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

Colorectal Cancer Clinical Trial

— McCAVE  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02141295
• Other study ID #: BP29262
• Secondary ID: 2013-005108-32
• Status: Terminated
• Phase: Phase 2
• Start date: June 30, 2014
• Est. completion date: February 1, 2017

Study information

• Verified date: March 2020
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 197
• Est. completion date: February 1, 2017
• Est. primary completion date: July 29, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Drug:
• 5-FU
5-FU will be administered according to dose and schedule described in respective arm.
• Bevacizumab
Bevacizumab will be administered according to dose and schedule described in respective arm.
• Folinic acid
Folinic acid will be administered according to dose and schedule described in respective arm.
• Oxaliplatin
Oxaliplatin will be administered according to dose and schedule described in respective arm.
• Vanucizumab
Vanucizumab will be administered according to dose and schedule described in respective arm.

Locations

Country	Name	City	State
Australia	Monash Medical Centre-Moorabbin Campus	Clayton	Victoria
Australia	Calvary Mater Newcastle	Waratah	New South Wales
Australia	The Queen Elizabeth Hospital	Woodville	South Australia
Austria	Salzburger Landeskliniken LKH	Salzburg
Austria	Oö. Gesundheits- und Spitals-AG/LKH Steyr	Steyr
Belgium	Imeldaziekenhuis	Bonheiden
France	Centre Paul Papin	Angers Cedex 2
France	Institut De Cancerologie De L'Ouest; Medical Oncology	Saint Herblain
Spain	Hospital Universitario Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital del Mar; Servicio de Oncologia	Barcelona
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona
Spain	Institut Catala d Oncologia Hospital Duran i Reynals	Barcelona
Spain	Hospital Universitario Reina Sofia; Servicio de Oncologia	Córdoba	Cordoba
Spain	HM Sanchinarro - CIOCC; Servicio de Oncologia	Madrid
Spain	Hospital General Universitario Gregorio Marañon; Servicio de Oncologia	Madrid
Spain	Hospital Universitario Clínico San Carlos; Servicio de Oncologia	Madrid
Spain	Hospital Universitario Marques de Valdecilla	Santander	Cantabria
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Clinico Universitario de Valencia	Valencia
United Kingdom	Aberdeen Royal Infirmary; Medical Oncology Dept	Aberdeen
United Kingdom	Guys and St Thomas NHS Foundation Trust, Guys Hospital	London
United Kingdom	Maidstone Hospital	Maidstone
United Kingdom	Queen's Hospital; Oncology	Romford
United Kingdom	The Royal Marsden Hospital	Sutton
United States	Alabama Oncology	Birmingham	Alabama
United States	Oncology Hematology Care Inc	Cincinnati	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	California Cancer Associates for Research & Excellence, Inc.	Encinitas	California
United States	SCRI Florida Cancer Specialists South	Fort Myers	Florida
United States	Ctr for Cancer and Blood Disorders	Fort Worth	Texas
United States	Fresno cCare	Fresno	California
United States	University of California San Diego Medical Center	La Jolla	California
United States	Sarah Cannon Research Inst.	Nashville	Tennessee
United States	Ocala Oncology Center	Ocala	Florida
United States	Northern Utah Associates	Ogden	Utah
United States	Cancer Therapy & Research Center	San Antonio	Texas
United States	Va Greater Los Angeles Healthcare System	Sepulveda	California
United States	Arizona Clinical Research Ctr	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  France,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline, every 8 weeks, up to approximately 29 months
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.	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)
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).	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)
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.	Baseline until death from any cause (maximum up to approximately 3.5 years)
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.	Up to approximately 29 months
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.	End of study (EoS, within 28 to 42 days after last dose, latest at 29 months)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
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.	Cycle 8
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.	Cycle 8
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.	Cycle 8
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.	Cycle 8