Colorectal Cancer
Conditions
Brief summary
This is a Phase 2 multicenter, randomized, parallel arms, double-blind study of vanucizumab to evaluate the efficacy and safety of vanucizumab in combination with oxaliplatin, folinic acid, and 5-fluorouracil (5-FU) (mFOLFOX-6) versus bevacizumab (Avastin) + mFOLFOX-6 in participants with previously untreated metastatic colorectal cancer (mCRC). The study consists of 2 parts: a safety run-in open-label, single-arm part (Part 1) and a randomized, parallel-arms, double-blind part (Part 2). During Part 1 at least 6 eligible participants will receive 2000 milligrams (mg) vanucizumab every 2 weeks + mFOLFOX-6 in order to confirm the dose and schedule that will be used in Part 2. In Part 2, all eligible participants will be randomized in a ratio of 1:1 to receive either mFOLFOX-6 + vanucizumab or mFOLFOX-6 + bevacizumab. Study treatment (induction and maintenance) will be given on Day 1 of each 14-day cycle. Induction therapy will consist of up to 8 cycles of mFOLFOX-6 plus either bevacizumab or vanucizumab. Maintenance therapy will consist of 5-fluorouracil and folinic acid plus either vanucizumab or bevacizumab for up to 24 months or until disease progression, unacceptable toxicity, Investigator decision or consent withdrawal, whichever occurs first.
Interventions
DRUG5-FU
5-FU will be administered according to dose and schedule described in respective arm.
DRUGBevacizumab
Bevacizumab will be administered according to dose and schedule described in respective arm.
DRUGFolinic acid
Folinic acid will be administered according to dose and schedule described in respective arm.
DRUGOxaliplatin
Oxaliplatin will be administered according to dose and schedule described in respective arm.
DRUGVanucizumab
Vanucizumab will be administered according to dose and schedule described in respective arm.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed mCRC not amenable to potentially curative resection with at least one measurable metastatic lesion, as defined by RECIST v1.1 * Eastern Cooperative Oncology Group (World Health Organization) performance status of 0 or 1 * Adequate hematologic, liver, coagulation, renal, and cardiovascular function * Recovery from all reversible AEs of previous medical therapies to baseline or National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 1, except for alopecia (any grade) * Negative serum pregnancy test within 7 days prior to starting study treatment in premenopausal women and women less than (\< 2) years after the onset of menopause
Exclusion criteria
* Any prior systemic therapy (including chemotherapy, antibody therapy, tyrosine kinase inhibitors, immunotherapy, hormonal therapy) before Day 1 of Cycle 1 for treatment of mCRC * Malignancies other than CRC within 5 years prior to randomization, except for those with a minimal risk of metastasis or death, such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, ductal carcinoma in situ treated surgically with curative intent * Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to Day 1 of Cycle 1, except palliative radiotherapy to bone lesions within 7 days prior to Day 1 of Cycle 1 * Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to Day 1 of Cycle * Pregnant or lactating women * Symptomatic central nervous system (CNS) metastases or carcinomatous meningitis. Asymptomatic patients must be clinically stable with regard to their CNS/ meningeal metastatic involvement, have completed previous therapy (including radiation and/ or surgery) at least 4 weeks prior to study drug administration, are not receiving steroid therapy or taper, and are not receiving anti-convulsive medication for any CNS involvement * Active infection requiring IV antibiotics * Active autoimmune disease that is not controlled by nonsteroidal anti-inflammatory drugs (NSAIDs), inhaled corticosteroids, or the equivalent of less than or equal to (\</=) 10 mg/day prednisone * Sensory peripheral neuropathy greater than or equal to (\>/=) Grade 2 * Significant cardiovascular or cerebrovascular disease within 6 months prior to Day 1 of Cycle 1 * Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation * Current use of anticoagulants at therapeutic doses within 7 days prior to study drug administration. Prophylactic use of unfractioned heparin or low molecular weight heparin is permitted * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 of Cycle 1 or abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 60 days prior to Day 1 of Cycle 1 * History of intra-abdominal inflammatory process within 6 months prior to Day 1 of Cycle 1 including but not limited to peptic ulcer disease, diverticulitis, or colitis * Colonic prosthesis (stent) implant in place * History of abdominal or tracheo-oesophageal fistula or gastrointestinal (GI) perforation or intra abdominal abscess within 6 months prior to Day 1 of Cycle 1 * History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or a requirement for routine parenteral hydration, parenteral nutrition, or tube feeding within 6 months prior to Day 1 of Cycle 1 * Chronic daily treatment with NSAID (occasional use for the symptomatic relief of medical conditions, for example headache or fever is allowed) * Chronic daily treatment with corticosteroids (dose \> 10 mg/day methylprednisolone equivalent) excluding inhaled steroids * Evidence of abdominal free air not explained by paracentesis or recent surgical procedure * Metastatic disease that involve major airways or blood vessels, or centrally located mediastinal tumor masses (\< 30 millimeter from the carina) of large volume * History of bronchopulmonary hemorrhage NCI CTCAE \>/= Grade 2 within 2 months prior to randomization * Severe, nonhealing or open wound, active ulcer, or untreated bone fracture * Known dihydropyrimidine dehydrogenase deficiency or thymidylate synthase gene polymorphism predisposing the patient for 5-FU toxicity * Any other condition, diseases, metabolic dysfunction, active or uncontrolled infections/inflammation, physical examination finding, mental status or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates participation in the clinical study due to safety concerns, compliance with clinical study procedures or that may affect the interpretation of the results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS), Time to Event | Baseline, every 8 weeks, up to approximately 29 months | Efficacy of vanucizumab was evaluated in terms of PFS as Investigator-Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). PFS was defined as the time between randomization and the date of first documented disease progression or death from any cause on study, whichever occurred first. Death on study was defined as death from any cause within 30 days of the last study treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Objective Response, as Assessed Using RECIST v. 1.1 | Baseline (within 28 days prior to Day 1), then every 8 weeks until PD, start of other anticancer therapy, withdrawal of consent, or death (up to approximately 29 months) | Efficacy of vanucizumab was evaluated in terms of duration of objective response as assessed using RECIST v. 1.1. This was computed using the PFS definition with death on study (deaths that occurred outside the 30 days window from the last study treatment are excluded). |
| Overall Survival (OS) | Baseline until death from any cause (maximum up to approximately 3.5 years) | Efficacy of vanucizumab was evaluated in terms of OS as the time from randomization until death from any cause. 99999 = data not estimable due to the low number of deaths. |
| Percentage of Participants With Adverse Events (AEs) | Up to approximately 29 months | Safety is evaluated in terms of percentage of participants with at least one serious adverse event and percentage of participants with at least one adverse event. |
| Number of Participants With Human Anti-human Antibodies (HAHAs) Against Vanucizumab | End of study (EoS, within 28 to 42 days after last dose, latest at 29 months) | Safety is evaluated in terms of number of participants with Human Anti-human Antibodies (HAHAs) Against Vanucizumab. |
| Area Under the Plasma Concentration-Time Curve (AUC) of Vanucizumab | Cycles 1 and 8 of parts 1 and 2 | PK profile of vanucizumab was evaluated in terms of AUC |
| Maximum Observed Plasma Concentration (Cmax) of Vanucizumab | Cycles 1 and 8 of parts 1 and 2 | PK profile of vanucizumab was evaluated in terms of Cmax |
| Percentage of Participants With Objective Response (ORR) as Assessed Using RECIST v. 1.1 | Baseline (within 28 days prior to Day 1), then every 8 weeks until progressive disease (PD), start of other anticancer therapy, withdrawal of consent, or death (up to approximately 29 months) | Efficacy of vanucizumab was evaluated in terms of Percentage of Participants With ORR as Investigator-Assessed Using RECIST v. 1.1. Best Overall Confirmed Response. |
| Time to Reach Cmax (Tmax) of Vanucizumab | Cycles 1 and 8 of parts 1 and 2 | PK profile of vanucizumab was evaluated in terms of Tmax |
| Plasma Terminal Half-Life (t1/2) of Vanucizumab | Cycle 8 | PK profile of vanucizumab was evaluated in terms of t1/2, values are reported for cycle 8 of both part 1 (safety run-in) and part 2 of the study. |
| Plasma Clearance at Steady State (CLss) of Vanucizumab | Cycle 8 | PK profile of vanucizumab was evaluated in terms of CLss, values are reported for cycle 8 of both part 1 (safety run-in) and part 2 of the study. |
| Volume of Distribution at Steady State (Vss) of Vanucizumab | Cycle 8 | PK profile of vanucizumab was evaluated in terms of Vss, values are reported for cycle 8 of both part 1 (safety run-in) and part 2 of the study. |
| Cmax Accumulation Ratio (AR) of Vanucizumab | Cycle 8 | PK profile of vanucizumab was evaluated in terms of Cmax Ratio, values are reported for cycle 8 of both part 1 (safety run-in) and part 2 of the study. |
| Minimum Observed Plasma Concentration (Clast) of Vanucizumab | Cycles 1 and 8 of parts 1 and 2 | PK profile of vanucizumab was evaluated in terms of Clast |
Countries
Australia, Austria, Belgium, France, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Participants with previously untreated metastatic colorectal cancer (mCRC) as defined by RECIST v1.1 were enrolled globally from 7 countries.
Participants by arm
| Arm | Count |
|---|---|
| Safety Run-In 8 eligible participants received 2000 milligrams (mg) vanucizumab + mFOLFOX-6 every two weeks for up to 8 cycles in order to confirm the dose and schedule for the randomized part. | 8 |
| Vanucizumab + mFOLFOX-6 In the induction therapy participants received vanucizumab at a dose of 2000 mg as IV infusion; oxaliplatin at a dose of 85 mg/m\^2 as IV infusion; folinic acid at a dose of 400 mg/m\^2 as IV infusion; and 5-FU at a dose of 400 mg/m\^2 as starting IV bolus followed by 2400 mg/m\^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). Subsequently, in the maintenance therapy participants received vanucizumab at a dose of 2000 mg as IV infusion; folinic acid at a dose of 400 mg/m\^2 as IV infusion; and 5-FU at a dose of 400 mg/m\^2 as starting IV bolus followed by 2400 mg/m\^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months. | 94 |
| Bevacizumab + mFOLFOX-6 In the induction therapy participants received bevacizumab at a dose of 5 milligram per kilogram (mg/kg) as IV infusion; oxaliplatin at a dose of 85 mg/m\^2 as IV infusion; folinic acid at a dose of 400 mg/m\^2 as IV infusion; and 5-FU at a dose of 400 mg/m\^2 as starting IV bolus followed by 2400 mg/m\^2 as IV infusion every 2 weeks for up to 8 cycles (approximately 4 months). Subsequently, in the maintenance therapy participants received bevacizumab at a dose of 5 milligram per kilogram (mg/kg) as IV infusion; folinic acid at a dose of 400 mg/m\^2 as IV infusion; and 5-FU at a dose of 400 mg/m\^2 as starting IV bolus followed by 2400 mg/m\^2 as IV infusion every 2 weeks until disease progression, unacceptable toxicities, consent withdrawal or Investigator's decision for a maximum of 24 months. | 95 |
| Total | 197 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 18 | 11 |
| Overall Study | Non-compliance | 0 | 1 | 0 |
| Overall Study | Physician Decision | 2 | 19 | 14 |
| Overall Study | Progressive disease | 3 | 32 | 50 |
| Overall Study | Reason not specified | 0 | 9 | 10 |
| Overall Study | Study terminated by sponsor | 0 | 6 | 6 |
| Overall Study | Withdrawal by Subject | 0 | 9 | 4 |
Baseline characteristics
| Characteristic | Safety Run-In | Vanucizumab + mFOLFOX-6 | Bevacizumab + mFOLFOX-6 | Total |
|---|---|---|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 10.8 | 62.7 years STANDARD_DEVIATION 11 | 62.3 years STANDARD_DEVIATION 10.6 | 62.5 years STANDARD_DEVIATION 0.2 |
| Age, Customized Adults (18-64 years) | 4 Participants | 48 Participants | 53 Participants | 105 Participants |
| Age, Customized From 65-84 years | 4 Participants | 46 Participants | 42 Participants | 92 Participants |
| Sex: Female, Male Female | 3 Participants | 38 Participants | 57 Participants | 98 Participants |
| Sex: Female, Male Male | 5 Participants | 56 Participants | 38 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 8 | 24 / 93 | 27 / 95 |
| other Total, other adverse events | 8 / 8 | 91 / 93 | 94 / 95 |
| serious Total, serious adverse events | 3 / 8 | 46 / 93 | 41 / 95 |
Outcome results
Primary
Progression-free Survival (PFS), Time to Event
Efficacy of vanucizumab was evaluated in terms of PFS as Investigator-Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). PFS was defined as the time between randomization and the date of first documented disease progression or death from any cause on study, whichever occurred first. Death on study was defined as death from any cause within 30 days of the last study treatment.
Time frame: Baseline, every 8 weeks, up to approximately 29 months
Population: This analysis was based on the ITT population, which consisted of all participants who were randomized (Part II only) and received any amount of the study treatment (5 FU/folinic acid, oxaliplatin, bevacizumab, or vanucizumab) in the bevacizumab + mFOLFOX-6 and vanucizumab + mFOLFOX-6 arms. Participants in the safety-run in were not included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vanucizumab + mFOLFOX-6 | Progression-free Survival (PFS), Time to Event | 338.0 days |
| Bevacizumab + mFOLFOX-6 | Progression-free Survival (PFS), Time to Event | 309.0 days |
Comparison: Kaplan-Meier methods were used to estimate median PFS for each treatment arm and the 95% CIs for median PFS were computed using the Brookmeyer and Crowley method. The stratified Cox proportional hazard was used to estimate the hazard ratio (i.e., the magnitude of the treatment effect) and the corresponding 95% confidence interval. The stratification factors are number of metastatic sites (1 vs. \>1) and country/region (USA vs rest of the world).p-value: =0.675395% CI: [0.6, 1.39]Regression, Cox
Secondary
Area Under the Plasma Concentration-Time Curve (AUC) of Vanucizumab
PK profile of vanucizumab was evaluated in terms of AUC
Time frame: Cycles 1 and 8 of parts 1 and 2
Population: This endpoint was only reported for arms in which the participants received vanucizumab.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Vanucizumab + mFOLFOX-6 | Area Under the Plasma Concentration-Time Curve (AUC) of Vanucizumab | Cycle 1 | 73600 hr*ug/ml | Geometric Coefficient of Variation 20.7 |
| Vanucizumab + mFOLFOX-6 | Area Under the Plasma Concentration-Time Curve (AUC) of Vanucizumab | Cycle 8 | 112000 hr*ug/ml | Geometric Coefficient of Variation 11.2 |
| Bevacizumab + mFOLFOX-6 | Area Under the Plasma Concentration-Time Curve (AUC) of Vanucizumab | Cycle 8 | 82100 hr*ug/ml | Geometric Coefficient of Variation 31.6 |
| Bevacizumab + mFOLFOX-6 | Area Under the Plasma Concentration-Time Curve (AUC) of Vanucizumab | Cycle 1 | 63500 hr*ug/ml | Geometric Coefficient of Variation 27.2 |
Secondary
Cmax Accumulation Ratio (AR) of Vanucizumab
PK profile of vanucizumab was evaluated in terms of Cmax Ratio, values are reported for cycle 8 of both part 1 (safety run-in) and part 2 of the study.
Time frame: Cycle 8
Population: This endpoint was only reported for arms in which the participants received vanucizumab.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vanucizumab + mFOLFOX-6 | Cmax Accumulation Ratio (AR) of Vanucizumab | 1.51 Ratio | Geometric Coefficient of Variation 27.2 |
| Bevacizumab + mFOLFOX-6 | Cmax Accumulation Ratio (AR) of Vanucizumab | 1.63 Ratio | Geometric Coefficient of Variation 36.2 |
Secondary
Duration of Objective Response, as Assessed Using RECIST v. 1.1
Efficacy of vanucizumab was evaluated in terms of duration of objective response as assessed using RECIST v. 1.1. This was computed using the PFS definition with death on study (deaths that occurred outside the 30 days window from the last study treatment are excluded).
Time frame: Baseline (within 28 days prior to Day 1), then every 8 weeks until PD, start of other anticancer therapy, withdrawal of consent, or death (up to approximately 29 months)
Population: This analysis was based on the ITT population, which consisted of all participants in the bevacizumab + mFOLFOX-6 and vanucizumab + mFOLFOX-6 arms. Participants in the safety-run in were not included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vanucizumab + mFOLFOX-6 | Duration of Objective Response, as Assessed Using RECIST v. 1.1 | 342 days |
| Bevacizumab + mFOLFOX-6 | Duration of Objective Response, as Assessed Using RECIST v. 1.1 | 304 days |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Vanucizumab
PK profile of vanucizumab was evaluated in terms of Cmax
Time frame: Cycles 1 and 8 of parts 1 and 2
Population: This endpoint was only reported for arms in which the participants received vanucizumab.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Vanucizumab + mFOLFOX-6 | Maximum Observed Plasma Concentration (Cmax) of Vanucizumab | Cycle 1 | 463 ug/ml | Geometric Coefficient of Variation 18.5 |
| Vanucizumab + mFOLFOX-6 | Maximum Observed Plasma Concentration (Cmax) of Vanucizumab | Cycle 8 | 685 ug/ml | Geometric Coefficient of Variation 17.6 |
| Bevacizumab + mFOLFOX-6 | Maximum Observed Plasma Concentration (Cmax) of Vanucizumab | Cycle 1 | 500 ug/ml | Geometric Coefficient of Variation 26.3 |
| Bevacizumab + mFOLFOX-6 | Maximum Observed Plasma Concentration (Cmax) of Vanucizumab | Cycle 8 | 794 ug/ml | Geometric Coefficient of Variation 38.2 |
Secondary
Minimum Observed Plasma Concentration (Clast) of Vanucizumab
PK profile of vanucizumab was evaluated in terms of Clast
Time frame: Cycles 1 and 8 of parts 1 and 2
Population: Data were collected and analyzed for the reported arms only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Vanucizumab + mFOLFOX-6 | Minimum Observed Plasma Concentration (Clast) of Vanucizumab | Cycle 1 | 103 ug/ml | Geometric Coefficient of Variation 67.2 |
| Vanucizumab + mFOLFOX-6 | Minimum Observed Plasma Concentration (Clast) of Vanucizumab | Cycle 8 | 361 ug/ml | Geometric Coefficient of Variation 39.8 |
Secondary
Number of Participants With Human Anti-human Antibodies (HAHAs) Against Vanucizumab
Safety is evaluated in terms of number of participants with Human Anti-human Antibodies (HAHAs) Against Vanucizumab.
Time frame: End of study (EoS, within 28 to 42 days after last dose, latest at 29 months)
Population: Endpoint includes only arms in which the participants received vanucizumab. n for the vanucizumab + mFOLFOX-6 arm changed from 94 to 93 due to the withdrawal of a participant that was randomized to this arm, but received only chemotherapy before leaving the study. This participant is included in the ITT population but not in the safety population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vanucizumab + mFOLFOX-6 | Number of Participants With Human Anti-human Antibodies (HAHAs) Against Vanucizumab | 2 Participants |
| Bevacizumab + mFOLFOX-6 | Number of Participants With Human Anti-human Antibodies (HAHAs) Against Vanucizumab | 1 Participants |
Secondary
Overall Survival (OS)
Efficacy of vanucizumab was evaluated in terms of OS as the time from randomization until death from any cause. 99999 = data not estimable due to the low number of deaths.
Time frame: Baseline until death from any cause (maximum up to approximately 3.5 years)
Population: This analysis was based on the ITT population, which consisted of all participants in the bevacizumab + mFOLFOX-6 and vanucizumab + mFOLFOX-6 arms. Participants in the safety-run in were not included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vanucizumab + mFOLFOX-6 | Overall Survival (OS) | 746.0 days |
| Bevacizumab + mFOLFOX-6 | Overall Survival (OS) | NA days |
Comparison: Kaplan-Meier methods were used to estimate median OS for each treatment arm and the 95% CIs for median OS were computed using the Brookmeyer and Crowley method. The stratified Cox proportional hazard was used to estimate the hazard ratio (i.e., the magnitude of the treatment effect) and the corresponding 95% confidence interval. The stratification factors are number of metastatic sites (1 vs. \>1) and country/region (USA vs rest of the world).p-value: =0.57495% CI: [0.49, 1.49]Log Rank
Secondary
Percentage of Participants With Adverse Events (AEs)
Safety is evaluated in terms of percentage of participants with at least one serious adverse event and percentage of participants with at least one adverse event.
Time frame: Up to approximately 29 months
Population: n for the vanucizumab + mFOLFOX-6 arm changed from 94 to 93 due to the withdrawal of a participant that was randomized to this arm, but received only chemotherapy before leaving the study. This participant is included in the ITT population but not in the safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vanucizumab + mFOLFOX-6 | Percentage of Participants With Adverse Events (AEs) | Serious Adverse events | 37.5 Percentage of Participants |
| Vanucizumab + mFOLFOX-6 | Percentage of Participants With Adverse Events (AEs) | Adverse events | 100 Percentage of Participants |
| Bevacizumab + mFOLFOX-6 | Percentage of Participants With Adverse Events (AEs) | Serious Adverse events | 49.5 Percentage of Participants |
| Bevacizumab + mFOLFOX-6 | Percentage of Participants With Adverse Events (AEs) | Adverse events | 100.0 Percentage of Participants |
| Bevacizumab + mFOLFOX-6 | Percentage of Participants With Adverse Events (AEs) | Serious Adverse events | 43.2 Percentage of Participants |
| Bevacizumab + mFOLFOX-6 | Percentage of Participants With Adverse Events (AEs) | Adverse events | 100.0 Percentage of Participants |
Secondary
Percentage of Participants With Objective Response (ORR) as Assessed Using RECIST v. 1.1
Efficacy of vanucizumab was evaluated in terms of Percentage of Participants With ORR as Investigator-Assessed Using RECIST v. 1.1. Best Overall Confirmed Response.
Time frame: Baseline (within 28 days prior to Day 1), then every 8 weeks until progressive disease (PD), start of other anticancer therapy, withdrawal of consent, or death (up to approximately 29 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vanucizumab + mFOLFOX-6 | Percentage of Participants With Objective Response (ORR) as Assessed Using RECIST v. 1.1 | 62.5 Percentage of Participants |
| Bevacizumab + mFOLFOX-6 | Percentage of Participants With Objective Response (ORR) as Assessed Using RECIST v. 1.1 | 43.6 Percentage of Participants |
| Bevacizumab + mFOLFOX-6 | Percentage of Participants With Objective Response (ORR) as Assessed Using RECIST v. 1.1 | 51.6 Percentage of Participants |
Secondary
Plasma Clearance at Steady State (CLss) of Vanucizumab
PK profile of vanucizumab was evaluated in terms of CLss, values are reported for cycle 8 of both part 1 (safety run-in) and part 2 of the study.
Time frame: Cycle 8
Population: This endpoint was only reported for arms in which the participants received vanucizumab.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vanucizumab + mFOLFOX-6 | Plasma Clearance at Steady State (CLss) of Vanucizumab | 15.3 ml/hr | Geometric Coefficient of Variation 26.7 |
| Bevacizumab + mFOLFOX-6 | Plasma Clearance at Steady State (CLss) of Vanucizumab | 18.0 ml/hr | Geometric Coefficient of Variation 29 |
Secondary
Plasma Terminal Half-Life (t1/2) of Vanucizumab
PK profile of vanucizumab was evaluated in terms of t1/2, values are reported for cycle 8 of both part 1 (safety run-in) and part 2 of the study.
Time frame: Cycle 8
Population: This endpoint was only reported for arms in which the participants received vanucizumab.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vanucizumab + mFOLFOX-6 | Plasma Terminal Half-Life (t1/2) of Vanucizumab | 202 hr | Geometric Coefficient of Variation 12.4 |
| Bevacizumab + mFOLFOX-6 | Plasma Terminal Half-Life (t1/2) of Vanucizumab | 157 hr | Geometric Coefficient of Variation 30.3 |
Secondary
Time to Reach Cmax (Tmax) of Vanucizumab
PK profile of vanucizumab was evaluated in terms of Tmax
Time frame: Cycles 1 and 8 of parts 1 and 2
Population: This endpoint was only reported for arms in which the participants received vanucizumab.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Vanucizumab + mFOLFOX-6 | Time to Reach Cmax (Tmax) of Vanucizumab | Cycle 1 | 2.79 hr |
| Vanucizumab + mFOLFOX-6 | Time to Reach Cmax (Tmax) of Vanucizumab | Cycle 8 | 4.04 hr |
| Bevacizumab + mFOLFOX-6 | Time to Reach Cmax (Tmax) of Vanucizumab | Cycle 1 | 2.05 hr |
| Bevacizumab + mFOLFOX-6 | Time to Reach Cmax (Tmax) of Vanucizumab | Cycle 8 | 1.58 hr |
Secondary
Volume of Distribution at Steady State (Vss) of Vanucizumab
PK profile of vanucizumab was evaluated in terms of Vss, values are reported for cycle 8 of both part 1 (safety run-in) and part 2 of the study.
Time frame: Cycle 8
Population: This endpoint was only reported for arms in which the participants received vanucizumab.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Vanucizumab + mFOLFOX-6 | Volume of Distribution at Steady State (Vss) of Vanucizumab | 4400 ml | Geometric Coefficient of Variation 25.1 |
| Bevacizumab + mFOLFOX-6 | Volume of Distribution at Steady State (Vss) of Vanucizumab | 4140 ml | Geometric Coefficient of Variation 29.7 |