Gilead Sciences
07/07/2008
01/02/2024
ALL
135
18
No
The goals of this clinical study are to learn more about the safety, tolerability and effectiveness of magrolimab in combination with bevacizumab and 5-fluorouracil, irinotecan, and leucovorin (FOLFIRI) in previously treated participants with advanced inoperable metastatic colorectal cancer (mCRC). The primary objectives of this study are: (safety run-in cohort) to evaluate safety and tolerability, and the recommended Phase 2 dose (RP2D) and (randomized cohort) to evaluate the efficacy of magrolimab in combination with bevacizumab and 5-fluorouracil, irinotecan, and leucovorin (FOLFIRI) in previously treated participants with advanced inoperable metastatic colorectal cancer (mCRC).
A Phase 2, Randomized, Open-Label Study Evaluating the Safety and Efficacy of Magrolimab in Combination With Bevacizumab and FOLFIRI Versus Bevacizumab and FOLFIRI in Previously Treated Advanced Inoperable Metastatic Colorectal Cancer (mCRC)
- Previously treated individuals with inoperable metastatic colorectal cancer (mCRC) who are ineligible for checkpoint inhibitor therapy (microsatellite instability (MSI)-H or mismatch repair deficient (dMMR) and are excluded).
- Histologically or cytologically confirmed adenocarcinoma originating in the colon or rectum (excluding appendiceal and anal canal cancers) who have progressed on or after 1 prior systemic therapy in the setting where curative resection is not indicated. This therapy must have included chemotherapy based on 5-FU or capecitabine with oxaliplatin and either bevacizumab, or for patients with RAS wild-type and left-sided tumors, bevacizumab, cetuximab, or panitumumab.
- Measurable disease (RECIST V1.1 criteria).
- Individuals must have an eastern cooperative oncology group (ECOG) performance status of 0 or 1.
- Life expectancy of at least 12 weeks.
- Laboratory measurements, blood counts: adequate hemoglobin, neutrophil, and platelet counts
- Adequate liver function.
- Adequate renal function.
- Prior anticancer therapy including chemotherapy, hormonal therapy, or investigational agents within 3 weeks or within at least 4 half-lives prior to magrolimab dosing (up to a maximum of 4 weeks), whichever is shorter.
- Known v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E or MSI-H mutations or dMMR.
- Persistent Grade 2 or more gastrointestinal bleeding.
- Individuals with prior irinotecan therapy.
- Clinically significant coronary artery disease or myocardial infarction within 6 months prior to inclusion.
- Peripheral neuropathy of more than Grade 2 (CTCAE Version 5.0).
- Known dihydropyrimidine dehydrogenase deficiency.
- Acute intestinal obstruction or subobstruction, history of inflammatory intestinal disease or extended resection of the small intestine. Presence of a colonic prosthesis.
- Unhealed wound, active gastric or duodenal ulcer, or bone fracture.
- History of abdominal fistulas, trachea-oesophageal fistulas, any other Grade 4 gastrointestinal perforations, nongastrointestinal fistulas, or intra-abdominal abscesses 6 months prior to screening.
- Uncontrolled arterial hypertension.
- Thromboembolic event in the 6 months before inclusion (eg, transitory ischemic stroke, stroke, subarachnoid hemorrhage) except peripheral deep vein thrombosis treated with anticoagulants.
- Active central nervous system (CNS) disease. Individuals with asymptomatic and stable, treated CNS lesions (radiation and/or surgery and/or other CNS-directed therapy who have not received corticosteroids for at least 4 weeks) are allowed.
- Red blood cell (RBC) transfusion dependence, defined as requiring more than 2 units of packed RBC transfusions during the 4-week period prior to screening.
- History of hemolytic anemia, autoimmune thrombocytopenia, or Evans syndrome in the last 3 months.
- Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient.
- Known inherited or acquired bleeding disorders.
- Significant disease or medical conditions, as assessed by the investigator and sponsor, that would substantially increase the risk-benefit ratio of participating in the study.
- Second malignancy, except treated basal cell or localized squamous skin carcinomas, or localized prostate cancer.
- Uncontrolled pleural effusion.
| PARTICIPANT GROUP ARM | INTERVENTION TREATMENT |
|---|---|
| Experimental: Safety Run-in Cohort: Magrolimab + Bevacizumab + FOLFIRI Participants will receive magrolimab in de-escalating doses to establish recommended Phase 2 dose (RP2D) in combination with + bevacizumab (5 mg/kg every 2 weeks) + FOLFIRI (irinotecan 180 mg/m^2 + leucovorin 400 mg/m^2 + fluorouracil 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous on Days 1, 2, 15, and 16 of a 28-Day Cycle). | Drug: Magrolimab - Administered intravenously Other Names: - GS-4721 Drug: Bevacizumab - Administered intravenously Drug: Irinotecan - Administered intravenously Other Names: - CAMPTOSAR® Drug: Fluorouracil - Administered intravenously Drug: Leucovorin - Administered intravenously |
| Experimental: Randomized Cohort: Magrolimab + Bevacizumab + FOLFIRI Participants will receive the RP2D determined in the Safety Run-in cohort of magrolimab in combination with bevacizumab (5 mg/kg every 2 weeks) + FOLFIRI (irinotecan 180 mg/m^2 + leucovorin 400 mg/m^2 + fluorouracil 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous on Days 1, 2, 15, and 16 of a 28-Day Cycle). | Drug: Magrolimab - Administered intravenously Other Names: GS-4721 Drug: Bevacizumab - Administered intravenously Drug: Irinotecan - Administered intravenously Other Names: - CAMPTOSAR® Drug: Fluorouracil - Administered intravenously Drug: Leucovorin - Administered intravenously |
| Active Comparator: Randomized Cohort: Bevacizumab + FOLFIRI Participants will receive bevacizumab (5 mg/kg every 2 weeks) + FOLFIRI (irinotecan 180 mg/m^2 + leucovorin 400 mg/m^2 + fluorouracil 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous on Days 1, 2, 15, and 16 of a 28-Day Cycle). | Drug: Bevacizumab - Administered intravenously Drug: Irinotecan - Administered intravenously Other Names: - CAMPTOSAR® Drug: Fluorouracil - Administered intravenously Drug: Leucovorin - Administered intravenously |
| Measures | Measure Description | MEASURE TIME FRAME |
|---|---|---|
| Safety Run-in Cohort: Percentage of Participants Experiencing Dose-limiting Toxicities (DLTs) According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | First dose date up to 28 days | |
| Safety Run-in Cohort: Percentage of Participants Experiencing Adverse Events (AEs) According to the NCI-CTCAE Version 5.0 | First dose date up to 3 years | |
| Safety Run-in Cohort: Percentage of Participants Experiencing Laboratory Abnormalities According to NCI-CTCAE Version 5.0 | First dose date up to 3 years | |
| Randomized Cohort: Progression-free Survival (PFS) as Determined by Investigator Assessment Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | PFS is defined as the time from the date of randomization until the earliest date of documented disease progression, or death from any cause, whichever occurs first. | Up to 3 years |
| MEASURES | MEASURE DESCRIPTION | MEASURE TIME FRAME |
|---|---|---|
| Randomized Cohort: Objective Response Rate (ORR) as Determined by Investigator Assessment Using RECIST Version 1.1 | Confirmed ORR is defined as the proportion of participants with complete response (CR) or partial response (PR) on 2 consecutive assessments, at least 28 days apart. | Up to 3 years |
| Randomized Cohort: Duration of Response (DOR) as Assessed by Investigator Assessment Per RECIST Version 1.1 | DOR is defined as time from first documentation of CR or PR to the earliest date of documented disease progression, or death from any cause, whichever occurs first. | Up to 3 years |
| Randomized Cohort: Overall Survival (OS) | OS is defined as time from date of randomization to death from any cause. | Up to 3 years |
| Randomized Cohort: Change From Baseline of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core Questionnaire EORTC-QLQ-C30 Score | The EORTC QLQ-C30 is a questionnaire to assess quality of life of cancer patients, it is composed of 30 questions (items) resulting in 5 functional scales, 1 global health status scale, 3 symptom scales, and 6 single items. Scoring of the QLQ-C30 is performed according to QLQ-C30 Scoring manual. All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the participant), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the participant). | Baseline, up to 3 years |
| Randomized Cohort: Change From Baseline of the 5-level EuroQol 5 dimensions questionnaire (EQ-5D-5L) Score | EQ-5D-5L is an instrument for use as a measure of health outcome.The EQ-5D-5L consists of 2 sections: the EuroQoL (5 dimensions) (EQ-5D) descriptive system and the EuroQoL visual analogue scale (EQ-VAS). The descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Rating gets recorded on a vertical VAS in which the endpoints are labeled best imaginable health state is 100 (on the top) and worst imaginable health state is 0 (on the bottom). Higher scores of EQ-VAS indicate better health. | Baseline, up to 3 years |
| Randomized Cohort: the Change From Baseline of the Functional Assessment of Cancer Therapy (FACT) Colorectal Symptom Index (FCSI) Score | The FCSI is a set of brief, clinically relevant, colorectal cancer symptoms for assessing symptomatic response. It comprises the most important symptoms associated with colorectal cancer, including energy, pain, weight, diarrhea, nausea, swelling or cramps in the stomach area, appetite, ability to enjoy life, and overall quality of life. The 9 questions are combined in three algorithms to provide information for 3 domains: colorectal cancer symptoms, physical well-being, and functional well-being. Each of the 9 items are scored from "0" to "4" representing "Not at All" through to "Very Much True". The raw score for all items is transformed to a 0-100 scale, and the average for each of the 3 subscales is calculated; high scores illustrate an improved state. | Baseline, up to 3 years |
| Safety Run-in and Randomized Cohorts: Magrolimab Concentration Versus Time | Up to end of treatment (approximately 3 years) | |
| Safety Run-in and Randomized Cohorts: Antidrug Antibodies (ADA) to Magrolimab | Up to end of treatment (approximately 3 years) |