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Advanced Colon AdenocarcinomaPhase 1NCT04362839

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

A Phase 1 study testing Ipilimumab, Nivolumab and Regorafenib in people with Advanced Colon Adenocarcinoma and Metastatic Colon Adenocarcinoma, run by City of Hope Medical Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ipilimumab, Nivolumab and Regorafenib
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
39 participants
Where
1 siteUnited States
Study dates
27 May 2020to 11 Dec 2025
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
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  • 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)
  • Alanine transaminase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN if no liver metastases; ALT or AST =< 5 x ULN allowed for patients with liver involvement (performed within 7 days before treatment initiation)
  • Platelet count >= 100,000 /mm^3 (performed within 7 days before treatment initiation)
  • Hemoglobin (Hb) >= 9 g/dL (performed within 7 days before treatment initiation)
  • White blood cells (WBC) >= 2000/uL (performed within 7 days before treatment initiation)
  • Absolute neutrophil count (ANC) >= 1500/mm^3 (performed within 7 days before treatment initiation)
  • Serum creatinine =< 1.5 x ULN or creatinine clearance >= 40 mL/min (measured or calculated using the Cockcroft-Gault formula) (performed within 7 days before treatment initiation)
  • Measurable disease as determined by RECISTv1.1
  • Provision of recent tumor tissue (as defined below) is mandatory for all participants at screening (Formalin-fixed paraffin-embedded block or minimum of 20 slides)
  • Tumor tissue obtained within 180 days of enrollment and after the last dose of most recent anti-cancer therapy
  • Or a new biopsy Exceptions for patients with no recent baseline tumor tissues or biopsies may be considered after documented discussion and approval with the principal investigator (PI) of the study
  • Anticipated life expectancy greater than 3 months
  • Be able to swallow and absorb oral tablets
  • Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of study intervention and 120 days after last dose of regorafenib and 5 months after the last dose of nivolumab. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study intervention and 120 days after last dose of regorafenib and 7 months after the last dose of nivolumab. In addition, male participants must be willing to refrain from sperm donation during this time. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

Who cannot join

  • 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
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  • 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
  • Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus (T1DM), hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
  • Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
  • History of (non-infectious) pneumonitis that required steroids or current pneumonitis
  • History of interstitial lung disease
  • Subjects with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission prior to study entry and no additional therapy is required or anticipated to be required during the study period
  • Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy
  • Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed treatment (such as radiotherapy or surgery). Participants with stable CNS disease or previously treated lesions are eligible for study entry. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of 10 mg daily prednisone (or equivalent)
  • Ongoing infection > grade 2 NCI-CTCAE requiring systemic therapy
  • Known history of human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies)
  • Any positive test result for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating presence of virus, e.g. hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive (except if HCV-ribonucleic acid [RNA] negative)
  • Pregnancy or breast feeding
  • Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up (FU) schedule
  • Previous treatment with live vaccine within 30 days of planned start of study drugs (seasonal flu vaccines that do not contain a live virus are permitted)
  • Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation

Trial locations and contacts

1 site in 1 country.

United States1 site

  • City of Hope Medical Center

    Duarte, California, 91010

Other trials in United States

About this study

Official title: A Phase I Clinical Trial of Regorafenib, Nivolumab, and Ipilimumab in Advanced Chemotherapy Resistant Metastatic MSS Colorectal Cancer

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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To determine the recommended dose level of the combination of regorafenib, nivolumab and ipilimumab in patients with advanced metastatic colorectal cancer.

SECONDARY OBJECTIVES:

  1. Assess the objective overall response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.

II. Estimate the duration of response, duration of stable disease (SD), progression free survival (PFS), and overall survival (OS).

III. Describe the safety of this regimen as determined by frequency and severity of associated adverse events.

EXPLORATORY OBJECTIVES:

  1. Correlate the presence of colony stimulating factor 1 receptor (CSF1R)+ macrophages, regulatory T cells (Tregs), TILs (tumor infiltrating lymphocytes) and tumor PD-L1, CTLA-4 and PD1 expression (at baseline and post treatment) on tumor biopsies with response rate.

II. Characterize the systemic immune alteration through evaluation of mandatory pre and post cycle 1, and cycle 2, and at progression blood draws.

OUTLINE: This is a dose-escalation study of regorafenib.

Patients receive regorafenib orally (PO) once daily (QD) on days 1-21, nivolumab intravenously (IV) over 30 minutes every 2 weeks (Q2W), and ipilimumab IV over 30 minutes every 6 weeks (Q6W). Cycles repeat every 28 day for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 90 days, then every 3 months for up to 5 years.

Medical subject headings
Colonic Neoplasms, Colorectal Neoplasms, Rectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IpilimumabBiological

    Also called Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4

    Given IV

  • NivolumabBiological

    Also called BMS-936558, MDX-1106, NIVO, ONO-4538

    Given IV

  • RegorafenibDrug

    Also called BAY 73-4506, Stivarga

    Given PO

Study groups in NCT04362839
Study groupRoleWhat they receive
Treatment (regorafenib, nivolumab, ipilimumab)ExperimentalPatients 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.
Receives: Biological: Ipilimumab; Biological: Nivolumab; Drug: Regorafenib

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Up to 90 days post treatment

Secondary outcomes (4)

  1. Progression-free survival

    Assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Will be summarized using the Kaplan-Meier method.

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

  2. Duration of response

    Assessed using RECIST v 1.1. Duration of response (possibly censored) will be reported for each response.

    Measured: Time to progression or death, assessed up to 5 years

  3. Overall survival

    Assessed using RECIST v 1.1. Will be summarized using the Kaplan-Meier method.

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

  4. Objective response rate (ORR)

    ORR is defined as the percentage of measurable disease participants who have achieved either complete response (CR) or partial response (PR). Assessed using RECIST v 1.1.

    Measured: Up to 5 years post treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Apr 2020
  2. Study start27 May 2020
  3. Primary completion11 Dec 2025
  4. Study completion11 Dec 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
39 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04362839
Sponsor's protocol ID
19417
Other IDs
NCI-2020-01818, 19417
Status last verified
Jan 2026
First submitted
23 Apr 2020
Last updated
28 Jan 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 36892833

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Ipilimumab, Nivolumab and Regorafenib in people with Advanced Colon Adenocarcinoma and Metastatic Colon Adenocarcinoma, run by City of Hope Medical Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 28 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Recommended dose level of the combination (time frame: Up to 90 days post treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04362839, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Jan 2026.

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