Multiple Myeloma
Conditions
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.
Interventions
DRUGCarfilzomib
Carfilzomib was administered as a 30-minute IV infusion on days 1, 8, and 15 of each 28-day treatment cycle.
DRUGDexamethasone
Dexamethasone was administered at a dose of 40 mg IV or orally (PO) on days 1, 8, 15, and 22 for the first 8 cycles; starting with cycle 9 dexamethasone was administered on days 1, 8, and 15.
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Multiple myeloma with relapsing or progressive disease at study entry 2. Measurable disease, as defined by 1 or more of the following (assessed within 21 days prior to enrollment): 1. Serum M-protein ≥ 0.5 g/dL, or 2. Urine M-protein ≥ 200 mg/24 hours, or 3. 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 3. 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 4. Age ≥ 18 years 5. Life expectancy ≥ 6 months 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 7. 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 8. 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 9. 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 10. 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 11. 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 12. 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 13. Written informed consent in accordance with federal, local, and institutional guidelines 14. 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 15. 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
1. Multiple myeloma of Immunoglobulin M (IgM) subtype 2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 3. Plasma cell leukemia (\> 2.0 × 10\^9/L circulating plasma cells by standard differential) 4. Waldenström's macroglobulinemia 5. Amyloidosis 6. Glucocorticoid therapy (prednisone \> 30 mg/day or equivalent) within 7 days prior to enrollment 7. Cytotoxic chemotherapy with approved or investigational anticancer therapeutics within 28 days prior to enrollment 8. Treatment with bortezomib (Velcade®), thalidomide (Thalomid®) or lenalidomide (Revlimid®) within 21 days prior to enrollment 9. 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) 10. Immunotherapy within 21 days prior to enrollment 11. Major surgery within 21 days prior to enrollment 12. 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 13. 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 14. Known human immunodeficiency virus (HIV) seropositivity 15. 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) 16. Patients with known cirrhosis 17. Second malignancy within the past 3 years, except: 1. Adequately treated basal cell or squamous cell skin cancer 2. Carcinoma in situ of the cervix 3. Prostate cancer \< Gleason score 6 with stable prostate-specific antigen (PSA) over 12 months 4. Breast carcinoma in situ with full surgical resection 5. Treated medullary or papillary thyroid cancer 18. Patients with myelodysplastic syndrome 19. Significant neuropathy (Grades 3 to 4) within 14 days prior to enrollment 20. Female patients who are pregnant or lactating 21. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib) 22. Prior carfilzomib treatment 23. Prior participation in any Onyx-sponsored Phase 3 trial 24. Patients with contraindication to dexamethasone 25. 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 26. Ongoing graft-versus-host disease 27. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment 28. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment 29. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 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) | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | Time to progression (TTP) was defined as the time from first dose to disease progression evaluated by the investigator according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). TTP was calculated using Kaplan-Meier methods; participants with no baseline and/or post-baseline disease assessments, who started a new anticancer therapy before documentation of disease progression or death, died or had disease progression immediately after more than 1 consecutively missed disease assessment visit or who were alive without documentation of disease progression before the data cutoff date were censored. |
| 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 | Duration of response (DOR) was defined as the time from first evidence of PR or better to disease progression or death due to any cause. DOR was calculated using Kaplan-Meier methods; Participants with no baseline disease assessments, starting a new anticancer therapy before documentation of disease progression or death, death or disease progression immediately after more than 1 consecutively missed disease assessment visit, or alive without documentation of disease progression before the data cut-off date were censored. |
| 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. | Adverse events were graded using National Cancer Institute-Common Terminology Criteria for Adverse Events (version 4.03). |
| 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. | — |
| 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. | — |
| 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. | Clinical benefit rate was defined as the percentage of participants whose best response was sCR, CR, VGPR, PR, or minimal response (MR), where MR is defined by the European Group for Blood and Marrow Transplant (EBMT) criteria as a 25% to 49% reduction in the level of serum M-protein or a 50% to 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg /24 hour, maintained for a minimum of 8 weeks. |
| 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. | — |
| 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. | — |
| 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. | — |
| 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. | — |
| 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. | — |
| 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. | — |
| 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 | Progression-free survival (PFS) was defined as the time from first dose to the earlier of disease progression or death due to any cause. The duration of PFS was calculated using Kaplan-Meier methods; participants with no baseline and/or post-baseline disease assessments, who started a new anticancer therapy before documentation of disease progression or death, died or had disease progression immediately after more than 1 consecutively missed disease assessment visit or who were alive without documentation of disease progression before the data cutoff date were censored. Participants were evaluated for disease response and progression by the investigator according to the IMWG-URC. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 32 centers in the United States. Participants were enrolled from September 2012 to September 2014.
Pre-assignment details
In phase 1 participants were enrolled into 1 of 4 sequential dose-escalating cohorts to establish the maximum tolerated dose (MTD) of carfilzomib plus dexamethasone. In phase 2 participants were enrolled to evaluate the efficacy and safety of carfilzomib plus dexamethasone at the MTD established in phase 1.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Carfilzomib 45 mg/m² Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 45 mg/m². 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. | 3 |
| Phase 1: Carfilzomib 56 mg/m² Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 56 mg/m². 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. | 3 |
| Phase 1: Carfilzomib 70 mg/m² Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². 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. | 15 |
| Phase 1: Carfilzomib 88 mg/m² Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 88 mg/m². 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. | 6 |
| Phase 2: Carfilzomib 70 mg/m² Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8 and 15 of each 28-day cycle. The carfilzomib dose was 20 mg/m² on day 1 of cycle 1; thereafter, subsequent carfilzomib dosing was 70 mg/m². 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. | 89 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 | 3 | 13 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 2 | 0 | 12 |
| Overall Study | Progressive Disease | 2 | 1 | 9 | 3 | 43 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 0 | 15 |
Baseline characteristics
| Characteristic | Phase 1: Carfilzomib 56 mg/m² | Phase 1: Carfilzomib 70 mg/m² | Phase 1: Carfilzomib 88 mg/m² | Phase 2: Carfilzomib 70 mg/m² | Phase 1: Carfilzomib 45 mg/m² | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 73.7 years STANDARD_DEVIATION 2.1 | 62.4 years STANDARD_DEVIATION 10.4 | 58.2 years STANDARD_DEVIATION 8.8 | 68.7 years STANDARD_DEVIATION 9.6 | 69.3 years STANDARD_DEVIATION 15.6 | 67.5 years STANDARD_DEVIATION 10.1 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active) | 2 Participants | 6 Participants | 3 Participants | 39 Participants | 1 Participants | 51 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restrictive but ambulatory) | 1 Participants | 9 Participants | 3 Participants | 50 Participants | 2 Participants | 65 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 10 Participants | 0 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 15 Participants | 5 Participants | 79 Participants | 3 Participants | 105 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 2 Participants | 0 Participants | 6 Participants | 0 Participants | 9 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 11 Participants | 6 Participants | 79 Participants | 3 Participants | 101 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 5 Participants | 40 Participants | 1 Participants | 52 Participants |
| Sex: Female, Male Male | 1 Participants | 11 Participants | 1 Participants | 49 Participants | 2 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 15 / 15 | 6 / 6 | 87 / 89 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 4 / 15 | 1 / 6 | 35 / 89 |
Outcome results
Primary
Overall Response Rate (ORR)
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.
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.
Population: Participants who received at least 1 dose of any investigational product (carfilzomib or dexamethasone).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Overall Response Rate (ORR) | 33.3 percentage of participants |
| Phase 1: Carfilzomib 56 mg/m² | Overall Response Rate (ORR) | 100 percentage of participants |
| Phase 1: Carfilzomib 70 mg/m² | Overall Response Rate (ORR) | 93.3 percentage of participants |
| Phase 1: Carfilzomib 88 mg/m² | Overall Response Rate (ORR) | 66.7 percentage of participants |
| Phase 2: Carfilzomib 70 mg/m² | Overall Response Rate (ORR) | 74.2 percentage of participants |
| Phase 1+2: Carfilzomib 70 mg/m² | Overall Response Rate (ORR) | 76.9 percentage of participants |
Primary
Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)
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
Time frame: 28 days
Population: Participants in phase 1 who received at least 1 dose of any investigational product (carfilzomib or dexamethasone).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| Phase 1: Carfilzomib 56 mg/m² | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| Phase 1: Carfilzomib 70 mg/m² | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 1 participants |
| Phase 1: Carfilzomib 88 mg/m² | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 2 participants |
Secondary
Area Under the Plasma Concentration-time Curve During the Dosing Interval (0-168 Hours) for Carfilzomib
Time frame: 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.
Population: Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Area Under the Plasma Concentration-time Curve During the Dosing Interval (0-168 Hours) for Carfilzomib | 259 hr*ng/mL | Geometric Coefficient of Variation 28 |
| Phase 1: Carfilzomib 56 mg/m² | Area Under the Plasma Concentration-time Curve During the Dosing Interval (0-168 Hours) for Carfilzomib | 1040 hr*ng/mL | Geometric Coefficient of Variation 21.6 |
| Phase 1: Carfilzomib 70 mg/m² | Area Under the Plasma Concentration-time Curve During the Dosing Interval (0-168 Hours) for Carfilzomib | 1160 hr*ng/mL | Geometric Coefficient of Variation 34.8 |
Secondary
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) fo Carfilzomib
Time frame: 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.
Population: Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) fo Carfilzomib | 259 hr*ng/mL | Geometric Coefficient of Variation 28 |
| Phase 1: Carfilzomib 56 mg/m² | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) fo Carfilzomib | 1040 hr*ng/mL | Geometric Coefficient of Variation 21.6 |
| Phase 1: Carfilzomib 70 mg/m² | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUCinf) fo Carfilzomib | 1160 hr*ng/mL | Geometric Coefficient of Variation 34.8 |
Secondary
Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Carfilzomib
Time frame: 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.
Population: Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Carfilzomib | 281 hr*ng/mL | Geometric Coefficient of Variation 52.7 |
| Phase 1: Carfilzomib 56 mg/m² | Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Carfilzomib | 1040 hr*ng/mL | Geometric Coefficient of Variation 21.7 |
| Phase 1: Carfilzomib 70 mg/m² | Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Carfilzomib | 1210 hr*ng/mL | Geometric Coefficient of Variation 31.4 |
Secondary
Clearance of Carfilzomib After IV Infusion
Time frame: 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.
Population: Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Clearance of Carfilzomib After IV Infusion | 147 liters/hour | Geometric Coefficient of Variation 31 |
| Phase 1: Carfilzomib 56 mg/m² | Clearance of Carfilzomib After IV Infusion | 131 liters/hour | Geometric Coefficient of Variation 29.6 |
| Phase 1: Carfilzomib 70 mg/m² | Clearance of Carfilzomib After IV Infusion | 138 liters/hour | Geometric Coefficient of Variation 35 |
Secondary
Clinical Benefit Response Rate
Clinical benefit rate was defined as the percentage of participants whose best response was sCR, CR, VGPR, PR, or minimal response (MR), where MR is defined by the European Group for Blood and Marrow Transplant (EBMT) criteria as a 25% to 49% reduction in the level of serum M-protein or a 50% to 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg /24 hour, maintained for a minimum of 8 weeks.
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.
Population: Participants who received at least 1 dose of any investigational product (carfilzomib or dexamethasone).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Clinical Benefit Response Rate | 66.7 percentage of participants |
| Phase 1: Carfilzomib 56 mg/m² | Clinical Benefit Response Rate | 100.0 percentage of participants |
| Phase 1: Carfilzomib 70 mg/m² | Clinical Benefit Response Rate | 100.0 percentage of participants |
| Phase 1: Carfilzomib 88 mg/m² | Clinical Benefit Response Rate | 83.3 percentage of participants |
| Phase 2: Carfilzomib 70 mg/m² | Clinical Benefit Response Rate | 80.9 percentage of participants |
| Phase 1+2: Carfilzomib 70 mg/m² | Clinical Benefit Response Rate | 83.7 percentage of participants |
Secondary
Duration of Response
Duration of response (DOR) was defined as the time from first evidence of PR or better to disease progression or death due to any cause. DOR was calculated using Kaplan-Meier methods; Participants with no baseline disease assessments, starting a new anticancer therapy before documentation of disease progression or death, death or disease progression immediately after more than 1 consecutively missed disease assessment visit, or alive without documentation of disease progression before the data cut-off date were censored.
Time frame: From randomization until the data cut-off date of 22 July 2016; median follow-up time for DOR was 14.3 months
Population: Participants who received at least 1 dose of any investigational product (carfilzomib or dexamethasone) with a best overall response of sCR, CR, VGPR, or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Duration of Response | 18.9 months |
| Phase 1: Carfilzomib 56 mg/m² | Duration of Response | NA months |
| Phase 1: Carfilzomib 70 mg/m² | Duration of Response | 16.3 months |
| Phase 1: Carfilzomib 88 mg/m² | Duration of Response | 11.9 months |
| Phase 2: Carfilzomib 70 mg/m² | Duration of Response | 18.0 months |
| Phase 1+2: Carfilzomib 70 mg/m² | Duration of Response | 18.0 months |
Secondary
Maximum Plasma Concentration of Carfilzomib
Time frame: 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.
Population: Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Maximum Plasma Concentration of Carfilzomib | 789 ng/mL | Geometric Coefficient of Variation 65.5 |
| Phase 1: Carfilzomib 56 mg/m² | Maximum Plasma Concentration of Carfilzomib | 2390 ng/mL | Geometric Coefficient of Variation 30.7 |
| Phase 1: Carfilzomib 70 mg/m² | Maximum Plasma Concentration of Carfilzomib | 3090 ng/mL | Geometric Coefficient of Variation 27.3 |
Secondary
Mean Residence Time Observed From Time Zero to Infinity (MRT0-∞) for Carfilzomib
Time frame: 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.
Population: Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Mean Residence Time Observed From Time Zero to Infinity (MRT0-∞) for Carfilzomib | 0.118 hours | Geometric Coefficient of Variation 130.5 |
| Phase 1: Carfilzomib 56 mg/m² | Mean Residence Time Observed From Time Zero to Infinity (MRT0-∞) for Carfilzomib | 0.108 hours | Geometric Coefficient of Variation 55.4 |
| Phase 1: Carfilzomib 70 mg/m² | Mean Residence Time Observed From Time Zero to Infinity (MRT0-∞) for Carfilzomib | 0.0571 hours | Geometric Coefficient of Variation 110 |
Secondary
Number of Participants With Adverse Events
Adverse events were graded using National Cancer Institute-Common Terminology Criteria for Adverse Events (version 4.03).
Time frame: 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.
Population: Participants who received at least 1 dose of any investigational product (carfilzomib or dexamethasone).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Number of Participants With Adverse Events | Serious adverse events | 1 Participants |
| Phase 1 Carfilzomib 45 mg/m² | Number of Participants With Adverse Events | Fatal adverse events | 0 Participants |
| Phase 1 Carfilzomib 45 mg/m² | Number of Participants With Adverse Events | AE leading to discontinuation of carfilzomib & dex | 0 Participants |
| Phase 1 Carfilzomib 45 mg/m² | Number of Participants With Adverse Events | All adverse events | 3 Participants |
| Phase 1 Carfilzomib 45 mg/m² | Number of Participants With Adverse Events | Adverse events ≥ grade 3 | 1 Participants |
| Phase 1 Carfilzomib 45 mg/m² | Number of Participants With Adverse Events | AE leading to discontinuation of carfilzomib | 0 Participants |
| Phase 1: Carfilzomib 56 mg/m² | Number of Participants With Adverse Events | All adverse events | 3 Participants |
| Phase 1: Carfilzomib 56 mg/m² | Number of Participants With Adverse Events | Adverse events ≥ grade 3 | 2 Participants |
| Phase 1: Carfilzomib 56 mg/m² | Number of Participants With Adverse Events | AE leading to discontinuation of carfilzomib & dex | 0 Participants |
| Phase 1: Carfilzomib 56 mg/m² | Number of Participants With Adverse Events | AE leading to discontinuation of carfilzomib | 0 Participants |
| Phase 1: Carfilzomib 56 mg/m² | Number of Participants With Adverse Events | Fatal adverse events | 0 Participants |
| Phase 1: Carfilzomib 56 mg/m² | Number of Participants With Adverse Events | Serious adverse events | 0 Participants |
| Phase 1: Carfilzomib 70 mg/m² | Number of Participants With Adverse Events | AE leading to discontinuation of carfilzomib | 2 Participants |
| Phase 1: Carfilzomib 70 mg/m² | Number of Participants With Adverse Events | Fatal adverse events | 0 Participants |
| Phase 1: Carfilzomib 70 mg/m² | Number of Participants With Adverse Events | Adverse events ≥ grade 3 | 9 Participants |
| Phase 1: Carfilzomib 70 mg/m² | Number of Participants With Adverse Events | Serious adverse events | 4 Participants |
| Phase 1: Carfilzomib 70 mg/m² | Number of Participants With Adverse Events | All adverse events | 15 Participants |
| Phase 1: Carfilzomib 70 mg/m² | Number of Participants With Adverse Events | AE leading to discontinuation of carfilzomib & dex | 2 Participants |
| Phase 1: Carfilzomib 88 mg/m² | Number of Participants With Adverse Events | AE leading to discontinuation of carfilzomib | 3 Participants |
| Phase 1: Carfilzomib 88 mg/m² | Number of Participants With Adverse Events | AE leading to discontinuation of carfilzomib & dex | 3 Participants |
| Phase 1: Carfilzomib 88 mg/m² | Number of Participants With Adverse Events | All adverse events | 6 Participants |
| Phase 1: Carfilzomib 88 mg/m² | Number of Participants With Adverse Events | Adverse events ≥ grade 3 | 5 Participants |
| Phase 1: Carfilzomib 88 mg/m² | Number of Participants With Adverse Events | Fatal adverse events | 0 Participants |
| Phase 1: Carfilzomib 88 mg/m² | Number of Participants With Adverse Events | Serious adverse events | 1 Participants |
| Phase 2: Carfilzomib 70 mg/m² | Number of Participants With Adverse Events | Fatal adverse events | 5 Participants |
| Phase 2: Carfilzomib 70 mg/m² | Number of Participants With Adverse Events | All adverse events | 89 Participants |
| Phase 2: Carfilzomib 70 mg/m² | Number of Participants With Adverse Events | Adverse events ≥ grade 3 | 60 Participants |
| Phase 2: Carfilzomib 70 mg/m² | Number of Participants With Adverse Events | Serious adverse events | 35 Participants |
| Phase 2: Carfilzomib 70 mg/m² | Number of Participants With Adverse Events | AE leading to discontinuation of carfilzomib & dex | 14 Participants |
| Phase 2: Carfilzomib 70 mg/m² | Number of Participants With Adverse Events | AE leading to discontinuation of carfilzomib | 14 Participants |
Secondary
Progression-free Survival
Progression-free survival (PFS) was defined as the time from first dose to the earlier of disease progression or death due to any cause. The duration of PFS was calculated using Kaplan-Meier methods; participants with no baseline and/or post-baseline disease assessments, who started a new anticancer therapy before documentation of disease progression or death, died or had disease progression immediately after more than 1 consecutively missed disease assessment visit or who were alive without documentation of disease progression before the data cutoff date were censored. Participants were evaluated for disease response and progression by the investigator according to the IMWG-URC.
Time frame: From randomization until the data cut-off date of 22 July 2016; median follow-up time for PFS was 13.8 months
Population: Participants who received at least 1 dose of any investigational product (carfilzomib or dexamethasone).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Progression-free Survival | 13.6 months |
| Phase 1: Carfilzomib 56 mg/m² | Progression-free Survival | NA months |
| Phase 1: Carfilzomib 70 mg/m² | Progression-free Survival | 21.0 months |
| Phase 1: Carfilzomib 88 mg/m² | Progression-free Survival | 12.9 months |
| Phase 2: Carfilzomib 70 mg/m² | Progression-free Survival | 15.3 months |
| Phase 1+2: Carfilzomib 70 mg/m² | Progression-free Survival | 16.2 months |
Secondary
Terminal Half-life (T1/2,z) for Carfilzomib
Time frame: 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.
Population: Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Terminal Half-life (T1/2,z) for Carfilzomib | 0.648 hours | Geometric Coefficient of Variation 49 |
| Phase 1: Carfilzomib 56 mg/m² | Terminal Half-life (T1/2,z) for Carfilzomib | 0.883 hours | Geometric Coefficient of Variation 24.6 |
| Phase 1: Carfilzomib 70 mg/m² | Terminal Half-life (T1/2,z) for Carfilzomib | 0.816 hours | Geometric Coefficient of Variation 17.1 |
Secondary
Time to Maximum Plasma Concentration of Carfilzomib
Time frame: 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.
Population: Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Time to Maximum Plasma Concentration of Carfilzomib | 0.25 hours |
| Phase 1: Carfilzomib 56 mg/m² | Time to Maximum Plasma Concentration of Carfilzomib | 0.25 hours |
| Phase 1: Carfilzomib 70 mg/m² | Time to Maximum Plasma Concentration of Carfilzomib | 0.25 hours |
Secondary
Time To Progression
Time to progression (TTP) was defined as the time from first dose to disease progression evaluated by the investigator according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). TTP was calculated using Kaplan-Meier methods; participants with no baseline and/or post-baseline disease assessments, who started a new anticancer therapy before documentation of disease progression or death, died or had disease progression immediately after more than 1 consecutively missed disease assessment visit or who were alive without documentation of disease progression before the data cutoff date were censored.
Time frame: From randomization until the data cut-off date of 22 July 2016; median follow-up time for TTP was 13.4 months
Population: Participants who received at least 1 dose of any investigational product (carfilzomib or dexamethasone).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Time To Progression | 13.6 months |
| Phase 1: Carfilzomib 56 mg/m² | Time To Progression | NA months |
| Phase 1: Carfilzomib 70 mg/m² | Time To Progression | 21.0 months |
| Phase 1: Carfilzomib 88 mg/m² | Time To Progression | 12.9 months |
| Phase 2: Carfilzomib 70 mg/m² | Time To Progression | 16.2 months |
| Phase 1+2: Carfilzomib 70 mg/m² | Time To Progression | 17.2 months |
Secondary
Volume of Distribution Observed at Steady State (Vss) for Carfilzomib
Time frame: 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.
Population: Pharmacokinetic (PK) analyses were conducted for participants assigned to cohorts 3 and 4 in phase 1 (70 and 88 mg/m² carfilzomib) and a subset of participants in phase 2; only participants for whom PK parameters could be calculated were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Carfilzomib 45 mg/m² | Volume of Distribution Observed at Steady State (Vss) for Carfilzomib | 17.0 liters | Geometric Coefficient of Variation 133.3 |
| Phase 1: Carfilzomib 56 mg/m² | Volume of Distribution Observed at Steady State (Vss) for Carfilzomib | 14.2 liters | Geometric Coefficient of Variation 54.2 |
| Phase 1: Carfilzomib 70 mg/m² | Volume of Distribution Observed at Steady State (Vss) for Carfilzomib | 7.87 liters | Geometric Coefficient of Variation 78.4 |