Study of Magrolimab (Hu5F9-G4) in Combination With Cetuximab in Participants With Solid Tumors and Advanced Colorectal Cancer

• ClinicalTrials.gov Identifier: NCT02953782
• Recruitment Status: Completed
• First Posted: November 3, 2016
• Results First Posted: March 1, 2021
• Last Update Posted: March 1, 2021
• Sponsor: Gilead Sciences
• Collaborator: California Institute for Regenerative Medicine (CIRM)
• Information provided by (Responsible Party): Gilead Sciences

Study Description

Brief Summary:

The primary objectives of this study are: (Phase 1b) to investigate the safety and tolerability and to determine the recommended Phase 2 dose (RP2D) for magrolimab in combination with cetuximab; and (Phase 2) to evaluate overall response rate (ORR) of magrolimab in combination with cetuximab in participants with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutant and KRAS wild-type colorectal cancer (CRC).

Condition or disease	Intervention/treatment	Phase
Solid Tumor; Colorectal Cancer	Drug: Magrolimab; Drug: Cetuximab	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 78 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b/2 Trial of Hu5F9-G4 in Combination With Cetuximab in Patients With Solid Tumors and Advanced Colorectal Cancer
• Actual Study Start Date: November 2, 2016
• Actual Primary Completion Date: February 10, 2020
• Actual Study Completion Date: February 10, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1b Cohort 1: Magrolimab 10 mg/kg + Cetuximab 200 mg/m^2; Participants with solid tumor will receive a priming dose of magrolimab 1 mg/kg of body weight by intravenous (IV) infusion (approximately 3 hours infusion) on Day 1 followed by a maintenance dose of magrolimab 10 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 300 mg/m^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 200 mg/m^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. After Cycle 1 and thereafter, weekly maintenance dose for both magrolimab and cetuximab, will start on Day 1. Each cycle will consist of 4 weeks (28 days). Cetuximab will be administered 1 hour prior to magrolimab infusion on days when both are given. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented progressive disease (PD).	Drug: Magrolimab; Administered intravenously; Other Name: Hu5F9-G4; Drug: Cetuximab; Administered intravenously; Other Name: ERBITUX®
Experimental: Phase 1b Cohort 2: Magrolimab 10 mg/kg + Cetuximab 250 mg/m^2; Participants with solid tumor will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approximately 3 hours infusion) on Day 1 followed by a maintenance dose of magrolimab 10 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. After Cycle 1 and thereafter, weekly maintenance dose for both magrolimab and cetuximab, will start on Day 1. Each cycle will consist of 4 weeks (28 days). Cetuximab will be administered 1 hour prior to magrolimab infusion on days when both are given. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD.	Drug: Magrolimab; Administered intravenously; Other Name: Hu5F9-G4; Drug: Cetuximab; Administered intravenously; Other Name: ERBITUX®
Experimental: Phase 1b Cohort 3: Magrolimab 20 mg/kg + Cetuximab 250 mg/m^2; Participants with solid tumor will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approximately 3 hours infusion) on Day 1 followed by a maintenance dose of magrolimab 20 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. After Cycle 1 and thereafter, weekly maintenance dose for both magrolimab and cetuximab, will start on Day 1. Each cycle will consist of 4 weeks (28 days). Cetuximab will be administered 1 hour prior to magrolimab infusion on days when both are given. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD.	Drug: Magrolimab; Administered intravenously; Other Name: Hu5F9-G4; Drug: Cetuximab; Administered intravenously; Other Name: ERBITUX®
Experimental: Phase 1b Cohort 4: Magrolimab 30 mg/kg + Cetuximab 250 mg/m^2; Participants with solid tumor will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approximately 3 hours infusion) on Day 1 followed by a maintenance dose of magrolimab 30 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. After Cycle 1 and thereafter, weekly maintenance dose for both magrolimab and cetuximab, will start on Day 1. Each cycle will consist of 4 weeks (28 days). Cetuximab will be administered 1 hour prior to magrolimab infusion on days when both were given. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD.	Drug: Magrolimab; Administered intravenously; Other Name: Hu5F9-G4; Drug: Cetuximab; Administered intravenously; Other Name: ERBITUX®
Experimental: Phase 1b Cohort 5: Magrolimab 45 mg/kg + Cetuximab 250 mg/m^2; Participants with solid tumor will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approximately 3 hours infusion) on Day 1 followed by a maintenance dose of magrolimab 45 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. Participants will also receive a loading dose of magrolimab 45 mg/kg on Day 11 of Cycle 1. After Cycle 1, maintenance dose for both magrolimab and cetuximab will start on Day 1 with weekly dose in Cycle 2 and bi-weekly dose in Cycle 3 onwards for magrolimab. Each cycle will consist of 4 weeks. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD.	Drug: Magrolimab; Administered intravenously; Other Name: Hu5F9-G4; Drug: Cetuximab; Administered intravenously; Other Name: ERBITUX®
Experimental: Phase 2 Cohort 1 (KRASwt): Magrolimab 30 mg/kg + Cetuximab 250 mg/m^2; Participants with advanced colorectal cancer (CRC) who are KRAS wild type (KRASwt) and are refractory to anti-EGFRmAb therapy will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approximately 3 hours) on Day 1 followed by a maintenance dose of magrolimab 30 mg/kg of body weight by IV infusion (approximately 2 hours) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. After Cycle 1, maintenance dose for both magrolimab and cetuximab will start on Day 1; Days 8 and 22 are removed from Cycle 2 onwards for magrolimab. Each cycle will consist of 4 weeks. Cetuximab will be administered 1 hour prior to magrolimab infusion on days when both are given. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD.	Drug: Magrolimab; Administered intravenously; Other Name: Hu5F9-G4; Drug: Cetuximab; Administered intravenously; Other Name: ERBITUX®
Experimental: Phase 2 Cohort 2 (KRASm): Magrolimab 30 mg/kg + Cetuximab 250 mg/m^2; Participants with advanced CRC with KRAS mutation (KRASm) who have progressed or are not candidates for oxaliplatin or irinotecan-based therapy will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approximately 3 hours infusion) on Day 1 followed by a maintenance dose of magrolimab 30 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. After Cycle 1, maintenance dose for both magrolimab and cetuximab will start on Day 1; Days 8 and 22 are removed from Cycle 2 onwards for magrolimab. Each cycle will consist of 4 weeks. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD.	Drug: Magrolimab; Administered intravenously; Other Name: Hu5F9-G4; Drug: Cetuximab; Administered intravenously; Other Name: ERBITUX®
Experimental: Phase 2 Cohort 3 (KRASm): Magrolimab 45 mg/kg + Cetuximab 250 mg/m^2; Participants with advanced CRC with KRASm who have progressed or are not candidates for oxaliplatin or irinotecan-based therapy will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approx. 3 hours) on Day 1 followed by a maintenance dose of magrolimab 45 mg/kg of body weight by IV infusion (approx. 2 hours) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. Participants will also receive a loading dose of magrolimab 45 mg/kg of body weight on Day 11 of Cycle 1. After Cycle 1, maintenance dose for both magrolimab and cetuximab will start on Day 1; Days 8 and 22 are removed from Cycle 3 onwards for magrolimab. Each cycle will consist of 4 weeks. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD.	Drug: Magrolimab; Administered intravenously; Other Name: Hu5F9-G4; Drug: Cetuximab; Administered intravenously; Other Name: ERBITUX®

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Dose Limiting Toxicities (DLT) [ Time Frame: From first dose up to Day 28 ]

   DLT was defined as any Grade (GR) 3 or greater adverse event (AE) that was assessed as related to study treatment with the exceptions of:

   GR 3: anemia (hemolytic anemia that is medically significant tis considered a DLT), indirect/unconjugated hyperbilirubinemia, electrolyte abnormalities, elevation in alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase that resolved to ≤ Grade 2 with supportive care within 1 week and is not associated with other clinically significant consequences; nausea, vomiting, or diarrhea that resolved to ≤ Grade 2 with supportive care within 72 hours; fatigue that resolved to ≤ Grade 2 within 2 weeks on study; drug-related infusion reactions in the absence of an optimal pretreatment regimen; tumor lysis syndrome or electrolyte disturbances, hypomagnesemia, that resolved to ≤ Grade 2 or baseline within 1 week;

   GR 3 or 4: lymphopenia or leukopenia.

2. Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From first dose date up to last dose date plus 30 days (maximum: 15.3 months) ]
   An AE was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE was any unfavorable and unintended sign, symptom, disease, and/or laboratory or physiological observation that may or may not be related to the investigational medicinal product. A TEAE was defined as AEs worsening or occurring during or after a participant's first exposure to study drug and within 30 days after the last administration of study drug or initiation of new anticancer therapy, whichever occurred first.
3. Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) [ Time Frame: From Screening until 38.89 months (assessed on Day 1 of Cycle 3 then every 8 weeks [Q8W] from Cycle 5 onwards up to 38.89 months; 1 cycle = 4 weeks) ]
   Objective response rate was defined as the percentage of participants with objective response which consisted of complete response (CR)+ partial response (PR) determined by RECIST v 1.1. CR: Disappearance of all target and all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures :

1. Pharmacokinetic (PK) Parameter: Cmax of Magrolimab [ Time Frame: Pre-magrolimab dose (within 12 hours) and 1-hour post-magrolimab dose (infusion duration = approximately 3 hours on Day 1 and 2 hours on other days) on Days 1 (Cycle 1 Day 1), 8 (Cycle 1 Day 8), and 29 (Cycle 2 Day 1) (1 cycle = 4 weeks) ]
   Cmax is defined as the maximum concentration of drug.
2. PK Parameter: Tmax of Magrolimab [ Time Frame: Pre-magrolimab dose (within 12 hours) and 1-hour post-magrolimab dose (infusion duration = approximately 3 hours on Day 1 and 2 hours on other days) on Days 8 (Cycle 1 Day 8) and 29 (Cycle 2 Day 1) (1 cycle = 4 weeks) ]
   Tmax is defined as the time (observed time point) of Cmax.
3. PK Parameter: AUClast of Magrolimab [ Time Frame: Pre-magrolimab dose (within 12 hours) and 1-hour post-magrolimab dose (infusion duration = approximately 3 hours on Day 1 and 2 hours on other days) on Days 8 (Cycle 1 Day 8) and 29 (Cycle 2 Day 1) (1 cycle = 4 weeks) ]
   AUClast is defined as the concentration of drug from time zero to the last observable concentration.
4. PK Parameter: AUCtau of Magrolimab [ Time Frame: Pre-magrolimab dose (within 12 hours) and 1-hour post-magrolimab dose (infusion duration = approximately 3 hours on Day 1 and 2 hours on other days) on Days 8 (Cycle 1 Day 8) and 29 (Cycle 2 Day 1) (1 cycle = 4 weeks) ]
   AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
5. Percentage of Participants With Anti-drug Antibodies (ADA) [ Time Frame: Baseline; post-treatment (assessed continuously up to 30 days after last dose; maximum 15.3 months ) ]
   Percentage of Participants With Positive ADA at any timepoint was reported.
6. Disease Control Rate (DCR) as Assessed by RECIST v1.1 [ Time Frame: From Screening until 38.89 months (assessed on Cycle 3 Day 1 then every 8 weeks from Cycle 5 onwards up to 38.89 months; 1 cycle = 4 weeks) ]
   DCR was defined as the percentage of participants with disease control which consisted of CR+PR+SD. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters measured while on study. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum measured while on study (this included the baseline sum if that was 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. Unequivocal progression of existing non-target lesions.
7. Duration of Response (DOR) as Assessed by RECIST v1.1 [ Time Frame: From first objective response until documented PD (assessed on Cycle 3 Day 1 then every 8 weeks from Cycle 5 onwards up to 38.89 months; 1 cycle = 4 weeks) ]
   DOR was measured from when the first (objective) response was met (i.e., CR or PR) until the first date of objectively documented PD. Participants who did not have objectively PD was censored at their last documented progression-free date. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum measured while on study (this included the baseline sum if that was 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. Unequivocal progression of existing non-target lesions. Kaplan Meier estimate was used for analysis.
8. Progression Free Survival (PFS) as Assessed by RECIST v1.1 [ Time Frame: From first dose until documented PD/death (assessed on Cycle 3 Day 1 then every 8 weeks from Cycle 5 onwards up to 38.89 months; 1 cycle = 4 weeks) ]
   PFS was measured from first dose until the first date of objectively documented PD or death. Participants who did not have objectively documented PD and not died was censored at their last documented progression-free date. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum measured while on study (this included the baseline sum if that was 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. Unequivocal progression of existing non-target lesions. Kaplan Meier estimate was used for analysis.
9. Overall Survival (OS) [ Time Frame: From first dose until death (assessed on Cycle 3 Day 1 then every 8 weeks from Cycle 5 onwards up to 38.89 months; 1 cycle = 4 weeks) ]
   OS was measured from first dose until death. Participants who did not die were censored at their last known alive date. Kaplan Meier estimate was used for analysis.

Eligibility Criteria

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

Criteria

Key Inclusion Criteria:

• Histological Diagnosis

  • Phase 1b only: Advanced solid malignancy with an emphasis on colorectal cancer (CRC), head and neck, breast, pancreatic and ovarian cancers who have been treated with at least one regimen of prior systemic therapy, or who refuse systemic therapy, and for which there is no curative therapy available.
  • Phase 2:
• KRAS Mutant CRC: Advanced KRAS mutant CRC who have progressed or are ineligible for both irinotecan and oxaliplatin based chemotherapy
• KRAS Wild-Type CRC: Advanced KRAS wild type CRC who have progressed or are ineligible for fluoropyrimidine, irinotecan, and oxaliplatin based chemotherapy and who are relapsed or refractory to at least 1 prior systemic therapy that included an anti-epidermal growth factor receptor (EGFR) antibody, such as cetuximab, panitumumab or others.
• Adequate performance status and hematological, liver, and kidney function
• Phase 2 only: Willing to consent to 1 mandatory pre-treatment and 1 on-treatment tumor biopsy

Key Exclusion Criteria:

• Active brain metastases
• Prior treatment with cluster of differentiation 47 (CD47) or signal regulatory protein alpha (SIRPα) targeting agents.
• Phase 2 only: second malignancy within the last 3 years.
• Known active or chronic hepatitis B or C infection or human immunodeficiency virus (HIV)
• Pregnancy or active breastfeeding

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

Contacts and Locations

Locations

United States, California

UCLA

Los Angeles, California, United States, 90404

Stanford University

Palo Alto, California, United States, 94305-5757

United States, Michigan

Wayne State University

Detroit, Michigan, United States, 48201

START Midwest

Grand Rapids, Michigan, United States, 49503

United States, Pennsylvania

UPENN

Philadelphia, Pennsylvania, United States, 19104

United States, Tennessee

Sarah Cannon Research Institute

Nashville, Tennessee, United States, 37203

United States, Texas

Md Anderson

Houston, Texas, United States, 77030

START Center for Cancer Care

San Antonio, Texas, United States, 78229

Sponsors and Collaborators

Gilead Sciences

California Institute for Regenerative Medicine (CIRM)

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

  Study Documents (Full-Text)

Documents provided by Gilead Sciences:

Study Protocol  [PDF] September 28, 2018

Statistical Analysis Plan  [PDF] February 12, 2020

More Information

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT02953782
• Other Study ID Numbers: 5F9004
• First Posted: November 3, 2016
• Results First Posted: March 1, 2021
• Last Update Posted: March 1, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Colorectal Neoplasms; Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Cetuximab; Hu5F9-G4; Antineoplastic Agents, Immunological; Antineoplastic Agents