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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Bortezomib + bevacizumab | Experimental | 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. |
|
| Bortezomib + placebo | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bevacizumab | Drug | 15 mg/kg administered by intravenous infusion |
| |
| 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). |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Virginia (Ginny) Paton, M.D. | Genentech, Inc. | Study Director |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Randomized Patients | Posted | Number | participants | From randomization to the end of study (clinical cut-off; up to 116 weeks). |
|
Participants were monitored for AEs from initiation of treatment to 30 days after treatment termination.
Two patients who were randomized to the BORT + P arm received at least one dose of bevacizumab during the study and were analyzed as bevacizumab-treated patients. Therefore, 50 patients in the BORT + P arm and 50 patients were included in the BORT + BV arm in the safety analysis.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Communications | Hoffman-LaRoche | 800-821-8590 |
| ID | Term |
|---|---|
| D009101 | Multiple Myeloma |
| D054219 | Neoplasms, Plasma Cell |
| ID | Term |
|---|---|
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D020141 | Hemostatic Disorders |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D000068258 | Bevacizumab |
| D000069286 | Bortezomib |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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| Bortezomib |
| Drug |
1.3 mg/m^2 administered by intravenous bolus injection |
|
| placebo | Drug | Intravenous repeating dose |
|
| 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). |
| Progression not resulting in death |
|
| Non-protocol-specified therapy |
|
| Physician Decision |
|
| Withdrawal by Subject |
|
| Other |
|
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG001 | 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. |
|
|
| 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. | Randomized Patients | Posted | Number | 95% Confidence Interval | Percentage of Participants | From randomization to the end of study (clinical cut-off; up to 116 weeks). |
|
|
|
| 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. | Randomized Patients with an overall response | Posted | Median | 95% Confidence Interval | Months | From randomization to the end of study (clinical cut-off; up to 116 weeks). |
|
|
|
|
| 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. | Randomized Patients | Posted | Median | 95% Confidence Interval | Months | From randomization until death from any cause, up until the end of study (clinical cut-off; up to 116 weeks). |
|
|
|
|
| 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. | Randomized Patients | Posted | Median | 95% Confidence Interval | months | From randomization to disease progression or death on study (up to 116 weeks). |
|
|
|
|
| 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. | 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. | Posted | Number | Participants | Participants were monitored for AEs from initiation of treatment to 30 days after treatment termination (up to 122 weeks). |
|
|
|
| 26 |
| 50 |
| 41 |
| 50 |
| EG001 | 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. | 24 | 50 | 43 | 50 |
| Febrile Neutropenia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
|
| Atrial Flutter | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Pericarditis | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Vertigo | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Ulcerative Keratitis | Eye disorders | MedDRA | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Lower Gastrointestinal Haemorrhage | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Rectal Haemorrhage | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Rectal Perforation | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Upper Gastrointestinal Haemorrhage | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA | Systematic Assessment |
|
| Drug Withdrawal Syndrome | General disorders | MedDRA | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA | Systematic Assessment |
|
| Abscess Jaw | Infections and infestations | MedDRA | Systematic Assessment |
|
| Appendicitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Arthritis Bacterial | Infections and infestations | MedDRA | Systematic Assessment |
|
| Bacteraemia | Infections and infestations | MedDRA | Systematic Assessment |
|
| Bacterial Infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Bronchitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Diverticulitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Gastrointestinal Infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Upper Respiratory Tract Infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Ureteritis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Viral Infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Hip Fracture | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Tibia Fracture | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Failure To Thrive | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Hypercalcaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Uterine Leiomyoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Haemorrhage Intracranial | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Peripheral Sensory Neuropathy | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Subarachnoid Haemorrhage | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Transient Ischaemic Attack | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Renal Failure Acute | Renal and urinary disorders | MedDRA | Systematic Assessment |
|
| Renal Failure Chronic | Renal and urinary disorders | MedDRA | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Pulmonary Embolism | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Erythema Multiforme | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA | Systematic Assessment |
|
| Orthostatic Hypotension | Vascular disorders | MedDRA | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA | Systematic Assessment |
|
| Neuralgia | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Neuropathy Peripheral | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA | Systematic Assessment |
|
| Upper Respiratory Tract Infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Urinary Tract Infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
| D002318 |
| Cardiovascular Diseases |
| D010265 | Paraproteinemias |
| D001796 | Blood Protein Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D006474 | Hemorrhagic Disorders |
| D008232 | Lymphoproliferative Disorders |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D001897 | Boronic Acids |
| D000148 | Acids, Noncarboxylic |
| D000143 | Acids |
| D007287 | Inorganic Chemicals |
| D001896 | Boron Compounds |
| D009930 | Organic Chemicals |
| D011719 | Pyrazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
Unstratified analysis. |
| Log Rank |
| 0.6665 |
The tests were exploratory because patients were not randomized to the two arms with respect to response status. |
| Hazard Ratio (HR) |
| 0.836 |
| 2-Sided |
| 95 |
| 0.369 |
| 1.893 |
The hazard ratios were estimated using Cox regression. |
| Superiority or Other |
Unstratified analysis |
| Log Rank |
| 0.2634 |
| Hazard Ratio (HR) |
| 0.608 |
| 2-Sided |
| 95 |
| 0.251 |
| 1.468 |
The hazard ratios were estimated using Cox regression. |
| Superiority or Other |
| Unstratified Analysis. | Log Rank | 0.2009 | Hazard Ratio (HR) | 0.713 | 2-Sided | 95 | 0.424 | 1.200 | Hazard ratio relative to BORT + P was estimated using Cox regression. | Superiority or Other |
| Febrile neutropenia (any grade) |
|
| Gastrointestinal Perforation (Any Grade) |
|
| Hypertension (Grade >= 3) |
|
| Left Ventricular Systolic Dysfunction (Grade >= 3) |
|
| Neutropenia (Grade >= 3) |
|
| Osteonecrosis of the Jaw |
|
| Peripheral Neuropathy (Grade >= 3) |
|
| Pulmonary and CNS Bleeding (Any Grade) |
|
| Thrombocytopenia (Grade >= 3) |
|
| Vernous Thromboembolic Events (Grade >=3) |
|