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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Biological: Simtuzumab
* Drug: Placebo to match SIM
* Drug: Leucovorin
* Drug: Irinotecan
* Drug: Fluorouracil


Participation Criteria
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Eligibility Criteria
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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.

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: FOLFIRI + SIM 700 mg (Part A)<br>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<br>* SIM administered via intravenous infusion over 30 minutes<br>* Other names: SIM; GS-6624;Drug: Leucovorin<br>* l-Leucovorin 200 mg/m^2 or dl-leucovorin 400 mg/m^2 administered via intravenous infusion over 2 hours<br>* Other names: Folinic acid;Drug: Irinotecan<br>* Irinotecan 180 mg/m^2 administered via intravenous infusion over 90 minutes<br>Drug: Fluorouracil<br>* Fluorouracil 400 mg/m^2 administered via intravenous bolus and 2400 mg/m^2 via intravenous infusion over 46 hours<br>|
| Experimental: FOLFIRI + SIM 200 mg (Part B)<br>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<br>* SIM administered via intravenous infusion over 30 minutes<br>* Other names: SIM; GS-6624;Drug: Leucovorin<br>* l-Leucovorin 200 mg/m^2 or dl-leucovorin 400 mg/m^2 administered via intravenous infusion over 2 hours<br>* Other names: Folinic acid;Drug: Irinotecan<br>* Irinotecan 180 mg/m^2 administered via intravenous infusion over 90 minutes<br>Drug: Fluorouracil<br>* Fluorouracil 400 mg/m^2 administered via intravenous bolus and 2400 mg/m^2 via intravenous infusion over 46 hours<br>|
| Experimental: FOLFIRI + SIM 700 mg (Part B)<br>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<br>* SIM administered via intravenous infusion over 30 minutes<br>* Other names: SIM; GS-6624;Drug: Leucovorin<br>* l-Leucovorin 200 mg/m^2 or dl-leucovorin 400 mg/m^2 administered via intravenous infusion over 2 hours<br>* Other names: Folinic acid;Drug: Irinotecan<br>* Irinotecan 180 mg/m^2 administered via intravenous infusion over 90 minutes<br>Drug: Fluorouracil<br>* Fluorouracil 400 mg/m^2 administered via intravenous bolus and 2400 mg/m^2 via intravenous infusion over 46 hours<br>|
| Experimental: FOLFIRI + Placebo (Part B)<br>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: Placebo to match SIM<br>* Placebo to match SIM administered via intravenous infusion over 30 minutes<br>Drug: Leucovorin<br>* l-Leucovorin 200 mg/m^2 or dl-leucovorin 400 mg/m^2 administered via intravenous infusion over 2 hours<br>* Other names: Folinic acid;Drug: Irinotecan<br>* Irinotecan 180 mg/m^2 administered via intravenous infusion over 90 minutes<br>Drug: Fluorouracil<br>* Fluorouracil 400 mg/m^2 administered via intravenous bolus and 2400 mg/m^2 via intravenous infusion over 46 hours<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSI, Gilead, Gilead Sciences, GS-6624, Colorectal Cancer, KRAS, Oncology, monoclonal antibody