A Phase 1/2 Study of Weekly Carfilzomib in Combination With Dexamethasone for Progressive Multiple Myeloma
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Amgen
- Enrollment
- 116
- Locations
- 33
- Primary Endpoint
- Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)
Study Overview
Brief Summary
The study had the following primary objectives:
- Phase 1: to determine the maximum tolerated dose (MTD) of once-weekly (QW) carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior therapies
- Phase 2: to estimate the overall response rate (ORR) for patients with relapsed or refractory multiple myeloma who received 1 to 3 prior therapies treated with carfilzomib and dexamethasone QW at the MTD established in phase 1.
Detailed Description
This is a Phase 1/2, multicenter, single-arm, nonrandomized, open-label and dose-escalation study of weekly carfilzomib and dexamethasone for patients with progressive multiple myeloma. The Phase 1 dose escalation portion will enroll patients into sequential dose-escalating cohorts consisting of 3 patients each to establish the maximum tolerated dose (MTD) of carfilzomib administered weekly as a 30 minute intravenous (IV) infusion with dexamethasone. The Phase 2 portion will enroll patients using the MTD established for carfilzomib from the Phase 1 portion of the study. Dexamethasone will be administered IV or orally at the same dose and schedule as used in the Phase 1 portion of the study.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Multiple myeloma with relapsing or progressive disease at study entry
- •Measurable disease, as defined by 1 or more of the following (assessed within 21 days prior to enrollment):
- •Serum M-protein ≥ 0.5 g/dL, or
- •Urine M-protein ≥ 200 mg/24 hours, or
- •Only in patients who do not meet a or b, then use serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal kappa/lambda ratio
- •Prior treatment with 1 to 3 prior regimens for multiple myeloma for Phase 1 and Phase 2 (induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as 1 line of therapy
- •Age ≥ 18 years
- •Life expectancy ≥ 6 months
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- •Adequate hepatic function within 21 days prior to enrollment, with bilirubin < 1.5 × the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 × ULN
- •Left ventricular ejection fraction (LVEF) ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated acquisition scan (MUGA) is acceptable if ECHO is not available
- •Absolute neutrophil count (ANC) ≥ 1000/mm³ within 21 days prior to enrollment. Screening ANC is to be independent of growth factor support for ≥ 1 week
- •Hemoglobin ≥ 8.0 g/dL within 21 days prior to enrollment. Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed; however, most recent RBC transfusion must have been at least 7 days prior to obtaining screening hemoglobin
- •Platelet count ≥ 50,000/mm³ (≥ 30,000/mm³ if myeloma involvement in the bone marrow is > 50%) within 21 days prior to enrollment. Patients must not have received platelet transfusions for at least 7 days prior to obtaining the screening platelet count
- •Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min within 21 days prior to enrollment. Calculation based on standard formula, such as the Cockcroft and Gault: [(140 - Age) x Mass (kg) / (72 x Creatinine mg/dL)]; multiply result by 0.85 if female
- •Written informed consent in accordance with federal, local, and institutional guidelines
- •Female patients of childbearing potential (FCBP) must have a negative serum pregnancy test within 21 days prior to enrollment and agree to use an effective method of contraception during and for 3 months following last dose of drug (more frequent pregnancy tests may be conducted if required per local regulations). Postmenopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from a pregnancy test
- •Male patients must agree to use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with an FCBP
Exclusion Criteria
- •Multiple myeloma of Immunoglobulin M (IgM) subtype
- •POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
- •Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential)
- •Waldenström's macroglobulinemia
- •Amyloidosis
- •Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 7 days prior to enrollment
- •Cytotoxic chemotherapy with approved or investigational anticancer therapeutics within 28 days prior to enrollment
- •Treatment with bortezomib (Velcade®), thalidomide (Thalomid®) or lenalidomide (Revlimid®) within 21 days prior to enrollment
- •Focal radiation therapy within 7 days prior to enrollment. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to enrollment (ie, prior radiation must have been to < 30% of the bone marrow)
- •Immunotherapy within 21 days prior to enrollment
- •Major surgery within 21 days prior to enrollment
- •Active congestive heart failure (New York Heart Association [NYHA] Classes III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within 6 months prior to enrollment
- •Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B virus [HBV]), or antifungal agents within 14 days prior to enrollment
- •Known human immunodeficiency virus (HIV) seropositivity
- •Known hepatitis B or C virus infection (except for patients with HBV who are receiving and responding to HBV antiviral therapy: these patients are allowed)
- •Patients with known cirrhosis
- •Second malignancy within the past 3 years, except:
- •Adequately treated basal cell or squamous cell skin cancer
- •Carcinoma in situ of the cervix
- •Prostate cancer < Gleason score 6 with stable prostate-specific antigen (PSA) over 12 months
- •Breast carcinoma in situ with full surgical resection
- •Treated medullary or papillary thyroid cancer
- •Patients with myelodysplastic syndrome
- •Significant neuropathy (Grades 3 to 4) within 14 days prior to enrollment
- •Female patients who are pregnant or lactating
- •Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
- •Prior carfilzomib treatment
- •Prior participation in any Onyx-sponsored Phase 3 trial
- •Patients with contraindication to dexamethasone
- •Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
- •Ongoing graft-versus-host disease
- •Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment
- •Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment
- •Any other clinically significant medical disease or psychiatric condition that, in the Investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent
Arms & Interventions
Carfilzomib
In phase 1 participants were assigned to one of four sequential dose-escalating cohorts to receive 45, 56, 70 or 88 mg/m² carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
In phase 2 participants received carfilzomib at the maximum tolerated dose (MTD) established in the Phase 1 portion of the study on days 1, 8 and 15 plus 40 mg dexamethasone IV or orally at the same schedule as used in the Phase 1 portion of the study.
Participants were treated until confirmed progressive disease, unacceptable toxicity, withdrew consent for further treatment, were lost to follow-up, died, or the sponsor closed the study.
Intervention: Carfilzomib (Drug)
Carfilzomib
In phase 1 participants were assigned to one of four sequential dose-escalating cohorts to receive 45, 56, 70 or 88 mg/m² carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
In phase 2 participants received carfilzomib at the maximum tolerated dose (MTD) established in the Phase 1 portion of the study on days 1, 8 and 15 plus 40 mg dexamethasone IV or orally at the same schedule as used in the Phase 1 portion of the study.
Participants were treated until confirmed progressive disease, unacceptable toxicity, withdrew consent for further treatment, were lost to follow-up, died, or the sponsor closed the study.
Intervention: Dexamethasone (Drug)
Outcomes
Primary Outcomes
Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)
Time Frame: 28 days
The MTD was defined as the highest carfilzomib dose at which \< 33% of participants had a treatment-related DLT during the first 28-day cycle. A DLT was categorized as nonhematologic or hematologic and defined as follows: Nonhematologic: * ≥ grade 3 nonhematological toxicity (excluding nausea, vomiting, diarrhea, fatigue lasting \< 14 days, increased serum creatinine or electrolyte abnormalities not clinically significant or requiring treatment) * ≥ grade 3 acute kidney injury (creatinine \> 3 x baseline or \> 4.0 mg/dL) lasting \> 72 hours * ≥ grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal antiemetic/antidiarrheal therapy Hematologic: * grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 500/mm³) for \> 7 days * febrile neutropenia (ANC \< 1000/mm³ with a fever ≥ 38.3ºC) of any duration * grade 4 thrombocytopenia (\< 25 000/mm³) for \> 14 days, despite holding treatment * grade 3 or 4 thrombocytopenia (\< lower limit of normal) associated with \> grade 1 bleeding
Overall Response Rate (ORR)
Time Frame: Disease response was assessed once every treatment cycle (28 days) and 30 days after last dose; the median overall treatment duration was 33.6 weeks.
Disease response was evaluated by the investigator according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). ORR was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in BM. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-protein with urine M-protein \<100 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline. PR: ≥ 50% reduction of serum M-protein and reduction in urine M-protein by ≥ 90% or to \< 200 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.
Secondary Outcomes
- Time To Progression(From randomization until the data cut-off date of 22 July 2016; median follow-up time for TTP was 13.4 months)
- Duration of Response(From randomization until the data cut-off date of 22 July 2016; median follow-up time for DOR was 14.3 months)
- Number of Participants With Adverse Events(From the first day of study treatment and within 30 days of the last day of study treatment; median duration of treatment was 33.6 weeks.)
- Maximum Plasma Concentration of Carfilzomib(Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.)
- Area Under the Plasma Concentration-time Curve During the Dosing Interval (0-168 Hours) for Carfilzomib(Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.)
- Mean Residence Time Observed From Time Zero to Infinity (MRT0-∞) for Carfilzomib(Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.)
- Progression-free Survival(From randomization until the data cut-off date of 22 July 2016; median follow-up time for PFS was 13.8 months)
- Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) fo Carfilzomib(Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.)
- Clearance of Carfilzomib After IV Infusion(Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.)
- Time to Maximum Plasma Concentration of Carfilzomib(Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.)
- Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Carfilzomib(Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.)
- Volume of Distribution Observed at Steady State (Vss) for Carfilzomib(Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.)
- Clinical Benefit Response Rate(Disease response was assessed once every treatment cycle (28 days) and 30 days after last dose; the median overall treatment duration was 33.6 weeks.)
- Terminal Half-life (T1/2,z) for Carfilzomib(Day 1 cycle 1 (20 mg/m² carfilzomib), cycle 1 day 15 (phase 1 70 and 88 mg/m² carfilzomib), and cycle 2 day 15 (phase 2 70 mg/m² carfilzomib) from predose to 4 hours after the end of the infusion.)