Multiple Myeloma
Conditions
Keywords
Onyx, PR171, carfilzomib, multiple myeloma, relapsed, refractory
Brief summary
To evaluate the overall response rate and safety and tolerability of carfilzomib in subjects with relapsed and refractory multiple myeloma. Patients must have received prior treatment with bortezomib and either thalidomide or lenalidomide and be refractory to their last treatment.
Interventions
DRUGcarfilzomib
Subjects will receive carfilzomib 20 mg/m2 as an intravenous bolus over 2 minutes on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles. A maximum of 12 cycles will be administered.
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Disease Related * Multiple myeloma * Subjects must have measurable disease defined as one of the following: * Serum M-protein ≥ 1 g/dL * Urine M-protein ≥ 200 mg/24 hours * Serum FLC ≥ 10 mg/dL with abnormal ratio (A0 Only) * Quantitative immunoglobulin levels using nephelometry or turbidometry (only if protein electrophoresis was felt to be unreliable for M-protein measurement) (A0 Only) * Subjects must have been responsive (i.e., achieved an MR or better) to first-line, standard of care therapy * Refractory to the most recently received therapy. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy. * Subjects must have received ≥ 2 prior regimens for relapsed disease. Induction therapy and stem cell transplant will be considered as one regimen (A1 Only) * Subjects must have received prior treatment with bortezomib, and either thalidomide or lenalidomide * Subjects must have received an alkylating agent either alone or in combination with other myeloma treatments (history of stem cell transplant is acceptable) (A1 Only) * Subjects must have received an anthracycline either alone or in combination with other myeloma treatments, unless not clinically indicated (A1 Only) * Demographic * Males and females \> 18 years of age * Life expectancy of more than three months * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 * Laboratory * Adequate hepatic function, with bilirubin less than 2.0 times the upper limit of normal, and AST and ALT of less than 3.0 times the upper limit of normal * Uric acid within normal range (A0 Only) * Total white blood cell (WBC) count ≥ 2.0 × 109/L, absolute neutrophil count (ANC) ≥ 1.0 × 109/L, hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50.0 × 109/L (A0 Only) * Absolute neutrophil count \> 1,000/mm3, hemoglobin \> 8.0 g/dL, and platelet count \> 50,000/mm3 (A1 Only) * Subjects should be platelet transfusion independent * Screening ANC should be independent of G-CSF or GM-CSF support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks * Subjects may receive red blood cell (RBC) or platelet transfusions or receive supportive care such as erythropoietin and darbepoetin in accordance with institutional guidelines * Calculated and measured creatinine clearance of ≥ 30 mL/minute, calculated using the formula of Cockcroft and Gault \[(140 - Age) X Mass (kg) / (72 X Creatinine mg/dL)\]. Multiply result by 0.85 if female. * Ethical / Other * Written informed consent in accordance with federal, local, and institutional guidelines * Female subjects of child-bearing potential must have a negative serum pregnancy test within seven days of the first dose and agree to use dual methods of contraception during and for 3 months following last dose of drug. Post menopausal females (\> 45 years old and without menses for \> 1 year) and surgically sterilized females are exempt from a pregnancy test. Male subjects must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a female of child-bearing potential.
Exclusion criteria
* Disease Related * Multiple Myeloma IgM (A1 Only) * Subjects who failed to achieve at least a confirmed MR(≥ 25% reduction in M-protein for ≥ 6 weeks) (A1 Only) * Subjects with non-secretory multiple myeloma, defined as \< 1 g/dL M-protein in serum and \< 200 mg/24 hr M-protein in urine * Subjects with disease measurable only by serum free light chain (SFLC) analysis (A1 Only) * Glucocorticoid therapy (prednisone \> 10 mg/day orally or equivalent) within the last three weeks * POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) * Plasma cell leukemia * Chemotherapy with approved or investigative anticancer therapeutics including steroid therapy within the three weeks prior to first dose * Radiation therapy or immunotherapy in the previous four weeks; localized radiation therapy within 1 week prior to first dose * Participation in an investigational therapeutic study within three weeks or within five drug half-lives (t1/2) prior to Day 1, whichever time is greater * Prior treatment with carfilzomib * Concurrent Conditions * Major surgery within three weeks before Day 1 * Congestive heart failure (New York Heart Association class III to IV), symptomatic cardiac ischemia, cardiomyopathy, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months, LVEF \< 40 * Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first dose * Known or suspected HIV infection or subjects who are HIV seropositive * Active hepatitis A,B,or C infection * Non-hematologic malignancy within the past three years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or c) prostate cancer \<Gleason Grade 6 with stable PSA * Subjects with treatment related myelodysplastic syndrome * Significant neuropathy (Grade 3, 4 or Grade 2 with pain) at the time of study initiation * Subjects in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac or renal impairment (A1 Only) * Subjects with known or suspected amyloidosis (A1 Only) * Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis (A1 Only) * 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 (A1 Only) * Ethical / Other * Female subjects who are pregnant or lactating * Serious psychiatric or medical conditions that could interfere with treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate (ORR) | A0: Subjects evaluated for disease response on Day 24 of Cycles 2, 4, 6, 9, and 12. Onset of response measured on Day 15 of Cycle 1. A1: Subjects evaluated for disease response on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12 and at End of Study. | For both A0 and A1, to evaluate the best overall response rate (stringent complete response \[sCR\]+ complete response \[CR\]+ very good partial response \[VGPR\]+ partial response \[PR\]) in patients with multiple myeloma who had previously received bortezomib and either thalidomide or lenalidomide, had relapsed after two or more therapies, and were refractory to the most recently received therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Response (CBR) (A1 Only) | Response assessments same as described in primary outcome measure | sCR, CR, VGPR, PR, and minimal response (MR) |
| Duration of Response (A0 Only) | Response assessments same as described in primary outcome measure | Duration of response (DOR) was calculated separately for subjects with clinical benefit response or overall response. DOR is defined as the time from first evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death. |
| Duration of Response (A1 Only) | Response assessments same as described in primary outcome measure | Duration of response (DOR) was calculated separately for subjects with clinical benefit response or overall response. DOR is defined as the time from first evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death. |
| Time to Progression (A0 Only) | Response assessments same as described in primary outcome measure | Time to progression (TTP) is defined as the time from the study entry (first dose of carfilzomib) to disease progression. |
| Clinical Benefit Response (CBR) (A0 Only) | Response assessments same as described in primary outcome measure | sCR, CR, VGPR, PR, and minimal response (MR) |
| Progression-free Survival (A0 Only) | Response assessments same as described in primary outcome measure | The PFS was defined as the time from the start of treatment to progressive disease (PD) determined by PI or until death. |
| Progression-free Survival (A1 Only) | Response assessments same as described in primary outcome measure | The PFS was defined as the time from the start of treatment to progressive disease (PD) determined by PI or until death. |
| Overall Survival (A1 Only) | Patients were to be followed by telephone contact for disease progression and OS every 3 months after study discontinuation for the first year and every 6 months thereafter for up to 2 years | The time from start of treatment to death due to any cause OS was to be censored on the date the subject was last known to be alive for those who were alive or lost to follow-up as of a data analysis cutoff date. |
| Time to Progression (A1 Only) | Response assessments same as described in primary outcome measure | Time to progression (TTP) is defined as the time from the study entry (first dose of carfilzomib) to disease progression. |
Countries
Canada, United States
Participant flow
Recruitment details
Results of this study are reported in 2 parts, depending on whether a patient was enrolled and treated under the original protocol (referred to as 'A0') or under Amendment 1 and subsequent amendments (referred to as 'A1').
Participants by arm
| Arm | Count |
|---|---|
| Carfilzomib (A0) Subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 of 28 day cycle | 46 |
| Carfilzomib (A1) In Cycle 1, subjects will receive carfilzomib 20 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16. If all doses are administered and well-tolerated over the 28-day cycle, beginning with Cycle 2 the dose will escalate to 27 mg/m2 intravenously on Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles. | 266 |
| Total | 312 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 13 | 33 |
| Overall Study | Progressive Disease | 23 | 157 |
| Overall Study | various reasons | 4 | 14 |
| Overall Study | Withdrawal by Subject | 2 | 22 |
Baseline characteristics
| Characteristic | Carfilzomib (A0) | Carfilzomib (A1) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 20 Participants | 120 Participants | 140 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 146 Participants | 172 Participants |
| Sex: Female, Male Female | 21 Participants | 111 Participants | 132 Participants |
| Sex: Female, Male Male | 25 Participants | 155 Participants | 180 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 46 / 46 | 266 / 266 |
| serious Total, serious adverse events | 20 / 46 | 126 / 266 |
Outcome results
Primary
Best Overall Response Rate (ORR)
For both A0 and A1, to evaluate the best overall response rate (stringent complete response \[sCR\]+ complete response \[CR\]+ very good partial response \[VGPR\]+ partial response \[PR\]) in patients with multiple myeloma who had previously received bortezomib and either thalidomide or lenalidomide, had relapsed after two or more therapies, and were refractory to the most recently received therapy
Time frame: A0: Subjects evaluated for disease response on Day 24 of Cycles 2, 4, 6, 9, and 12. Onset of response measured on Day 15 of Cycle 1. A1: Subjects evaluated for disease response on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12 and at End of Study.
Population: Analysis population described in reporting groups below
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib (A0) | Best Overall Response Rate (ORR) | 16.7 % of participants w/ PR or better |
| Carfilzomib (A1) | Best Overall Response Rate (ORR) | 23.7 % of participants w/ PR or better |
Secondary
Clinical Benefit Response (CBR) (A0 Only)
sCR, CR, VGPR, PR, and minimal response (MR)
Time frame: Response assessments same as described in primary outcome measure
Population: Response-evaluable Population: Enrolled patients who completed at least 1 cycle of carfilzomib and who underwent disease assessments at Screening, Cycle 1 Day 15, and Cycle 2 Day 24. This analysis set also included patients who discontinued treatment during this time due to an AE that was considered probably related to carfilzomib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Carfilzomib (A0) | Clinical Benefit Response (CBR) (A0 Only) | Complete Response | 0 participants |
| Carfilzomib (A0) | Clinical Benefit Response (CBR) (A0 Only) | Very Good Partial Response | 0 participants |
| Carfilzomib (A0) | Clinical Benefit Response (CBR) (A0 Only) | Partial Response | 7 participants |
| Carfilzomib (A0) | Clinical Benefit Response (CBR) (A0 Only) | Minimal Response | 3 participants |
| Carfilzomib (A0) | Clinical Benefit Response (CBR) (A0 Only) | Clinical Benefit Response (sCR+CR+VGPR+PR+MR) | 10 participants |
Secondary
Clinical Benefit Response (CBR) (A1 Only)
sCR, CR, VGPR, PR, and minimal response (MR)
Time frame: Response assessments same as described in primary outcome measure
Population: Response-Evaluable Population:~1. had measurable disease at Baseline~2. received at least 1 dose of carfilzomib~3. underwent baseline disease response assessments and at least 1 post-baseline disease assessment, or discontinued protocol treatment before Cycle 2 Day 1 due to an AE that was considered to be possibly or probably related to carfilzomib
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Carfilzomib (A0) | Clinical Benefit Response (CBR) (A1 Only) | Clinical Benefit Response (sCR+CR+VGPR+PR+MR) | 95 participants |
| Carfilzomib (A0) | Clinical Benefit Response (CBR) (A1 Only) | Complete Response | 1 participants |
| Carfilzomib (A0) | Clinical Benefit Response (CBR) (A1 Only) | Very Good Partial Response | 13 participants |
| Carfilzomib (A0) | Clinical Benefit Response (CBR) (A1 Only) | Partial Response | 47 participants |
| Carfilzomib (A0) | Clinical Benefit Response (CBR) (A1 Only) | Minimal Response | 34 participants |
Secondary
Duration of Response (A0 Only)
Duration of response (DOR) was calculated separately for subjects with clinical benefit response or overall response. DOR is defined as the time from first evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death.
Time frame: Response assessments same as described in primary outcome measure
Population: Subjects with overall response within the response-evaluable population were included in the analysis of DOR. See analysis population description of response-evaluable population above.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib (A0) | Duration of Response (A0 Only) | 219 days |
Secondary
Duration of Response (A1 Only)
Duration of response (DOR) was calculated separately for subjects with clinical benefit response or overall response. DOR is defined as the time from first evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death.
Time frame: Response assessments same as described in primary outcome measure
Population: Subjects with overall response within the response-evaluable population were included in the analysis of DOR. See overall analysis population description of response-evaluable population above.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib (A0) | Duration of Response (A1 Only) | 7.8 months |
| Carfilzomib (A1) | Duration of Response (A1 Only) | 8.3 months |
Secondary
Overall Survival (A1 Only)
The time from start of treatment to death due to any cause OS was to be censored on the date the subject was last known to be alive for those who were alive or lost to follow-up as of a data analysis cutoff date.
Time frame: Patients were to be followed by telephone contact for disease progression and OS every 3 months after study discontinuation for the first year and every 6 months thereafter for up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib (A0) | Overall Survival (A1 Only) | 15.4 months |
| Carfilzomib (A1) | Overall Survival (A1 Only) | 15.6 months |
Secondary
Progression-free Survival (A0 Only)
The PFS was defined as the time from the start of treatment to progressive disease (PD) determined by PI or until death.
Time frame: Response assessments same as described in primary outcome measure
Population: Response-evaluable Population: Enrolled patients who completed at least 1 cycle of carfilzomib and who underwent disease assessments at Screening, Cycle 1 Day 15, and Cycle 2 Day 24. This analysis set also included patients who discontinued treatment during this time due to an AE that was considered probably related to carfilzomib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib (A0) | Progression-free Survival (A0 Only) | 3.5 months |
Secondary
Progression-free Survival (A1 Only)
The PFS was defined as the time from the start of treatment to progressive disease (PD) determined by PI or until death.
Time frame: Response assessments same as described in primary outcome measure
Population: Response-Evaluable Population:~1. had measurable disease at Baseline~2. received at least 1 dose of carfilzomib~3. underwent baseline disease response assessments and at least 1 post-baseline disease assessment, or discontinued protocol treatment before Cycle 2 Day 1 due to an AE that was considered to be possibly or probably related to carfilzomib
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib (A0) | Progression-free Survival (A1 Only) | 3.7 months |
Secondary
Time to Progression (A0 Only)
Time to progression (TTP) is defined as the time from the study entry (first dose of carfilzomib) to disease progression.
Time frame: Response assessments same as described in primary outcome measure
Population: Response-evaluable Population: Enrolled patients who completed at least 1 cycle of carfilzomib and who underwent disease assessments at Screening, Cycle 1 Day 15, and Cycle 2 Day 24. This analysis set also included patients who discontinued treatment during this time due to an AE that was considered probably related to carfilzomib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib (A0) | Time to Progression (A0 Only) | 3.5 months |
Secondary
Time to Progression (A1 Only)
Time to progression (TTP) is defined as the time from the study entry (first dose of carfilzomib) to disease progression.
Time frame: Response assessments same as described in primary outcome measure
Population: Response-Evaluable Population:~1. had measurable disease at Baseline~2. received at least 1 dose of carfilzomib~3. underwent baseline disease response assessments and at least 1 post-baseline disease assessment, or discontinued protocol treatment before Cycle 2 Day 1 due to an AE that was considered to be possibly or probably related to carfilzomib
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib (A0) | Time to Progression (A1 Only) | 3.9 months |