Regorafenib, Ipilimumab and Nivolumab for the Treatment of Chemotherapy Resistant Microsatellite Stable Metastatic Colorectal Cancer

NCT04362839 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: 19417NCI-2020-01818
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial studies the side effects and best dose of regorafenib when given together with ipilimumab and nivolumab in treating patients with microsatellite stable colorectal cancer that has spread to other places in the body (metastatic) and remains despite chemotherapy treatment (resistant). Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving regorafenib, ipilimumab and nivolumab may slow the tumor growth and/or shrink the tumor size in patients with colorectal cancer.

Conditions

Advanced Colon Adenocarcinoma; Metastatic Colon Adenocarcinoma; Metastatic Colorectal Adenocarcinoma; Metastatic Colorectal Carcinoma; Metastatic Rectal Adenocarcinoma; Stage III Colon Cancer AJCC v8; Stage IIIA Colon Cancer AJCC v8; Stage IIIA Rectal Cancer AJCC v8; Stage IIIB Colon Cancer AJCC v8; Stage IIIB Rectal Cancer AJCC v8; Stage IIIC Colon Cancer AJCC v8; Stage IIIC Rectal Cancer AJCC v8; Stage IV Colon Cancer AJCC v8; Stage IV Colorectal Cancer AJCC v8; Stage IV Rectal Cancer AJCC v8; Stage IVA Colon Cancer AJCC v8; Stage IVA Colorectal Cancer AJCC v8; Stage IVA Rectal Cancer AJCC v8; Stage IVB Colon Cancer AJCC v8; Stage IVB Colorectal Cancer AJCC v8; Stage IVB Rectal Cancer AJCC v8; Stage IVC Colon Cancer AJCC v8; Stage IVC Colorectal Cancer AJCC v8; Stage IVC Rectal Cancer AJCC v8; Stage III Rectal Cancer AJCC v8

Outcome Measures

Primary Outcomes (1)

• Recommended dose level of the combination

  Toxicities will be graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v). 5.0. Dose limiting toxicity (DLT) will be graded per CTCAE v5.0. Any of the following adverse events occurring during the primary DLT observation period (4 weeks, from the time of first administration of regorafenib, ipilimumab and nivolumab\[cycle 1 day 1\] until the planned administration of the second cycle of regorafenib (cycle 2 day 1) that are at least probable attributable to many of the 3 agents or their combination will be classified as a DLT.

  Up to 90 days post treatment

Secondary Outcomes (4)

• Progression-free survival

  Time to disease progression/ relapse or death as a result of any cause, assessed up to 5 years

• Duration of response

  Time to progression or death, assessed up to 5 years

• Overall survival

  Time to death as a result of any cause, assessed up to 5 years

• Objective response rate (ORR)

  Up to 5 years post treatment

Other Outcomes (1)

• Immune response

  Baseline, assessed up to 5 years post treatment

Study Arms (1)

Treatment (regorafenib, nivolumab, ipilimumab)

EXPERIMENTAL

Patients receive regorafenib PO QD on days 1-21, nivolumab IV over 30 minutes Q2W, and ipilimumab IV over 30 minutes Q6W. Cycles repeat every 28 day for up to 2 years in the absence of disease progression or unacceptable toxicity.

Biological: Ipilimumab; Biological: Nivolumab; Drug: Regorafenib

Interventions

Ipilimumab BIOLOGICAL

Given IV

Also known as: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, Yervoy

Treatment (regorafenib, nivolumab, ipilimumab)

Nivolumab BIOLOGICAL

Given IV

Also known as: BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo

Treatment (regorafenib, nivolumab, ipilimumab)

Regorafenib DRUG

Given PO

Also known as: BAY 73-4506, Stivarga

Treatment (regorafenib, nivolumab, ipilimumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A signed informed consent must be obtained prior to conducting any study-specific procedures
• Histological or cytological confirmed advanced, metastatic, or progressive mismatch repair protein proficient (pMMR)/microsatellite stable (MSS) adenocarcinoma of colon or rectum
• Microsatellite status should be performed per local standard of practice (e.g., immunohistochemistry \[IHC\] and/or polymerase chain reaction \[PCR\], or next-generation sequencing). Only participants with pMMR/MSS metastatic colorectal cancer (mCRC) are eligible
• Known extended RAS and BRAF status as per local standard of practice
• Participant must have progressed following exposure of all the following agents or below:
• Prior exposure to the following:
• Fluoropyrimidines (capecitabine or fluorouracil \[5-FU\])
• Irinotecan
• Oxaliplatin
• Anti-EGFR therapy if RAS and BRAF wild type with left colon primary
• Patient must have evidence of progression on or after the last treatment regimen received and within 6 months prior to study enrollment
• Patients who were intolerant to prior systemic chemotherapy regimens are eligible if there is documented evidence of clinically significant intolerance despite adequate supportive measures
• Adjuvant/neoadjuvant chemotherapy can be considered as one line of chemotherapy for advanced/metastatic disease if the participant had disease recurrence within 6 months of completion
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• Total bilirubin =\< 1.5 x the upper limit of normal (ULN) (performed within 7 days before treatment initiation)

You may not qualify if:

• Participants with microsatellite instability high (MSI-H) colorectal cancer
• Prior therapy with regorafenib, anti-PD-1, PD-L1, or CTLA-4 inhibitors
• Systemic anti-cancer treatment within 14 days or less than 5 half-lives (whichever is shorter) of the first dose of study treatment
• Has unresolved clinically significant toxicity of greater than or equal to National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) (NCI-CTCAE, v5.0) grade 2 attributed to any prior therapies (excluding anemia, lymphopenia, alopecia, skin pigmentation, and platinum-induced neurotoxicity)
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication)
• Congestive heart failure \>= New York Heart Association (NYHA) class 2
• Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), myocardial infarction less than 6 months before start of study drug
• Uncontrolled cardiac arrhythmias
• Poorly controlled hypertension, defined as a blood pressure consistently above 150/90 mmHg despite optimal medical management
• Persistent proteinuria of NCI-CTCAE grade 3. Urine dipstick result of 3+ or abnormal, based on type of urine test strip used, is allowed if protein excretion (estimated by urine protein/creatinine ratio on a random urine sample) is \< 3.5 g/24 hr
• Major surgical procedure or significant traumatic injury within 28 days before start of study medication. Note: If participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Non-healing wound, non-healing ulcer, or non-healing bone fracture
• Participants with evidence or history of any bleeding diathesis, irrespective of severity
• Any hemorrhage or bleeding event \>= NCI-CTCAE grade 3 within 28 days prior to the start of study medication
• Significant acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, malabsorption, or \>= NCI-CTCAE grade 2 diarrhea of any etiology

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

Location

Related Publications (1)

• Fakih M, Sandhu J, Lim D, Li X, Li S, Wang C. Regorafenib, Ipilimumab, and Nivolumab for Patients With Microsatellite Stable Colorectal Cancer and Disease Progression With Prior Chemotherapy: A Phase 1 Nonrandomized Clinical Trial. JAMA Oncol. 2023 May 1;9(5):627-634. doi: 10.1001/jamaoncol.2022.7845.

  PMID: 36892833 DERIVED

MeSH Terms

Conditions

Colonic Neoplasms; Colorectal Neoplasms; Rectal Neoplasms

Interventions

Ipilimumab; CTLA-4 Antigen; Nivolumab; regorafenib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immune Checkpoint Proteins; Costimulatory and Inhibitory T-Cell Receptors; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Antigens, Differentiation, T-Lymphocyte; Antigens, Differentiation; Antigens, Surface; Antigens; Biological Factors; Biomarkers

Study Officials

• Marwan G Fakih

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 23, 2020
• First Posted: April 27, 2020
• Study Start: May 27, 2020
• Primary Completion: December 11, 2025
• Study Completion: December 11, 2025
• Last Updated: January 28, 2026

Record last verified: 2026-01

Locations

US (1)