Multiple Myeloma
Conditions
Keywords
Avastin, AMBER, Myeloma, Velcade
Brief summary
This is a randomized, blinded, placebo-controlled, multicenter, Phase II study designed to provide a preliminary assessment of the safety and efficacy of combining bevacizumab with bortezomib in patients with relapsed or refractory multiple myeloma.
Interventions
DRUGBevacizumab
15 mg/kg administered by intravenous infusion
DRUGBortezomib
1.3 mg/m\^2 administered by intravenous bolus injection
DRUGplacebo
Intravenous repeating dose
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 * Previously diagnosed with multiple myeloma * Relapsed or refractory multiple myeloma with disease progression following one to three prior treatment regimens * Measurable multiple myeloma disease
Exclusion criteria
* Grade ≥ 2 peripheral neuropathy * Use of corticosteroids within 21 days prior to Day 1 * Use of other anti-myeloma therapy within 21 days prior to Day 1 * Intolerance to bortezomib or compounds containing boron * Life expectancy of \< 12 weeks * Current, recent, or planned participation in an experimental drug study * Active malignancy other than multiple myeloma within 5 years before screening * Prior treatment with bevacizumab * Inadequately controlled hypertension * Prior history of hypertensive crisis or hypertensive encephalopathy * New York Heart Association (NYHA) Class II or greater congestive heart failure (CHF) * Decreased left ventricular function at study entry * History of myocardial infarction or unstable angina within 6 months prior to Day 1 * History of stroke or transient ischemic attack within 6 months prior to Day 1 * Significant vascular disease or recent peripheral arterial thrombosis within 6 months prior to Day 1 * Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, or anticipation of need for major surgical procedure during the course of the study * Core biopsy or other minor surgical procedure, including placement of a vascular access device within 7 days prior to Day 1 * History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 * Serious, non-healing wound, active ulcer, or untreated bone fracture (for pathologic bone fractures consistent with multiple myeloma, patients may be eligible if no treatment is planned) * Albuminuria * Known hypersensitivity to any component of bevacizumab * Pregnancy (positive pregnancy test) or lactation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From randomization to disease progression or death on study (up to 116 weeks). | Progression-free survival (PFS) was defined as the time from randomization to disease progression or death on study from any cause within 30 days of the last response assessment. Disease progression was determined by the investigator using the International Myeloma Working Group's (IMWG) uniform response criteria. Median PFS was estimated using Kaplan-Meier methodology. For patients who were alive at the time of the analysis and whose disease had not yet progressed, PFS was censored at the time of the last response assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an Overall Response | From randomization to the end of study (clinical cut-off; up to 116 weeks). | Overall response was defined as a stringent complete response, complete response, very good partial response, or partial response (sCR, CR, VGPR, and PR, respectively) determined on two consecutive assessments ≤ 6 weeks apart and before the initiation of any new anti-tumor therapy, as assessed by the investigator using the International Myeloma Working Group's (IMWG's) uniform response criteria. Patients without a post-baseline response assessment or who died prior to their first scheduled response assessment were considered non-responders. |
| Percentage of Participants With an Overall Response | From randomization to the end of study (clinical cut-off; up to 116 weeks). | Overall response was defined as a stringent complete response, complete response, very good partial response, or partial response (sCR, CR, VGPR, and PR) determined on two consecutive assessments ≤ 6 weeks apart and before the initiation of any new anti-tumor therapy, as assessed by the investigator using the IMWG's uniform response criteria. Patients without a post-baseline response assessment or who died prior to their first scheduled response assessment were considered non-responders. |
| Duration of Response | From randomization to the end of study (clinical cut-off; up to 116 weeks). | Duration of response was defined as the time from the initial response to disease progression or death on study. Disease progression was determined by the investigator using the IMWG's uniform response criteria and defined as an increase of ≥25% from best response in: Serum M-protein and/or Urine M-protein and/or Marrow plasma cells; or new or increased plasmacytomas or bone lesions; or hypercalcemia due to myeloma. Duration of response was estimated using Kaplan-Meier. For patients who had not progressed or died, duration of response was censored at the date of the last response assessment. |
| Overall Survival (OS) | From randomization until death from any cause, up until the end of study (clinical cut-off; up to 116 weeks). | Overall survival was defined as the duration of time from randomization until death from any cause. All deaths were included, whether they occurred on study treatment or following treatment discontinuation. Overall survival was estimated using Kaplan-Meier. For patients who had not died, overall survival was censored at the date that the patient was last known to be alive. |
| Number of Participants With Selected Adverse Events (AEs) | Participants were monitored for AEs from initiation of treatment to 30 days after treatment termination (up to 122 weeks). | Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v3.0. All serious adverse events are listed in the Adverse Event Reporting section. |
Participant flow
Recruitment details
Phase II, randomized, blinded, placebo-controlled, multicenter study designed to provide a preliminary assessment of the safety and efficacy of combining bevacizumab with bortezomib in patients with relapsed or refractory multiple myeloma starting 11 July 2007 and completing 9 November 2009.
Participants by arm
| Arm | Count |
|---|---|
| BORT + P Participants received bortezomib 1.3 mg/m\^2 administered as a 3- to 5-second bolus intravenous injection on Days 1, 4, 8, and 11 of a 21-day cycle for a maximum of eight cycles and placebo intravenous infusion on the first day of each 21-day cycle during the blinded treatment phase. At the completion of the 8-cycle treatment phase, participants entered the observation phase until disease progression. | 53 |
| BORT + BV Participants received bortezomib 1.3 mg/m\^2 administered as a 3- to 5-second bolus intravenous injection on Days 1, 4, 8, and 11 of a 21-day cycle for a maximum of eight cycles and bevacizumab 15 mg/kg administered by intravenous infusion on the first day of each 21-day cycle during the blinded treatment phase. After completion of 8 cycles, participants could continue to receive bevacizumab as monotherapy until disease progression. | 49 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Death | 4 | 2 |
| Overall Study | Non-protocol-specified therapy | 7 | 5 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Physician Decision | 2 | 4 |
| Overall Study | Progression not resulting in death | 24 | 20 |
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | BORT + BV | Total | BORT + P |
|---|---|---|---|
| Age, Continuous | 65.6 years STANDARD_DEVIATION 9.3 | 65.2 years STANDARD_DEVIATION 9.2 | 64.9 years STANDARD_DEVIATION 9.2 |
| Sex: Female, Male Female | 20 Participants | 43 Participants | 23 Participants |
| Sex: Female, Male Male | 29 Participants | 59 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 41 / 50 | 43 / 50 |
| serious Total, serious adverse events | 26 / 50 | 24 / 50 |
Outcome results
Primary
Progression-free Survival (PFS)
Progression-free survival (PFS) was defined as the time from randomization to disease progression or death on study from any cause within 30 days of the last response assessment. Disease progression was determined by the investigator using the International Myeloma Working Group's (IMWG) uniform response criteria. Median PFS was estimated using Kaplan-Meier methodology. For patients who were alive at the time of the analysis and whose disease had not yet progressed, PFS was censored at the time of the last response assessment.
Time frame: From randomization to disease progression or death on study (up to 116 weeks).
Population: Randomized Patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BORT + P | Progression-free Survival (PFS) | 5.1 months |
| BORT + BV | Progression-free Survival (PFS) | 6.2 months |
Comparison: Unstratified Analysis.p-value: 0.200995% CI: [0.424, 1.2]Log Rank
Comparison: The null hypothesis was that there was no difference between the 2 treatment groups. The alternative hypothesis was that progression-free survival was longer in the BORT + BV group. Stratified Analysis.p-value: 0.280495% CI: [0.432, 1.276]Log Rank
Secondary
Duration of Response
Duration of response was defined as the time from the initial response to disease progression or death on study. Disease progression was determined by the investigator using the IMWG's uniform response criteria and defined as an increase of ≥25% from best response in: Serum M-protein and/or Urine M-protein and/or Marrow plasma cells; or new or increased plasmacytomas or bone lesions; or hypercalcemia due to myeloma. Duration of response was estimated using Kaplan-Meier. For patients who had not progressed or died, duration of response was censored at the date of the last response assessment.
Time frame: From randomization to the end of study (clinical cut-off; up to 116 weeks).
Population: Randomized Patients with an overall response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BORT + P | Duration of Response | 6.0 Months |
| BORT + BV | Duration of Response | 6.9 Months |
Comparison: Stratified analysisp-value: 0.917995% CI: [0.404, 2.261]Log Rank
Comparison: Unstratified analysis.p-value: 0.666595% CI: [0.369, 1.893]Log Rank
Secondary
Number of Participants With an Overall Response
Overall response was defined as a stringent complete response, complete response, very good partial response, or partial response (sCR, CR, VGPR, and PR, respectively) determined on two consecutive assessments ≤ 6 weeks apart and before the initiation of any new anti-tumor therapy, as assessed by the investigator using the International Myeloma Working Group's (IMWG's) uniform response criteria. Patients without a post-baseline response assessment or who died prior to their first scheduled response assessment were considered non-responders.
Time frame: From randomization to the end of study (clinical cut-off; up to 116 weeks).
Population: Randomized Patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BORT + P | Number of Participants With an Overall Response | 23 participants |
| BORT + BV | Number of Participants With an Overall Response | 25 participants |
Secondary
Number of Participants With Selected Adverse Events (AEs)
Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v3.0. All serious adverse events are listed in the Adverse Event Reporting section.
Time frame: Participants were monitored for AEs from initiation of treatment to 30 days after treatment termination (up to 122 weeks).
Population: Safety population: all patients who were randomized and received any amount of study treatment. Two patients who randomized to the BORT + P arm received at least 1 dose of bevacizumab and were analyzed as bevacizumab-treated patients. Therefore, the safety analysis included 50 patients in the BORT + P arm and 50 patients in the BORT + BV arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BORT + P | Number of Participants With Selected Adverse Events (AEs) | Hypertension (Grade >= 3) | 0 Participants |
| BORT + P | Number of Participants With Selected Adverse Events (AEs) | Gastrointestinal Perforation (Any Grade) | 1 Participants |
| BORT + P | Number of Participants With Selected Adverse Events (AEs) | Neutropenia (Grade >= 3) | 6 Participants |
| BORT + P | Number of Participants With Selected Adverse Events (AEs) | Left Ventricular Systolic Dysfunction (Grade >= 3) | 1 Participants |
| BORT + P | Number of Participants With Selected Adverse Events (AEs) | Peripheral Neuropathy (Grade >= 3) | 7 Participants |
| BORT + P | Number of Participants With Selected Adverse Events (AEs) | Osteonecrosis of the Jaw | 0 Participants |
| BORT + P | Number of Participants With Selected Adverse Events (AEs) | Pulmonary and CNS Bleeding (Any Grade) | 0 Participants |
| BORT + P | Number of Participants With Selected Adverse Events (AEs) | Bleeding other than pulmonary or CNS (Grade >=3) | 1 Participants |
| BORT + P | Number of Participants With Selected Adverse Events (AEs) | Thrombocytopenia (Grade >= 3) | 15 Participants |
| BORT + P | Number of Participants With Selected Adverse Events (AEs) | Febrile neutropenia (any grade) | 1 Participants |
| BORT + P | Number of Participants With Selected Adverse Events (AEs) | Vernous Thromboembolic Events (Grade >=3) | 1 Participants |
| BORT + P | Number of Participants With Selected Adverse Events (AEs) | Arterial thromboembolic events (any grade) | 0 Participants |
| BORT + BV | Number of Participants With Selected Adverse Events (AEs) | Vernous Thromboembolic Events (Grade >=3) | 0 Participants |
| BORT + BV | Number of Participants With Selected Adverse Events (AEs) | Arterial thromboembolic events (any grade) | 1 Participants |
| BORT + BV | Number of Participants With Selected Adverse Events (AEs) | Bleeding other than pulmonary or CNS (Grade >=3) | 2 Participants |
| BORT + BV | Number of Participants With Selected Adverse Events (AEs) | Gastrointestinal Perforation (Any Grade) | 0 Participants |
| BORT + BV | Number of Participants With Selected Adverse Events (AEs) | Hypertension (Grade >= 3) | 8 Participants |
| BORT + BV | Number of Participants With Selected Adverse Events (AEs) | Osteonecrosis of the Jaw | 1 Participants |
| BORT + BV | Number of Participants With Selected Adverse Events (AEs) | Febrile neutropenia (any grade) | 1 Participants |
| BORT + BV | Number of Participants With Selected Adverse Events (AEs) | Left Ventricular Systolic Dysfunction (Grade >= 3) | 0 Participants |
| BORT + BV | Number of Participants With Selected Adverse Events (AEs) | Neutropenia (Grade >= 3) | 10 Participants |
| BORT + BV | Number of Participants With Selected Adverse Events (AEs) | Peripheral Neuropathy (Grade >= 3) | 8 Participants |
| BORT + BV | Number of Participants With Selected Adverse Events (AEs) | Pulmonary and CNS Bleeding (Any Grade) | 1 Participants |
| BORT + BV | Number of Participants With Selected Adverse Events (AEs) | Thrombocytopenia (Grade >= 3) | 15 Participants |
Secondary
Overall Survival (OS)
Overall survival was defined as the duration of time from randomization until death from any cause. All deaths were included, whether they occurred on study treatment or following treatment discontinuation. Overall survival was estimated using Kaplan-Meier. For patients who had not died, overall survival was censored at the date that the patient was last known to be alive.
Time frame: From randomization until death from any cause, up until the end of study (clinical cut-off; up to 116 weeks).
Population: Randomized Patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BORT + P | Overall Survival (OS) | 24.0 Months |
| BORT + BV | Overall Survival (OS) | NA Months |
Comparison: Unstratified analysisp-value: 0.263495% CI: [0.251, 1.468]Log Rank
Comparison: Stratified analysisp-value: 0.313495% CI: [0.258, 1.552]Log Rank
Secondary
Percentage of Participants With an Overall Response
Overall response was defined as a stringent complete response, complete response, very good partial response, or partial response (sCR, CR, VGPR, and PR) determined on two consecutive assessments ≤ 6 weeks apart and before the initiation of any new anti-tumor therapy, as assessed by the investigator using the IMWG's uniform response criteria. Patients without a post-baseline response assessment or who died prior to their first scheduled response assessment were considered non-responders.
Time frame: From randomization to the end of study (clinical cut-off; up to 116 weeks).
Population: Randomized Patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BORT + P | Percentage of Participants With an Overall Response | 43.4 Percentage of Participants |
| BORT + BV | Percentage of Participants With an Overall Response | 51.0 Percentage of Participants |