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)
Overview
- Phase
- Phase 2
- Intervention
- Magrolimab
- Conditions
- Metastatic Colorectal Cancer
- Sponsor
- Gilead Sciences
- Enrollment
- 77
- Locations
- 51
- Primary Endpoint
- Safety Run-in Cohort: Number of Participants Experiencing Dose-limiting Toxicities (DLTs) According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
- Status
- Terminated
- Last Updated
- 10 months ago
Overview
Brief Summary
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).
Investigators
Eligibility Criteria
Inclusion Criteria
- •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-fluorouracil (5-FU) or capecitabine with oxaliplatin and either bevacizumab, or for individuals with rat sarcoma (RAS) wild-type and left-sided tumors, bevacizumab, cetuximab, or panitumumab.
- •Measurable disease (Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 criteria).
- •Individuals must have an eastern cooperative oncology group (ECOG) performance status of 0 or
- •Life expectancy of at least 12 weeks.
- •Laboratory measurements, blood counts: adequate hemoglobin, neutrophil, and platelet counts
- •Adequate liver function.
- •Adequate renal function.
Exclusion Criteria
- •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 gene mutation (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 (Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0).
- •Known dihydropyrimidine dehydrogenase deficiency.
- •Acute intestinal obstruction or sub-obstruction, 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.
Arms & Interventions
Safety Run-in Cohort: Magrolimab + Bevacizumab + FOLFIRI
Participants will receive magrolimab + bevacizumab + FOLFIRI as mentioned below: * Magrolimab 1 mg/kg on Cycle 1 Day 1; 30 mg/kg, every week (QW) beginning at Day 8 and for the next 6 doses (Cycle 1 Days 8, 15, and 22, and Cycle 2 Days 1, 8, 15, and 22); 30 mg/kg, every 2 weeks (Q2W) beginning 1 week after the last weekly 30 mg/kg dose (starting Cycle 3 Day 1 onwards) for every 28-day cycle. * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Magrolimab
Safety Run-in Cohort: Magrolimab + Bevacizumab + FOLFIRI
Participants will receive magrolimab + bevacizumab + FOLFIRI as mentioned below: * Magrolimab 1 mg/kg on Cycle 1 Day 1; 30 mg/kg, every week (QW) beginning at Day 8 and for the next 6 doses (Cycle 1 Days 8, 15, and 22, and Cycle 2 Days 1, 8, 15, and 22); 30 mg/kg, every 2 weeks (Q2W) beginning 1 week after the last weekly 30 mg/kg dose (starting Cycle 3 Day 1 onwards) for every 28-day cycle. * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Bevacizumab
Safety Run-in Cohort: Magrolimab + Bevacizumab + FOLFIRI
Participants will receive magrolimab + bevacizumab + FOLFIRI as mentioned below: * Magrolimab 1 mg/kg on Cycle 1 Day 1; 30 mg/kg, every week (QW) beginning at Day 8 and for the next 6 doses (Cycle 1 Days 8, 15, and 22, and Cycle 2 Days 1, 8, 15, and 22); 30 mg/kg, every 2 weeks (Q2W) beginning 1 week after the last weekly 30 mg/kg dose (starting Cycle 3 Day 1 onwards) for every 28-day cycle. * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Irinotecan
Safety Run-in Cohort: Magrolimab + Bevacizumab + FOLFIRI
Participants will receive magrolimab + bevacizumab + FOLFIRI as mentioned below: * Magrolimab 1 mg/kg on Cycle 1 Day 1; 30 mg/kg, every week (QW) beginning at Day 8 and for the next 6 doses (Cycle 1 Days 8, 15, and 22, and Cycle 2 Days 1, 8, 15, and 22); 30 mg/kg, every 2 weeks (Q2W) beginning 1 week after the last weekly 30 mg/kg dose (starting Cycle 3 Day 1 onwards) for every 28-day cycle. * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Fluorouracil
Safety Run-in Cohort: Magrolimab + Bevacizumab + FOLFIRI
Participants will receive magrolimab + bevacizumab + FOLFIRI as mentioned below: * Magrolimab 1 mg/kg on Cycle 1 Day 1; 30 mg/kg, every week (QW) beginning at Day 8 and for the next 6 doses (Cycle 1 Days 8, 15, and 22, and Cycle 2 Days 1, 8, 15, and 22); 30 mg/kg, every 2 weeks (Q2W) beginning 1 week after the last weekly 30 mg/kg dose (starting Cycle 3 Day 1 onwards) for every 28-day cycle. * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Leucovorin
Randomized Cohort: Magrolimab + Bevacizumab + FOLFIRI
Participants will receive magrolimab + bevacizumab + FOLFIRI as mentioned below: * Magrolimab 1 mg/kg on Cycle 1 Day 1; 30 mg/kg, QW beginning at Day 8 and for the next 6 doses (Cycle 1 Days 8, 15, and 22, and Cycle 2 Days 1, 8, 15, and 22); 30 mg/kg, Q2W beginning 1 week after the last weekly 30 mg/kg dose (starting Cycle 3 Day 1 onwards) for every 28-day cycle. * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Magrolimab
Randomized Cohort: Magrolimab + Bevacizumab + FOLFIRI
Participants will receive magrolimab + bevacizumab + FOLFIRI as mentioned below: * Magrolimab 1 mg/kg on Cycle 1 Day 1; 30 mg/kg, QW beginning at Day 8 and for the next 6 doses (Cycle 1 Days 8, 15, and 22, and Cycle 2 Days 1, 8, 15, and 22); 30 mg/kg, Q2W beginning 1 week after the last weekly 30 mg/kg dose (starting Cycle 3 Day 1 onwards) for every 28-day cycle. * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Bevacizumab
Randomized Cohort: Magrolimab + Bevacizumab + FOLFIRI
Participants will receive magrolimab + bevacizumab + FOLFIRI as mentioned below: * Magrolimab 1 mg/kg on Cycle 1 Day 1; 30 mg/kg, QW beginning at Day 8 and for the next 6 doses (Cycle 1 Days 8, 15, and 22, and Cycle 2 Days 1, 8, 15, and 22); 30 mg/kg, Q2W beginning 1 week after the last weekly 30 mg/kg dose (starting Cycle 3 Day 1 onwards) for every 28-day cycle. * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Irinotecan
Randomized Cohort: Magrolimab + Bevacizumab + FOLFIRI
Participants will receive magrolimab + bevacizumab + FOLFIRI as mentioned below: * Magrolimab 1 mg/kg on Cycle 1 Day 1; 30 mg/kg, QW beginning at Day 8 and for the next 6 doses (Cycle 1 Days 8, 15, and 22, and Cycle 2 Days 1, 8, 15, and 22); 30 mg/kg, Q2W beginning 1 week after the last weekly 30 mg/kg dose (starting Cycle 3 Day 1 onwards) for every 28-day cycle. * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Fluorouracil
Randomized Cohort: Magrolimab + Bevacizumab + FOLFIRI
Participants will receive magrolimab + bevacizumab + FOLFIRI as mentioned below: * Magrolimab 1 mg/kg on Cycle 1 Day 1; 30 mg/kg, QW beginning at Day 8 and for the next 6 doses (Cycle 1 Days 8, 15, and 22, and Cycle 2 Days 1, 8, 15, and 22); 30 mg/kg, Q2W beginning 1 week after the last weekly 30 mg/kg dose (starting Cycle 3 Day 1 onwards) for every 28-day cycle. * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Leucovorin
Randomized Cohort: Bevacizumab + FOLFIRI
Participants will receive bevacizumab + FOLFIRI as mentioned below: * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Bevacizumab
Randomized Cohort: Bevacizumab + FOLFIRI
Participants will receive bevacizumab + FOLFIRI as mentioned below: * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Irinotecan
Randomized Cohort: Bevacizumab + FOLFIRI
Participants will receive bevacizumab + FOLFIRI as mentioned below: * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Fluorouracil
Randomized Cohort: Bevacizumab + FOLFIRI
Participants will receive bevacizumab + FOLFIRI as mentioned below: * Bevacizumab: 5 mg/kg, Q2W (Days 1 and 15) of every 28-day cycle. * FOLFIRI (Irinotecan 180 mg/m\^2 + leucovorin 400 mg/m\^2 + fluorouracil 400 mg/m\^2 IV bolus on first day, followed by 2400 mg/m\^2 over the next 46 hours, Q2W (Days 1 and 15) of every 28-day cycle.
Intervention: Leucovorin
Outcomes
Primary Outcomes
Safety Run-in Cohort: Number of Participants Experiencing Dose-limiting Toxicities (DLTs) According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
Time Frame: First dose date up to 28 days
DLT was defined as any, * Grade 3 or higher hematologic toxicity including, serious hemolytic anemia, grade 4 neutropenia lasting \> 7 days * An event meeting Hy's Law criteria: * Treatment-emergent alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation (≥ 3 x ULN) and, * Treatment-emergent total bilirubin elevation (\> 2 x ULN), and absence of cholestasis (defined as alkaline phosphatase \< 2 x ULN), and * No other good explanation for the injury (hepatitis A, B, C, or other viral hepatic injury, alcohol ingestion, congestive heart failure, worsening liver metastases, hemolysis)) * Grade 3 or higher nonhematologic toxicity that has worsened in severity from pretreatment baseline during the DLT-assessment period * Grade 3 fatigue lasting \> 7 days * In the opinion of the investigator, the AE was at least possibly related to magrolimab
Safety Run-in Cohort: Percentage of Participants Experiencing Adverse Events (AEs) According to the NCI-CTCAE Version 5.0
Time Frame: First dose date up to last dose date (up to 36 weeks) plus 30 days
Treatment-emergent adverse events (TEAEs) were defined as any AE that begun on or after the date of first dose of study drug up to the date of last dose of study treatment plus 30 days or the day before initiation of subsequent anticancer therapy, whichever came first. An AE was any untoward medical occurrence in a clinical study participant administered a study drug that did not necessarily have a causal relationship with the treatment.
Safety Run-in Cohort: Percentage of Participants Experiencing Laboratory Abnormalities According to NCI-CTCAE Version 5.0
Time Frame: First dose date up to last dose date (up to 36 weeks) plus 30 days
Treatment-emergent laboratory abnormalities were defined as values that increase at least 1 toxicity grade after the date of first dose of study drug up to the date of last dose of study treatment plus 30 days or the day before initiation of subsequent anticancer therapy, whichever came first.
Randomized Cohort: Progression-free Survival (PFS) as Determined by Investigator Assessment Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Time Frame: Up to 83.4 weeks
PFS was defined as the time from the date of randomization until the earliest date of documented disease progression (PD) as determined by investigator assessment using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST V1.1), or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Kaplan-Meier (KM) estimates were used in outcome measure analysis.
Secondary Outcomes
- Randomized Cohort: Objective Response Rate (ORR) as Determined by Investigator Assessment Using RECIST Version 1.1(Up to 83.4 weeks)
- Randomized Cohort: Duration of Response (DOR) as Determined by Investigator Assessment Per RECIST Version 1.1(Up to 83.4 weeks)
- Randomized Cohort: Overall Survival (OS)(Up to 83.4 weeks)
- Randomized Cohort: Change From Baseline of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) - Core Questionnaire EORTC-QLQ-C30 Score(Baseline, Day 1 of Cycles 2, 3, 4 and last cycle (Cycle 8) (Each cycle was of 28 days))
- Randomized Cohort: Number of Participants With 5-level EuroQol 5 Dimensions Questionnaire (EQ-5D-5L) Score(Day 1 of Cycles 2, 3, 4 and last cycle (Cycle 8) (Each cycle is of 28 days))
- Randomized Cohort: Change From Baseline in the EuroQoL Visual Analogue Scale (EQ-VAS) Score(Baseline, Day 1 of Cycles 2, 3, 4 and last cycle (Cycle 8) (Each cycle is of 28 days))
- Randomized Cohort: Change From Baseline of the Functional Assessment of Cancer Therapy (FACT) Colorectal Symptom Index (FCSI) Score(Baseline, Day 1 of Cycles 2, 3, 4 and last cycle (Cycle 8) (Each cycle is of 28 days))
- Safety Run-in and Randomized Cohorts: Magrolimab Concentration Versus Time(Predose: Day 15, 29, 57, 113 and 169; Postdose: Day 57 (1 hour))
- Safety Run-in and Randomized Cohorts: Percentage of Participants With Antidrug Antibodies (ADA) to Magrolimab(Up to 36 weeks)