Multiple Myeloma
Conditions
Keywords
multiple myeloma
Brief summary
The primary objective was to determine the maximum tolerated dose of carfilzomib given twice weekly in combination with cyclophosphamide and dexamethasone for patients with newly diagnosed multiple myeloma.
Interventions
DRUGCyclophosphamide
Cyclophosphamide administered orally (PO) at the dose of 300 mg/m² on Days 1, 8, and 15 of each 28-day cycle.
DRUGDexamethasone
Dexamethasone administered PO or IV at 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle.
DRUGCarfilzomib
Carfilzomib administered as a 30-minute intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. On Days 1 and 2 of Cycle 1, all participants received carfilzomib at 20 mg/m².
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Newly diagnosed multiple myeloma 2. Measurable disease, as defined by 1 or more of the following * Serum M-protein ≥ 0.5 g/dL, or * Urine M-protein ≥ 200 mg/24 hours, or * In subjects without detectable serum or urine M-protein, serum free light chain (SFLC) \> 100 mg/L (involved light chain) and an abnormal kappa lambda ( κ/λ) ratio 3. Males and females ≥ 18 years of age 4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 5. Adequate hepatic function 6. Left ventricular ejection fraction (LVEF) ≥ 40% 7. Absolute neutrophil count (ANC) ≥ 1.0 × 10\^9/L 8. Platelet count ≥ 50 × 10\^9/L 9. Calculated or measured creatinine clearance (CrCl) of ≥ 15 mL/min
Exclusion criteria
1. Planned autologous hematopoietic stem cell transplantation (HSCT) for the initial therapy of newly diagnosed multiple myeloma 2. Multiple myeloma of immunoglobulin M (IgM) subtype 3. Prior systemic treatment for multiple myeloma 4. Glucocorticoid therapy within 14 days prior to enrollment that equals or exceeds the equivalent of dexamethasone 160 mg 5. Known amyloidosis 6. Active congestive heart failure (New York Heart Association \[NYHA\] Class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within 6 months prior to enrollment. 7. Known human immunodeficiency virus (HIV) seropositive, hepatitis C infection, and/or hepatitis B (subjects with hepatitis B surface antigen \[SAg\] or core antibody receiving and responding to antiviral therapy directed at hepatitis B are allowed) 8. Significant neuropathy (Grades ≥ 2) within 14 days prior to enrollment 9. Any other 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLTs) | First cycle treatment over 28-days | The MTD is defined as the highest carfilzomib dose at which fewer than 33% of participants experience a treatment-related dose-limiting toxicity (DLT) during the first 28-day cycle. The number of participants who experienced a DLT is reported. Dose-limiting toxicities are defined as any of the following carfilzomib-related adverse events: Nonhematologic: * ≥ Grade 3 non-hematological toxicity * ≥ Grade 3 acute kidney injury (creatinine \> 3 × baseline or \> 4.0 mg/dL) lasting \> 72 hours Hematologic: * Grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 0.5 × 10\^9/L) lasting for \> 7 days * Febrile neutropenia (ANC \< 1.0 × 10\^9/L with a fever ≥ 38.3ºC) of any duration * Grade 4 thrombocytopenia (\< 25 × 10\^9/L) that persists for \> 14 days, despite holding treatment * Grade 3 or 4 thrombocytopenia associated with \> Grade 1 bleeding |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Disease response was assessed at the end of each cycle and 30 days after the last treatment; maximum treatment duration was 32 weeks. | Participants were evaluated for disease response and progression by the investigator according to the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). Disease response and progression assessments included serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), serum immunofixation, serum free light chain (SFLC), bone marrow sample (including fluorescent in situ hybridization \[FISH\]), plasmacytoma evaluation, and skeletal survey. Overall response rate is defined as the percentage of participants with a best response of stringent complete response, complete response, very good partial response (VGPR), or partial response. |
| Time To Response (TTR) | Disease response was assessed at the end of each cycle and 30 days after the last treatment; maximum treatment duration was 32 weeks. | Time to response is defined as months from treatment start to first documentation of response of partial response or better. Summary of time to response includes confirmed responders of PR or better only. |
| Number of Participants With Adverse Events | From first dose of study drug until 30 days after last dose; median duration of treatment was 31 weeks. | Adverse events (AEs) were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 and using the following scale: Grade 1 = Mild, Grade 3 = Moderate; Grade 3 = Severe, Grade 4 = Life-threatening; Grade 5 = Fatal. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 9 centers in the United States.
Pre-assignment details
Eligible participants were enrolled into sequential dose-escalation cohorts consisting of 3 to 6 participants to establish the maximum tolerated dose (MTD) of carfilzomib when given in combination with cyclophosphamide and dexamethasone. Additional participants were enrolled in an expansion cohort at the established MTD to collect safety data.
Participants by arm
| Arm | Count |
|---|---|
| Carfilzomib 36 mg/m² Participants received 36 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. | 3 |
| Carfilzomib 45 mg/m² Participants received 45 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. | 3 |
| Carfilzomib 56 mg/m² Participants received 56 mg/m² carfilzomib IV infusion on days 1, 2, 8, 9,15, and 16 of each 28 day cycle (on days 1 and 2 of cycle 1, all participants received carfilzomib at 20 mg/m²), cyclophosphamide administered orally at 300 mg/m² on days 1, 8, and 15, and 40 mg dexamethasone on days 1, 8, 15, and 22, for up to eight 28 day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. | 16 |
| Total | 22 |
Baseline characteristics
| Characteristic | Carfilzomib 36 mg/m² | Carfilzomib 45 mg/m² | Carfilzomib 56 mg/m² | Total |
|---|---|---|---|---|
| Age, Continuous | 56.0 years | 63.0 years | 65.0 years | 62.5 years |
| European Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active) | 1 participants | 1 participants | 7 participants | 9 participants |
| European Cooperative Oncology Group (ECOG) Performance Status 1 (Restrictive but ambulatory) | 2 participants | 2 participants | 8 participants | 12 participants |
| European Cooperative Oncology Group (ECOG) Performance Status 2 (Ambulatory but unable to work) | 0 participants | 0 participants | 1 participants | 1 participants |
| Race Asian | 1 participants | 0 participants | 1 participants | 2 participants |
| Race Black or African American | 1 participants | 1 participants | 3 participants | 5 participants |
| Race Other | 0 participants | 0 participants | 1 participants | 1 participants |
| Race White | 1 participants | 2 participants | 11 participants | 14 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 9 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 16 / 16 |
| serious Total, serious adverse events | 0 / 3 | 1 / 3 | 5 / 16 |
Outcome results
Primary
Number of Participants With Dose-limiting Toxicities (DLTs)
The MTD is defined as the highest carfilzomib dose at which fewer than 33% of participants experience a treatment-related dose-limiting toxicity (DLT) during the first 28-day cycle. The number of participants who experienced a DLT is reported. Dose-limiting toxicities are defined as any of the following carfilzomib-related adverse events: Nonhematologic: * ≥ Grade 3 non-hematological toxicity * ≥ Grade 3 acute kidney injury (creatinine \> 3 × baseline or \> 4.0 mg/dL) lasting \> 72 hours Hematologic: * Grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 0.5 × 10\^9/L) lasting for \> 7 days * Febrile neutropenia (ANC \< 1.0 × 10\^9/L with a fever ≥ 38.3ºC) of any duration * Grade 4 thrombocytopenia (\< 25 × 10\^9/L) that persists for \> 14 days, despite holding treatment * Grade 3 or 4 thrombocytopenia associated with \> Grade 1 bleeding
Time frame: First cycle treatment over 28-days
Population: The Safety population is defined as all enrolled participants who received any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib 36 mg/m² | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| Carfilzomib 45 mg/m² | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| Carfilzomib 56 mg/m² | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
Secondary
Number of Participants With Adverse Events
Adverse events (AEs) were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 and using the following scale: Grade 1 = Mild, Grade 3 = Moderate; Grade 3 = Severe, Grade 4 = Life-threatening; Grade 5 = Fatal.
Time frame: From first dose of study drug until 30 days after last dose; median duration of treatment was 31 weeks.
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Carfilzomib 36 mg/m² | Number of Participants With Adverse Events | AE leading to discontinuation of study drug | 0 participants |
| Carfilzomib 36 mg/m² | Number of Participants With Adverse Events | Fatal adverse events | 0 participants |
| Carfilzomib 36 mg/m² | Number of Participants With Adverse Events | Adverse event ≥ Grade 3 | 3 participants |
| Carfilzomib 36 mg/m² | Number of Participants With Adverse Events | Any adverse event | 3 participants |
| Carfilzomib 36 mg/m² | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Carfilzomib 45 mg/m² | Number of Participants With Adverse Events | Any adverse event | 3 participants |
| Carfilzomib 45 mg/m² | Number of Participants With Adverse Events | AE leading to discontinuation of study drug | 1 participants |
| Carfilzomib 45 mg/m² | Number of Participants With Adverse Events | Serious adverse events | 1 participants |
| Carfilzomib 45 mg/m² | Number of Participants With Adverse Events | Adverse event ≥ Grade 3 | 3 participants |
| Carfilzomib 45 mg/m² | Number of Participants With Adverse Events | Fatal adverse events | 1 participants |
| Carfilzomib 56 mg/m² | Number of Participants With Adverse Events | Adverse event ≥ Grade 3 | 10 participants |
| Carfilzomib 56 mg/m² | Number of Participants With Adverse Events | Any adverse event | 16 participants |
| Carfilzomib 56 mg/m² | Number of Participants With Adverse Events | Fatal adverse events | 0 participants |
| Carfilzomib 56 mg/m² | Number of Participants With Adverse Events | Serious adverse events | 5 participants |
| Carfilzomib 56 mg/m² | Number of Participants With Adverse Events | AE leading to discontinuation of study drug | 4 participants |
Secondary
Overall Response Rate (ORR)
Participants were evaluated for disease response and progression by the investigator according to the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). Disease response and progression assessments included serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), serum immunofixation, serum free light chain (SFLC), bone marrow sample (including fluorescent in situ hybridization \[FISH\]), plasmacytoma evaluation, and skeletal survey. Overall response rate is defined as the percentage of participants with a best response of stringent complete response, complete response, very good partial response (VGPR), or partial response.
Time frame: Disease response was assessed at the end of each cycle and 30 days after the last treatment; maximum treatment duration was 32 weeks.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib 36 mg/m² | Overall Response Rate (ORR) | 66.7 percentage of participants |
| Carfilzomib 45 mg/m² | Overall Response Rate (ORR) | 100.0 percentage of participants |
| Carfilzomib 56 mg/m² | Overall Response Rate (ORR) | 87.5 percentage of participants |
Secondary
Time To Response (TTR)
Time to response is defined as months from treatment start to first documentation of response of partial response or better. Summary of time to response includes confirmed responders of PR or better only.
Time frame: Disease response was assessed at the end of each cycle and 30 days after the last treatment; maximum treatment duration was 32 weeks.
Population: Participants with an overall response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib 36 mg/m² | Time To Response (TTR) | 1.3 months |
| Carfilzomib 45 mg/m² | Time To Response (TTR) | 0.8 months |
| Carfilzomib 56 mg/m² | Time To Response (TTR) | 1.0 months |