A Study Evaluating the Efficacy and Safety of MEGF0444A Dosed to Progression in Combination With Bevacizumab and mFOLFOX-6 in Participants With Previously Untreated Metastatic Colorectal Cancer

• ClinicalTrials.gov Identifier: NCT01399684
• Recruitment Status: Completed
• First Posted: July 22, 2011
• Last Update Posted: August 26, 2016
• Sponsor: Genentech, Inc.
• Information provided by (Responsible Party): Genentech, Inc.

Study Description

Brief Summary:

This is a Phase II, multicenter, randomized, double-blind, placebo-controlled trial designed to estimate the efficacy of MEGF0444A treatment to disease progression, combined with oxaliplatin + folinic acid + 5-Fluorouracil (mFOLFOX-6) + bevacizumab therapy in participants with metastatic colorectal cancer (CRC).

Condition or disease	Intervention/treatment	Phase
Metastatic Colorectal Cancer	Drug: 5-Fluorouracil; Drug: Bevacizumab; Drug: Folinic acid; Drug: MEGF0444A; Drug: Oxaliplatin; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 127 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of MEGF0444A Dosed to Progression in Combination With Bevacizumab and FOLFOX in Patients With Previously Untreated Metastatic Colorectal Cancer
• Study Start Date: November 2011
• Actual Primary Completion Date: February 2014
• Actual Study Completion Date: February 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: MEGF0444A + mFOLFOX-6 + Bevacizumab; Participants will receive MEGF0444A + mFOLFOX-6 (oxaliplatin, folinic acid, and 5-fluorouracil) regimen + bevacizumab. Participants will receive oxaliplatin for up to 8 cycles (Cycle = 14 days) and 5-fluorouracil, folinic acid, bevacizumab and MEGF0444A will be administered until disease progression or unacceptable toxicity for a maximum of up to 52 cycles.	Drug: 5-Fluorouracil; Participants will receive 5-fluorouracil 400 milligrams per squared meter (mg/m^2) intravenous (IV) bolus and then 2400 mg/m^2 as a continuous IV infusion over 46-48 hours on Day 1 of every cycle until disease progression, unacceptable toxicity or at the maximum of 52 cycles, whichever occurs first.; Drug: Bevacizumab; Participants will be administered bevacizumab at a dose of 5 milligrams per kilogram (mg/kg) every 14 days until disease progression or unacceptable toxicity, for a maximum of 52 cycles, whichever occurs first.; Drug: Folinic acid; Participants will receive folinic acid 400 mg/m^2 IV infusion over 2 hours on Day 1 of every cycle until disease progression, unacceptable toxicity or at the maximum of 52 cycles, whichever occurs first.; Drug: MEGF0444A; Participants will be administered MEGF0444A at a fixed dose of 400 milligrams (mg) IV on Day 1 of Cycle 1, followed by subsequent doses of 400 mg every 14 days until disease progression or unacceptable toxicity, for a maximum of 52 cycles, whichever occurs first.; Drug: Oxaliplatin; Participants will receive oxaliplatin 85 mg/m^2 IV infusion over 90 minutes on Day 1 of every cycle for a maximum of 8 cycles.
Placebo Comparator: Placebo + mFOLFOX-6 + Bevacizumab; Participants will receive MEGF0444A matching placebo + mFOLFOX-6 regimen + bevacizumab. Participants will receive oxaliplatin for up to 8 cycles and 5-fluorouracil, folinic acid, bevacizumab and placebo will be administered until disease progression or unacceptable toxicity for a maximum of up to 52 cycles.	Drug: 5-Fluorouracil; Participants will receive 5-fluorouracil 400 milligrams per squared meter (mg/m^2) intravenous (IV) bolus and then 2400 mg/m^2 as a continuous IV infusion over 46-48 hours on Day 1 of every cycle until disease progression, unacceptable toxicity or at the maximum of 52 cycles, whichever occurs first.; Drug: Bevacizumab; Participants will be administered bevacizumab at a dose of 5 milligrams per kilogram (mg/kg) every 14 days until disease progression or unacceptable toxicity, for a maximum of 52 cycles, whichever occurs first.; Drug: Folinic acid; Participants will receive folinic acid 400 mg/m^2 IV infusion over 2 hours on Day 1 of every cycle until disease progression, unacceptable toxicity or at the maximum of 52 cycles, whichever occurs first.; Drug: Oxaliplatin; Participants will receive oxaliplatin 85 mg/m^2 IV infusion over 90 minutes on Day 1 of every cycle for a maximum of 8 cycles.; Drug: Placebo; Participants will be administered MEGF0444A matching placebo every 14 days until disease progression, unacceptable toxicity or at the maximum of 52 cycles, whichever occurs first.

Outcome Measures

Primary Outcome Measures :

1. Progression-Free Survival Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 as Determined by the Investigator [ Time Frame: Screening up to disease progression or death due to any cause, whichever occurs first (assessed every 8-9 weeks after Cycle 1 Day 1 up to approximately 27 months overall) ]

Secondary Outcome Measures :

1. Percentage of Participants with Objective Response (Complete Response [CR] or Partial Response [PR] Based on RECIST v 1.1 as Determined by the Investigator [ Time Frame: Screening up to disease progression or death due to any cause, whichever occurs first (assessed every 8 -9 weeks after Cycle 1 Day 1 up to approximately 27 months overall) ]
2. Duration of Response Based on RECIST v 1.1 as Determined by the Investigator [ Time Frame: Screening up to disease progression or death due to any cause, whichever occurs first (assessed every 8 -9 weeks after Cycle 1 Day 1 up to approximately 27 months overall) ]
3. Overall Survival (OS) [ Time Frame: Screening until death (up to approximately 27 months overall) ]
4. Percentage of Participants with Adverse Events [ Time Frame: Up to approximately 27 months overall ]
5. Maximum Serum Concentration (Cmax) of MEGF0444A [ Time Frame: Prior to the first infusion (first infusion being MEGF0444A administration), immediately after end of bevacizumab infusion on Day 1 of Cycles 1, 2; prior to first infusion on Day 1 of Cycles 3 and 8; at study drug discontinuation visit (up to 24 months) ]
6. Minimum Serum Concentration (Cmin) of MEGF0444A [ Time Frame: Prior to the first infusion (first infusion being MEGF0444A administration), immediately after end of bevacizumab infusion on Day 1 of Cycles 1, 2; prior to first infusion on Day 1 of Cycles 3 and 8; at study drug discontinuation visit (up to 24 months) ]
7. Cmax of Bevacizumab [ Time Frame: Prior to the first infusion (first infusion being MEGF0444A administration), immediately after end of bevacizumab infusion on Day 1 of Cycles 1, 2 ]
8. Cmin of Bevacizumab [ Time Frame: Prior to the first infusion (first infusion being MEGF0444A administration), immediately after end of bevacizumab infusion on Day 1 of Cycles 1, 2 ]
9. Plasma Concentration of 5-Fluorouracil [ Time Frame: Prior to the first infusion (first infusion being MEGF0444A administration), immediately after end of 5-fluorouracil bolus, 2 hours after end of 5-fluorouracil bolus, 12-24 hours after end of 5-fluorouracil bolus on Day 1 of Cycles 1, 2 ]
10. Plasma Concentration of Oxaliplatin [ Time Frame: Prior to the first infusion (first infusion being MEGF0444A administration), 5-10 minutes before end of oxaliplatin infusion, 2 hours after end of 5-fluorouracil bolus, 12-24 hours after end of 5-fluorouracil bolus on Day 1 of Cycles 1, 2 ]
11. Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) to MEGF0444A [ Time Frame: Pre-dose (within 1 hour before infusion start) on Day 1 of Cycles 1, 3 and 8, (cycle length = 14 days), at study drug discontinuation visit (up to 24 months) ]
12. Change From Baseline in ATAs Levels of MEGF0444A [ Time Frame: Pre-dose (within 1 hour before infusion start) on Day 1 of Cycles 1, 3 and 8, (cycle length = 14 days), at study drug discontinuation visit (up to 24 months) ]

Eligibility Criteria

• 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 CRC not amenable to potentially curative resection with at least one measurable metastatic lesion, as defined by RECIST v1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate hematologic and end organ function
• For female participants of childbearing potential and male participants with partners of childbearing potential, agreement to use a highly effective form of contraception and to continue its use for 6 months after the last dose of study treatment
• 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:

Disease-specific exclusions

• Any prior systemic therapy (including chemotherapy, antibody therapy, tyrosine kinase inhibitors, radiotherapy, immunotherapy, hormonal therapy or investigational therapy) before Day 1 of Cycle 1 for treatment of CRC General Medical Exclusions
• Malignancies other than CRC within 5 years prior to randomization, except for those with a negligible risk of metastasis or death
• Radiotherapy to any site for any reason within 28 days prior to Day 1 of Cycle 1
• Clinically detectable third-space fluid collections that cannot be controlled by drainage or other procedures prior to study entry
• Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to Day 1 of Cycle 1
• Lactating women
• Clinically suspected or confirmed central nervous system (CNS) metastases or carcinomatous meningitis
• Active infection requiring IV antibiotics
• Active autoimmune disease that is not controlled by nonsteroidal anti-inflammatory drugs, inhaled corticosteroids, or the equivalent of less than or equal to (</=) 10 milligrams per day (mg/day) prednisone
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, or cirrhosis
• Sensory peripheral neuropathy greater than or equal to (>/=) Grade 2 Bevacizumab-Specific Exclusions
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of bevacizumab or an investigational drug or that may affect the interpretation of the results or render the participant at high risk for treatment complications
• Inadequately controlled hypertension
• Prior history of hypertensive crisis or hypertensive encephalopathy
• New York Heart Association (NYHA) Class II or greater congestive heart failure (CHF)
• History of myocardial infarction or unstable angina within 6 months prior to Day 1
• History of stroke or transient ischemic attack (TIA) within 6 months prior to Day 1
• Significant vascular disease within 6 months prior to Day 1
• Evidence of bleeding diathesis or significant coagulopathy
• Current or recent (within 10 days of first dose of study treatment) use of aspirin or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol
• Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, or anticipation of need for major surgical procedure during the course of the study
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1
• History of abdominal or tracheo-oesophageal fistula or gastrointestinal (GI) perforation within 6 months prior to Day 1
• Clinical signs or symptoms of GI obstruction or a requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
• Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
• Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture 5-Fluorouracil-Specific Exclusion
• Known dihydropyrimidine dehydrogenase deficiency or thymidylate synthase gene polymorphism predisposing the participant for 5-fluorouracil toxicity

Contacts and Locations

Locations

United States, Alabama

Birmingham, Alabama, United States, 35205

United States, Arizona

Scottsdale, Arizona, United States, 85259

United States, California

Bakersfield, California, United States, 93309

Fullerton, California, United States, 92835

Los Angeles, California, United States, 90095-1772

Los Angeles, California, United States, 90095

Pasadena, California, United States, 91107

San Luis Obispo, California, United States, 93454

United States, Colorado

Aurora, Colorado, United States, 80045

United States, District of Columbia

Washington, District of Columbia, United States, 20007

United States, Florida

Jacksonville, Florida, United States, 32224

Ocala, Florida, United States, 34471

Port Saint Lucie, Florida, United States, 34952

United States, Georgia

Lawrenceville, Georgia, United States, 30045

Marietta, Georgia, United States, 30060

United States, Illinois

Harvey, Illinois, United States, 60426

United States, Indiana

Indianapolis, Indiana, United States, 46202

United States, Massachusetts

Boston, Massachusetts, United States, 02114

Boston, Massachusetts, United States, 02115

United States, Minnesota

Rochester, Minnesota, United States, 55905

United States, Nevada

Las Vegas, Nevada, United States, 89148

United States, North Carolina

Durham, North Carolina, United States, 27710

United States, Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Australia, Queensland

South Brisbane, Queensland, Australia, 4101

Australia, South Australia

Woodville South, South Australia, Australia, 5011

Australia, Victoria

Footscray, Victoria, Australia, 3011

Heidelberg, Victoria, Australia, 3084

Melbourne, Victoria, Australia, 3168

Belgium

Bruxelles, Belgium, 1070

Bruxelles, Belgium, 1200

Leuven, Belgium, 3000

Poland

Gdansk, Poland, 80-952

Krakow, Poland, 31-531

Poznan, Poland, 61-878

Warszawa, Poland, 02-781

Spain

Santander, Cantabria, Spain, 39008

Barcelona, Spain, 08035

Barcelona, Spain, 08907

Sevilla, Spain, 41013

Valencia, Spain, 46010

Sponsors and Collaborators

Genentech, Inc.

Investigators

• Study Director: Ina Rhee, M.D., Ph.D.; Genentech, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Garcia-Carbonero R, van Cutsem E, Rivera F, Jassem J, Gore I Jr, Tebbutt N, Braiteh F, Argiles G, Wainberg ZA, Funke R, Anderson M, McCall B, Stroh M, Wakshull E, Hegde P, Ye W, Chen D, Chang I, Rhee I, Hurwitz H. Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with FOLFOX and Bevacizumab for First-Line Metastatic Colorectal Cancer. Oncologist. 2017 Apr;22(4):375-e30. doi: 10.1634/theoncologist.2016-0133. Epub 2017 Mar 8. Erratum In: Oncologist. 2017 Oct;22(10 ):1281.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT01399684
• Other Study ID Numbers: MEF4982g; GO27812 ( Other Identifier: Hoffmann-La Roche ); 2011-001867-28 ( EudraCT Number )
• First Posted: July 22, 2011
• Last Update Posted: August 26, 2016
• Last Verified: August 2016

Additional relevant MeSH terms:

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; Fluorouracil; Oxaliplatin; Levoleucovorin; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Immunosuppressive Agents; Immunologic Factors; Antidotes