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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02141295
Recruitment Status : Terminated
First Posted : May 19, 2014
Results First Posted : March 25, 2020
Last Update Posted : March 25, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: 5-FU Drug: Bevacizumab Drug: Folinic acid Drug: Oxaliplatin Drug: Vanucizumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 197 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 30, 2014
Actual Primary Completion Date : July 29, 2016
Actual Study Completion Date : February 1, 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

Arm Intervention/treatment
Experimental: Part 1 (Induction): Vanucizumab + mFOLFOX-6
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
5-FU will be administered according to dose and schedule described in respective arm.

Drug: Folinic acid
Folinic acid will be administered according to dose and schedule described in respective arm.

Drug: Oxaliplatin
Oxaliplatin will be administered according to dose and schedule described in respective arm.

Drug: Vanucizumab
Vanucizumab will be administered according to dose and schedule described in respective arm.
Other Name: RO5520985

Experimental: Part 1 (Maintenance): Vanucizumab + 5-FU + Folinic acid
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
5-FU will be administered according to dose and schedule described in respective arm.

Drug: Folinic acid
Folinic acid will be administered according to dose and schedule described in respective arm.

Drug: Vanucizumab
Vanucizumab will be administered according to dose and schedule described in respective arm.
Other Name: RO5520985

Active Comparator: Part 2 (Induction): Bevacizumab + mFOLFOX-6
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
5-FU will be administered according to dose and schedule described in respective arm.

Drug: Bevacizumab
Bevacizumab will be administered according to dose and schedule described in respective arm.
Other Name: Avastin

Drug: Folinic acid
Folinic acid will be administered according to dose and schedule described in respective arm.

Drug: Oxaliplatin
Oxaliplatin will be administered according to dose and schedule described in respective arm.

Experimental: Part 2 (Induction): Vanucizumab + mFOLFOX-6
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
5-FU will be administered according to dose and schedule described in respective arm.

Drug: Folinic acid
Folinic acid will be administered according to dose and schedule described in respective arm.

Drug: Oxaliplatin
Oxaliplatin will be administered according to dose and schedule described in respective arm.

Drug: Vanucizumab
Vanucizumab will be administered according to dose and schedule described in respective arm.
Other Name: RO5520985

Active Comparator: Part 2 (Maintenance): Bevacizumab + 5-FU + Folinic acid
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
5-FU will be administered according to dose and schedule described in respective arm.

Drug: Bevacizumab
Bevacizumab will be administered according to dose and schedule described in respective arm.
Other Name: Avastin

Drug: Folinic acid
Folinic acid will be administered according to dose and schedule described in respective arm.

Experimental: Part 2 (Maintenance): Vanucizumab + 5-FU + Folinic acid
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
5-FU will be administered according to dose and schedule described in respective arm.

Drug: Folinic acid
Folinic acid will be administered according to dose and schedule described in respective arm.

Drug: Vanucizumab
Vanucizumab will be administered according to dose and schedule described in respective arm.
Other Name: RO5520985




Primary Outcome Measures :
  1. Progression-free Survival (PFS), Time to Event [ Time Frame: 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 Outcome Measures :
  1. Percentage of Participants With Objective Response (ORR) as Assessed Using RECIST v. 1.1 [ 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) ]
    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.

  2. Duration of Objective Response, as Assessed Using RECIST v. 1.1 [ 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) ]
    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).

  3. Overall Survival (OS) [ Time Frame: 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.

  4. Percentage of Participants With Adverse Events (AEs) [ Time Frame: 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.

  5. 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) ]
    Safety is evaluated in terms of number of participants with Human Anti-human Antibodies (HAHAs) Against Vanucizumab.

  6. Area Under the Plasma Concentration-Time Curve (AUC) of Vanucizumab [ Time Frame: Cycles 1 and 8 of parts 1 and 2 ]
    PK profile of vanucizumab was evaluated in terms of AUC

  7. Maximum Observed Plasma Concentration (Cmax) of Vanucizumab [ Time Frame: Cycles 1 and 8 of parts 1 and 2 ]
    PK profile of vanucizumab was evaluated in terms of Cmax

  8. Minimum Observed Plasma Concentration (Clast) of Vanucizumab [ Time Frame: Cycles 1 and 8 of parts 1 and 2 ]
    PK profile of vanucizumab was evaluated in terms of Clast

  9. Time to Reach Cmax (Tmax) of Vanucizumab [ Time Frame: Cycles 1 and 8 of parts 1 and 2 ]
    PK profile of vanucizumab was evaluated in terms of Tmax

  10. Plasma Terminal Half-Life (t1/2) of Vanucizumab [ Time Frame: 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.

  11. Plasma Clearance at Steady State (CLss) of Vanucizumab [ Time Frame: 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.

  12. Volume of Distribution at Steady State (Vss) of Vanucizumab [ Time Frame: 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.

  13. Cmax Accumulation Ratio (AR) of Vanucizumab [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02141295


Locations
Show Show 39 study locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
  Study Documents (Full-Text)

Documents provided by Hoffmann-La Roche:
Study Protocol  [PDF] February 10, 2016
Statistical Analysis Plan  [PDF] September 9, 2016

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02141295    
Other Study ID Numbers: BP29262
2013-005108-32 ( EudraCT Number )
First Posted: May 19, 2014    Key Record Dates
Results First Posted: March 25, 2020
Last Update Posted: March 25, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Folic Acid
Bevacizumab
Oxaliplatin
Levoleucovorin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antidotes
Protective Agents
Vitamin B Complex
Vitamins
Micronutrients
Hematinics