Efficacy and Safety of Simtuzumab (SIM) With FOLFIRI as Second Line Treatment in Colorectal Adenocarcinoma

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of GS-6624 Combined With FOLFIRI as Second Line Treatment for Metastatic KRAS Mutant Colorectal Adenocarcinoma That Has Progressed Following a First Line Oxaliplatin- and Fluoropyrimidine-Containing Regimen

The primary objective of this study is to compare the additive efficacy of SIM versus placebo in combination with leucovorin (folinic acid), irinotecan, and fluorouracil (FOLFIRI) as measured by improvement in progression-free survival (PFS) in participants with metastatic KRAS mutant colorectal adenocarcinoma who have progressed following a first-line oxaliplatin- and fluoropyrimidine-containing regimen.

Study Overview

• Status: Terminated
• Conditions: Colorectal Cancer
• Intervention / Treatment: Biological: Simtuzumab; Drug: Leucovorin; Drug: Irinotecan; Drug: Fluorouracil; Drug: Placebo to match SIM

• Study Type: Interventional
• Enrollment (Actual): 266
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Dijon, France
    • Centre Georges François Leclerc
  • Lille Cedex, France
    • Centre Oscar Lambret, Dept. de Cancerologie Digestive et Urologique
  • Montpellier Cedex 5, France
    • Centre Hospitalier Régional Universitaire Hôpital Saint Eloi
  • Nice Cedex 2, France
    • Centre Antoine Lacassagne
  • Rennes Cedex, France
    • Institut Paoli Calmettes Centre Régional de Lutte Contre le Cancer
  • Tours, France
    • Hôpital Trousseau - Service de Gastroenterologie
  • Auvergne
    • Clermont Ferrand, Auvergne, France, 63003
      • Centre Hospitalier Universitaire Estaing
  • Bretagne
    • Rennes Cedex, Bretagne, France, 35042
      • Centre Eugene Marquis
• Germany
  • Frankfurt, Germany
    • Städtisches Klinikum Frankfurt-Höchst
  • Hamburg, Germany, 22045
    • Katholisches Marienkrankenhaus gGmbH
  • Magdeburg, Germany
    • University Magdeburg
  • Baden-Wuerttemberg
    • Ulm, Baden-Wuerttemberg, Germany, 89081
      • Universitatsklinikum Ulm
  • Baden-Wuerttenberg
    • Mannheim, Baden-Wuerttenberg, Germany, 68167
      • Universitätsklinikums Mannheim
  • Bayern
    • München, Bayern, Germany, 81377
      • Ludwig-Maximilians-Universität München Klinikum Großhadern
  • Mecklenburg-Vorpommern
    • Rostock, Mecklenburg-Vorpommern, Germany, 18055
      • Universitätsklinikum Rostock
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30449
      • Klinikum Region Hannover GmbH, Krankenhaus Siloah
  • Nordrhein-Westfalen
    • Bochum, Nordrhein-Westfalen, Germany, 44892
      • Medizinische Universitätsklinik Bochum
    • Essen, Nordrhein-Westfalen, Germany, 45122
      • Universitätsklinikum Essen
  • Rheinland-Pfalz
    • Trier, Rheinland-Pfalz, Germany, 54290
      • Krankenanstalt Mutterhaus der Borromäerinnen e.V.
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Universitätsklinikum Dresden
  • Thuringen
    • Jena, Thuringen, Germany, 07747
      • Universitätsklinikum der Friedrich-Schiller-Universität Jena
• Italy
  • Milano, Italy, 20141
    • Istituto Europeo Di Oncologia
  • Milano, Italy, 20162
    • Ospedale Niguarda Cà Granda
  • Sassari, Italy, 07100
    • Ospedale Civile SS Annunziata ASL 1
  • Lucca
    • Lido di Camaiore, Lucca, Italy, 55043
      • Ospedale Unico Versilia
  • Monza E Brianza
    • Monza, Monza E Brianza, Italy, 20052
      • Azienda Ospedaliera San Gerardo di Monza
  • Reggio Nella Emilia
    • Reggio Emilia, Reggio Nella Emilia, Italy, 42100
      • Arcispedale Santa Maria Nuova IRCCS
• Poland
  • Bydgoszcz, Poland
    • Centrum Onkologii im. Prof. Franciszka Lukaszczyka w Bydgoszczy
  • Warszawa, Poland
    • Centralny Szpital Kliniczny Mswia
  • Warszawa, Poland
    • Centrum Onkologii - Instytut im Marii Sklodowskiej-Curie
  • Malopolskie
    • Kraków, Malopolskie, Poland, 31-826
      • Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie, Spólka z o. o.
  • Pomorskie
    • Gdansk, Pomorskie, Poland, 80-952
      • Uniwersyteckie Centrum Kliniczne
  • Warminsko-Mazurskie
    • Olsztyn, Warminsko-Mazurskie, Poland, 10-513
      • Olsztynski Osrodek Onkologiczny "Kopernik" sp. z o. o.
• Russian Federation
  • Arkhangelsk, Russian Federation
    • State Institution of Healthcare "Arkhangelsk Regional Clinical Oncology Dispensary"
  • Kazan, Russian Federation
    • Republican Clinical Oncologic Dispensary of Ministry of health of Republic Tatarstan
  • Kursk, Russian Federation
    • Kursk Regional Oncologic Dispensary
  • Moscow, Russian Federation
    • Cancer Research Center n.a. Blokhin, Chemotherapy Dept.
  • Moscow, Russian Federation
    • Non-State Institution of healthcare "Central Clinical Hospital #1 OAO RZD"
  • Moscow, Russian Federation
    • State Institution "Blokhin Cancer Research Centre RAMS"
  • Nizhny Novgorod, Russian Federation
    • Nizhny Novgorod City Oncology Dispensary
  • Omsk, Russian Federation
    • State Healthcare Institution of Omsk Region "Clinical Oncologic Dispensary"
  • Saint Petersburg, Russian Federation
    • N.N.Petrov Research Institute of Oncology
• Spain
  • Avila, Spain, 05004
    • Hospital Nuestra Senora de Sonsoles
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Gerona, Spain, 17007
    • Hospital Universitario de Girona Doctor Josep Trueta
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain
    • Hospital Universitario La Paz
  • Madrid, Spain, 28040
    • Hospital Clinico Universitario San Carlos
  • Madrid, Spain, 28050
    • Centro Integral Oncológico Clara Campal, Hospital de Madrid Norte-San Chinarro
  • Madrid, Spain
    • Instituto de Investigacion Sanitaria
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia
  • La Coruna
    • A Coruña, La Coruna, Spain, 15009
      • Centro Oncologico Regional de Galicia
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • Clearview Cancer Institute
  • Arizona
    • Gilbert, Arizona, United States
      • Banner MD Anderson Cancer Center
  • California
    • Alhambra, California, United States
      • Central Hematology Oncology Medical Group, Inc.
    • Bakersfield, California, United States
      • Comprehensive Blood and Cancer Center
    • Burbank, California, United States
      • Providence Saint Joseph Medical Center-Disney Family Cancer Center
    • Corona, California, United States
      • Wilshire Oncology Medical Group, Inc.
    • Fullerton, California, United States
      • Saint Jude Heritage Healthcare
    • La Jolla, California, United States
      • University of California San Diego Medical Center
    • Long Beach, California, United States
      • Pacific Shores Medical Group
    • Los Angeles, California, United States
      • UCLA Community Oncology Practice
    • Los Angeles, California, United States
      • Comprehensive Hematology Oncology Centers, Inc.
    • Los Angeles, California, United States
      • TORI Network (Translational Oncology Research Intl)
    • Palo Alto, California, United States
      • Stanford University Medical Center
    • Pomona, California, United States
      • Wilshire Oncology Medical Group, Inc.
    • Redondo Beach, California, United States
      • Cancer Care Associates Medical Group
    • Redondo Beach, California, United States
      • Pacific Shores Medical Group
    • San Diego, California, United States
      • Sharp Health Care
    • San Jose, California, United States
      • San Jose Medical Group
    • Santa Maria, California, United States
      • Central Coast Medical Oncology Corp
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University Smilow Cancer Hospital
  • District of Columbia
    • Washington, District of Columbia, United States
      • Georgetown University
  • Florida
    • Gainesville, Florida, United States
      • Florida Cancer Specialists
    • Orlando, Florida, United States
      • MD Anderson Cancer Center
    • Saint Petersburg, Florida, United States
      • Florida Cancer Specialists
  • Georgia
    • Atlanta, Georgia, United States
      • Peachtree Hematology Oncology Consultants, PC
    • Lawrenceville, Georgia, United States
      • Suburban Hematology Oncology Associates, PC
  • Illinois
    • Chicago, Illinois, United States
      • Northwestern University
  • Indiana
    • Indianapolis, Indiana, United States
      • Indiana University Simon Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States
      • Dana Farber Cancer Institute
  • Michigan
    • Kalamazoo, Michigan, United States
      • West Michigan Cancer Center
  • Mississippi
    • Tupelo, Mississippi, United States
      • Hematology and Oncology Associates at Bridgepoint
  • Missouri
    • Saint Joseph, Missouri, United States
      • Saint Joseph Oncology, Inc.
  • Montana
    • Missoula, Montana, United States, 59802
      • Montana Cancer Institute
  • Nebraska
    • Lincoln, Nebraska, United States
      • Southeast Nebraska Cancer Center
  • Nevada
    • Henderson, Nevada, United States
      • Comprehensive Cancer Centers of Nevada
    • Las Vegas, Nevada, United States
      • Comprehensive Cancer Centers of Nevada
  • New York
    • New York, New York, United States, 10016
      • New York University Clinical Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States
      • Oncology Hematology Care, Inc.
    • Middletown, Ohio, United States
      • Signal Point Clinical Research Center, LLC
    • Wilmington, Ohio, United States
      • Oncology Hematology Care, Inc.
  • Oregon
    • Portland, Oregon, United States
      • Kaiser Permanente Northwest Region Oncology Hematology
  • South Carolina
    • Columbia, South Carolina, United States
      • South Carolina Oncology Associates
  • Tennessee
    • Nashville, Tennessee, United States
      • Tennessee Oncology, PLLC
  • Texas
    • Dallas, Texas, United States
      • University of Texas Southwestern Medical Center at Dallas
    • Fort Worth, Texas, United States
      • Center for Cancer and Blood Disorders, PC
    • Lubbock, Texas, United States
      • Joe Arrington Cancer Research and Treatment Center
    • Temple, Texas, United States, 76508
      • Scott & White Memorial
    • Weatherford, Texas, United States
      • The Center for Cancer and Blood Disorders
  • Utah
    • Saint George, Utah, United States
      • Intermountain Healthcare
    • Salt Lake City, Utah, United States
      • Utah Cancer Specialists
  • Virginia
    • Fairfax, Virginia, United States, 22033
      • Virginal Cancer Specialists, PC
    • Midlothian, Virginia, United States
      • Virginia Cancer Institute
    • Richmond, Virginia, United States
      • Virginia Cancer Institute
  • Washington
    • Seattle, Washington, United States
      • Seattle Cancer Care Alliance
  • Wisconsin
    • Madison, Wisconsin, United States
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Metastatic colorectal carcinoma with KRAS mutation
• Received first line therapy and discontinued part or all of first line therapy
• Estimated life expectancy > 3 months
• Stage IV disease
• Eastern Cooperative Oncology Group (ECOG) performance status: 0-2
• Adequate hepatic and hematologic function
• No major operations within 4 weeks prior to treatment start

Exclusion Criteria:

• More than 1 prior chemotherapy regimen for Stage 4 colorectal cancer
• Experimental medical treatment within 30 days prior to study entry
• Known or suspected cerebral metastases
• History or presence of any form of cancer, other that colorectal cancer, within the 3 years prior to enrollment
• Known dihydropyrimidine dehydrogenase-deficiency (special screening not required)
• Subjects with angina pectoris, poorly controlled ventricular arrhythmias (does not include asymptomatic, occasional premature ventricular contractions), history of clinically significant coronary heart disease or cardiomyopathy, or electrocardiogram (ECG) abnormalities consistent with ischemia
• Uncontrolled hypertension (seated systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg) at screening
• Clinically active liver disease, including active hepatitis (any etiology) or cirrhosis
• Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy) within 21 days prior to randomization
• Prior irinotecan therapy for metastatic disease is not permitted
• Systemic fungal, bacterial, viral, or other infection

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FOLFIRI + SIM 700 mg (Part A); Participants will receive SIM 700 mg via intravenous infusion followed by FOLFIRI via intravenous infusion on Days 1 and 15 of each 28-day treatment cycle until disease progression or unacceptable toxicity.	Biological: Simtuzumab; SIM administered via intravenous infusion over 30 minutes; Other Names: SIM; GS-6624; Drug: Leucovorin; l-Leucovorin 200 mg/m^2 or dl-leucovorin 400 mg/m^2 administered via intravenous infusion over 2 hours; Other Names: Folinic acid; Drug: Irinotecan; Irinotecan 180 mg/m^2 administered via intravenous infusion over 90 minutes; Drug: Fluorouracil; Fluorouracil 400 mg/m^2 administered via intravenous bolus and 2400 mg/m^2 via intravenous infusion over 46 hours
Experimental: FOLFIRI + SIM 200 mg (Part B); Participants will receive SIM 200 mg via intravenous infusion followed by FOLFIRI via intravenous infusion on Days 1 and 15 of each 28-day treatment cycle until disease progression or unacceptable toxicity.	Biological: Simtuzumab; SIM administered via intravenous infusion over 30 minutes; Other Names: SIM; GS-6624; Drug: Leucovorin; l-Leucovorin 200 mg/m^2 or dl-leucovorin 400 mg/m^2 administered via intravenous infusion over 2 hours; Other Names: Folinic acid; Drug: Irinotecan; Irinotecan 180 mg/m^2 administered via intravenous infusion over 90 minutes; Drug: Fluorouracil; Fluorouracil 400 mg/m^2 administered via intravenous bolus and 2400 mg/m^2 via intravenous infusion over 46 hours
Experimental: FOLFIRI + SIM 700 mg (Part B); Participants will receive SIM 700 mg via intravenous infusion followed by FOLFIRI via intravenous infusion on Days 1 and 15 of each 28-day treatment cycle until disease progression or unacceptable toxicity.	Biological: Simtuzumab; SIM administered via intravenous infusion over 30 minutes; Other Names: SIM; GS-6624; Drug: Leucovorin; l-Leucovorin 200 mg/m^2 or dl-leucovorin 400 mg/m^2 administered via intravenous infusion over 2 hours; Other Names: Folinic acid; Drug: Irinotecan; Irinotecan 180 mg/m^2 administered via intravenous infusion over 90 minutes; Drug: Fluorouracil; Fluorouracil 400 mg/m^2 administered via intravenous bolus and 2400 mg/m^2 via intravenous infusion over 46 hours
Experimental: FOLFIRI + Placebo (Part B); Participants will receive placebo to match SIM via intravenous infusion followed by FOLFIRI via intravenous infusion on Days 1 and 15 of each 28-day treatment cycle until disease progression or unacceptable toxicity.	Drug: Leucovorin; l-Leucovorin 200 mg/m^2 or dl-leucovorin 400 mg/m^2 administered via intravenous infusion over 2 hours; Other Names: Folinic acid; Drug: Irinotecan; Irinotecan 180 mg/m^2 administered via intravenous infusion over 90 minutes; Drug: Fluorouracil; Fluorouracil 400 mg/m^2 administered via intravenous bolus and 2400 mg/m^2 via intravenous infusion over 46 hours; Drug: Placebo to match SIM; Placebo to match SIM administered via intravenous infusion over 30 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	The PFS was defined as the time from the date of randomization to the earliest event time of: a) death regardless of cause, or b) first indication of disease progression. PFS was analyzed using Kaplan-Meier (KM) estimates.	Randomization up to 27 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	The OS is measured as time from date of randomization to death regardless of cause. The OS was analyzed using KM estimates.	Randomization up to 33 months
Objective Response Rate (ORR)	Objective response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1) as Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD). The ORR was defined as the percentage of participants who achieved a CR or PR.	Randomization up to 27 months

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Hecht JR, Benson AB 3rd, Vyushkov D, Yang Y, Bendell J, Verma U. A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab in Combination with FOLFIRI for the Second-Line Treatment of Metastatic KRAS Mutant Colorectal Adenocarcinoma. Oncologist. 2017 Mar;22(3):243-e23. doi: 10.1634/theoncologist.2016-0479. Epub 2017 Feb 28.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2011
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: November 9, 2011
• First Submitted That Met QC Criteria: November 22, 2011
• First Posted (Estimate): November 24, 2011

Study Record Updates

• Last Update Posted (Actual): April 17, 2019
• Last Update Submitted That Met QC Criteria: March 26, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: monoclonal antibody; Oncology; Colorectal Cancer; KRAS; Gilead; Gilead Sciences; GSI; GS-6624
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Leucovorin; Irinotecan
• Other Study ID Numbers: GS-US-295-0203; 2011-003754-61 (EudraCT Number)