to randomization.
- Immunomodulatory agent therapy within 7 days prior to randomization.
- Radiotherapy within 21 days prior to randomization. However, if the radiation portal covers ≤ 5% of the bone marrow reserve, the patient is eligible irrespective of the end date of radiotherapy.
- Corticosteroid doses > 10 mg/day of prednisone or equivalent within 14 days prior to randomization.
- History of allergic reaction/hypersensitivity to any of the study medications, their analogues, or excipients in the various formulations.
- Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).
- Contraindication to any of the required concomitant drugs (including dexamethasone and filgrastim) or supportive treatments, antiviral drugs, or intolerance to hydration due to pre-existing pulmonary, cardiac or renal impairment.
- Any major surgery where adequate wound healing has not occurred prior to randomization.
- Medical, psychiatric or other conditions that may interfere with patient safety or compromise the patient's ability to understand the patient information, to give informed consent, to comply with the study protocol, or to complete the study.
- Known pulmonary hypertension of any severity.
- Concurrent cardiac disease (including symptomatic congestive heart failure [New York Heart Association Class III or IV], symptomatic cardiac ischemia, unstable angina pectoris or myocardial infarction within the previous 6 months, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless patient has a pacemaker) that, in the judgment of the Investigator, would make the patient inappropriate for study participation.
- Known human immunodeficiency virus (HIV) seropositivity.
- Active hepatitis B or hepatitis C infection.
- Acute active infection requiring treatment.
- Any other severe concurrent disease or condition (including severe graft-versus-host disease or requirement for dialysis) that, in the judgment of the Investigator, would make the patient inappropriate for study participation.
- Pregnant or breastfeeding women.
