A Study of Bevacizumab in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma (AMBER)

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Blinded, Placebo-Controlled, Multicenter, Phase II Study of Bevacizumab in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Bortezomib
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bortezomib + bevacizumab<br>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. | Drug: Bevacizumab<br>* 15 mg/kg administered by intravenous infusion<br>Drug: Bortezomib<br>* 1.3 mg/m^2 administered by intravenous bolus injection<br>|
| Active Comparator: Bortezomib + placebo<br>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. | Drug: Bortezomib<br>* 1.3 mg/m^2 administered by intravenous bolus injection<br>Drug: placebo<br>* Intravenous repeating dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From randomization to disease progression or death on study (up to 116 weeks). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From randomization to the end of study (clinical cut-off; up to 116 weeks). | 
| 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. | From randomization to the end of study (clinical cut-off; up to 116 weeks). | 
| 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. | From randomization to the end of study (clinical cut-off; up to 116 weeks). | 
| 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. | From randomization until death from any cause, up until the end of study (clinical cut-off; up to 116 weeks). | 
| 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. | Participants were monitored for AEs from initiation of treatment to 30 days after treatment termination (up to 122 weeks). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Avastin, AMBER, Myeloma, Velcade