A Study Comparing the Efficacy and Safety of Vanucizumab and FOLFOX With Bevacizumab and FOLFOX in Participants With Untreated Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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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.

Official Title
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A Phase II, Multicenter, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of RO5520985 (Vanucizumab) Plus FOLFOX Versus Bevacizumab Plus FOLFOX in Patients With Previously Untreated Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: 5-FU
* Drug: Bevacizumab
* Drug: Folinic acid
* Drug: Oxaliplatin
* Drug: Vanucizumab


Participation Criteria
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Eligibility Criteria
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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

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 (Induction): Vanucizumab + mFOLFOX-6<br>Participants will receive vanucizumab at a dose of 2000 milligram (mg) as intravenous (IV) infusion; oxaliplatin at a dose of 85 mg per meter-squared (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). | Drug: 5-FU<br>* 5-FU will be administered according to dose and schedule described in respective arm.<br>Drug: Folinic acid<br>* Folinic acid will be administered according to dose and schedule described in respective arm.<br>Drug: Oxaliplatin<br>* Oxaliplatin will be administered according to dose and schedule described in respective arm.<br>Drug: Vanucizumab<br>* Vanucizumab will be administered according to dose and schedule described in respective arm.<br>* Other names: RO5520985;|
| Experimental: Part 1 (Maintenance): Vanucizumab + 5-FU + Folinic acid<br>Participants will receive vanucizumab at a dose confirmed during induction 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. | Drug: 5-FU<br>* 5-FU will be administered according to dose and schedule described in respective arm.<br>Drug: Folinic acid<br>* Folinic acid will be administered according to dose and schedule described in respective arm.<br>Drug: Vanucizumab<br>* Vanucizumab will be administered according to dose and schedule described in respective arm.<br>* Other names: RO5520985;|
| Active Comparator: Part 2 (Induction): Bevacizumab + mFOLFOX-6<br>Participants will receive 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). | Drug: 5-FU<br>* 5-FU will be administered according to dose and schedule described in respective arm.<br>Drug: Bevacizumab<br>* Bevacizumab will be administered according to dose and schedule described in respective arm.<br>* Other names: Avastin;Drug: Folinic acid<br>* Folinic acid will be administered according to dose and schedule described in respective arm.<br>Drug: Oxaliplatin<br>* Oxaliplatin will be administered according to dose and schedule described in respective arm.<br>|
| Experimental: Part 2 (Induction): Vanucizumab + mFOLFOX-6<br>Participants will receive vanucizumab at a dose confirmed during part 1 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). | Drug: 5-FU<br>* 5-FU will be administered according to dose and schedule described in respective arm.<br>Drug: Folinic acid<br>* Folinic acid will be administered according to dose and schedule described in respective arm.<br>Drug: Oxaliplatin<br>* Oxaliplatin will be administered according to dose and schedule described in respective arm.<br>Drug: Vanucizumab<br>* Vanucizumab will be administered according to dose and schedule described in respective arm.<br>* Other names: RO5520985;|
| Active Comparator: Part 2 (Maintenance): Bevacizumab + 5-FU + Folinic acid<br>Participants will receive bevacizumab at a dose of 5 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. | Drug: 5-FU<br>* 5-FU will be administered according to dose and schedule described in respective arm.<br>Drug: Bevacizumab<br>* Bevacizumab will be administered according to dose and schedule described in respective arm.<br>* Other names: Avastin;Drug: Folinic acid<br>* Folinic acid will be administered according to dose and schedule described in respective arm.<br>|
| Experimental: Part 2 (Maintenance): Vanucizumab + 5-FU + Folinic acid<br>Participants will receive vanucizumab at a dose confirmed during part 1 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. | Drug: 5-FU<br>* 5-FU will be administered according to dose and schedule described in respective arm.<br>Drug: Folinic acid<br>* Folinic acid will be administered according to dose and schedule described in respective arm.<br>Drug: Vanucizumab<br>* Vanucizumab will be administered according to dose and schedule described in respective arm.<br>* Other names: RO5520985;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, every 8 weeks, up to approximately 29 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| 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). | 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) | 
| 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. | Baseline until death from any cause (maximum up to approximately 3.5 years) | 
| 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. | Up to approximately 29 months | 
| 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. | End of study (EoS, within 28 to 42 days after last dose, latest at 29 months) | 
| Area Under the Plasma Concentration-Time Curve (AUC) of Vanucizumab | PK profile of vanucizumab was evaluated in terms of AUC | Cycles 1 and 8 of parts 1 and 2 | 
| Maximum Observed Plasma Concentration (Cmax) of Vanucizumab | PK profile of vanucizumab was evaluated in terms of Cmax | Cycles 1 and 8 of parts 1 and 2 | 
| Minimum Observed Plasma Concentration (Clast) of Vanucizumab | PK profile of vanucizumab was evaluated in terms of Clast | Cycles 1 and 8 of parts 1 and 2 | 
| Time to Reach Cmax (Tmax) of Vanucizumab | PK profile of vanucizumab was evaluated in terms of Tmax | Cycles 1 and 8 of parts 1 and 2 | 
| 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. | Cycle 8 | 
| 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. | Cycle 8 | 
| 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. | Cycle 8 | 
| 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. | Cycle 8 |