Regorafenib in Combination With Pembrolizumab or Pembrolizumab for MSI-H Colorectal Cancer

January 16, 2026 updated by: Anwaar Saeed

Randomized Trial of Regorafenib in Combination With Pembrolizumab or Pembrolizumab Monotherapy With an Efficacy Lead-in of Regorafenib and Pembrolizumab for Patients With MSI-H Colorectal Cancer

This is a trial of Regorafenib in combination with pembrolizumab for patients with MSI-H colorectal cancer consisting of lead-in phase examining preliminary efficacy and safety, followed by a randomized phase to further examine efficacy.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Regorafenib is a multi-kinase inhibitor that targets several receptor tyrosine kinases including vascular endothelial growth factor receptor (VEGFR). Regorafenib may also have immunomodulatory affect in the tumor microenvironment. Preclinical and early clinical studies indicate there is a potential for synergistic activity of regorafenib with immune checkpoint inhibitors that can be leveraged to augment antitumor immunity. Pembrolizumab, anti-PD1 blockade, has been approved for patients with high microsatellite instability (MSI-H) colorectal cancer (CRC) as first line therapy. However, there is still an unmet need to enhance the efficacy of immune checkpoint inhibitors for patients with MSI-H colorectal cancer. The efficacy of TKI and immune checkpoint inhibitor combination have been shown in clinical studies for solid tumors particularly for those that are responsive to immune checkpoint inhibitors therapy. Therefore, there is strong rationale for the combination of regorafenib and pembrolizumab in MSI-H colorectal cancer in which there is increased VEGF activity compared to MSS counterpart. A recent retrospective study showed significantly improved response to regorafenib among patients with MSI-H colorectal cancer, compared to patients with MSS colorectal cancer. Collectively, this combination may increase anti-tumor immune response and clinical effectiveness of immunotherapy for patients with MSI-H colorectal cancer. Based on prior clinical trials, the target regorafenib dose in this study is determined to be 90 mg. However, patients in the lead-in phase will receive regorafenib 60 mg in combination with 200mg of pembrolizumab Q3 weeks in the first cycle to increase tolerance and study compliance. The dose of regorafenib will be increased to 90 mg by Cycle 2. An interim analysis will be performed after completion of data collection for the lead-in phase. Target enrollment for the lead-in phase is approximately 22 patients. Following the futility analysis in lead-in phase, the randomized phase target enrollment is determined to be 66 patients per arm, for a total trial enrollment of 154 participants. Patients who received 3 or less cycles of chemotherapy prior to the determination of MMR-D and MSI-H disease can be enrolled in this trial.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
1

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • United States
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15232
        • UPMC Hillman Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Histologically confirmed mismatch repair deficient or microsatellite instability high advanced stage colorectal cancer
  2. Measurable disease (per RECIST v1.1)
  3. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
  4. Age > 18
  5. The patient must be able to swallow oral medication.

  6. Adequate organ function based on the following lab assessments:

    1. ANC must be ≥ 1500/mm3
    2. platelet count must be ≥ 100,000/mm3
    3. WBC count ≥ 2.5 × 109 /L
    4. Hemoglobin must be ≥ 9 g/dL
    5. Alkaline phosphatase ≤ 2.5× upper limit of normal (ULN) with the exception of patients with documented liver or bone metastases who should have ALP ≤ 5.0× ULN
    6. AST and ALT ≤ 2.5× ULN with the exception of patients with documented liver metastases who may have AST and/or ALT ≤ 5.0× ULN
    7. International normalized ratio (INR) ≤ 1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving treatment with therapeutic anticoagulation
    8. Total bilirubin ≤ 1.5× ULN (≤ 3× ULN if Gilbert syndrome present)
    9. Serum albumin ≥ 2.8 g/dL or 28 g/L
    10. Creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula) or creatinine ≤ 1.5× ULN
  7. No more than three cycles of prior fluoropyrimidine-based chemotherapy including folinic acid, fluorouracil, and oxaliplatin (FOLFOX); folinic acid, fluorouracil, and irinotecan (FOLFIRI); and, folinic acid, fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) excluding adjuvant treatment
  8. Patients (male or female) of reproductive potential must agree to use an effective method of contraception (as discussed with treating physician) from the time consent is signed, during study therapy, and for at least 8 weeks after the last dose of study therapy.
  9. Patients who received no more than 1 cycle of pembrolizumab monotherapy will be still eligible to be enrolled in lead in phase of the trial

Exclusion Criteria:

  1. Prior anti-programmed death 1 (anti-PD-1) or anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) based therapy
  2. More than 3 cycles of chemotherapy or progression of disease on first line therapy excluding adjuvant treatment and any systemic anticancer treatment within 2 weeks or 5 half-lives (whichever is shorter) prior to start of study treatment
  3. Active autoimmune disease
  4. Pregnant or lactating females
  5. Uncontrolled human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV); patients with undetectable viral load and CD4 count > 200 will be eligible for enrollment
  6. Active untreated brain metastasis
  7. Uncontrolled hypertension (HTN: systolic pressure > 150 mmHg or diastolic pressure > 90 mmHg on repeated measurements) and cardiovascular events within 12 months of start of treatment
  8. Active infection or chronic infection requiring chronic suppressive antibiotics
  9. No active cancer such as colon cancer other than adenocarcinoma (e.g., sarcoma, lymphoma, carcinoid) within 1 year
  10. Patients with severe hepatic impairment (Child-Pugh C) are excluded as regorafenib has not been studied in this population and exposure might be increased in these patients
  11. Major surgical procedure or significant traumatic injury within 28 days before start of study medication
  12. Non-healing wound, non-healing ulcer, or non-healing bone fracture
  13. Patients with evidence or history of any bleeding diathesis, irrespective of severity

  14. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication:

    1. Major surgical procedure or significant traumatic injury within 28 days before start of study medication
    2. Non-healing wound, non-healing ulcer, or non-healing bone fracture
    3. Patients with evidence or history of any bleeding diathesis, irrespective of severity
    4. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Pembrolizumab + Regorafenib

Pembrolizumab: 200mg, Q3 weeks

Regorafenib: 60mg Cycle 1 Day 1 90 mg Cycle 2 Day 1
Drug: Regorafenib
A multi-kinase inhibitor that targets several receptor tyrosine kinases including vascular endothelial growth factor receptor (VEGFR), which may also have immunomodulatory affect in the tumor microenvironment.
Other Names:
  • BAY 73-4506
  • Stivarga
Drug: Pembrolizumab
An anti-PD1 blockade / immune checkpoint inhibitor treatment approved for patients with high microsatellite instability (MSI-H) colorectal cancer (CRC) as first line therapy.
Other Names:
  • Keytruda
Active Comparator: Pembrolizumab
Pembrolizumab: 200mg, Q3 weeks
Drug: Pembrolizumab
An anti-PD1 blockade / immune checkpoint inhibitor treatment approved for patients with high microsatellite instability (MSI-H) colorectal cancer (CRC) as first line therapy.
Other Names:
  • Keytruda

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Objective Response Rate (ORR), Lead-in Phase
Time Frame: Up to 12 months (lead-in phase)
Percentage of patients with partial response (PR) or complete response (CR) to the treatment per RECIST 1.1. criteria. v1.1. Per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or nontarget) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Up to 12 months (lead-in phase)
Progression-free Survival (PFS), Randomize Phase
Time Frame: Up to 24 months
Median number of months from time of randomization to the date of disease progression or death from any cause. Per RECISIT v1.1: Progressive Disease (PD):≥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). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.
Up to 24 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Adverse Events and Serious Adverse Events Related to Treatment
Time Frame: Up to 24 months (lead-in phase)
Percentage of patients that experience Adverse Events (AEs) and/or Serious Adverse Events (SAEs) related to study treatment, per NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The maximum grade for each type of toxicity will be recorded for each patient.
Up to 24 months (lead-in phase)
Adverse Events and Serious Adverse Events Related to Treatment
Time Frame: Up to 24 months (beginning at start of post lead-in phase)
Percentage of patients that experience Adverse Events (AEs) and/or Serious Adverse Events (SAEs) related to study treatment, per NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The maximum grade for each type of toxicity will be recorded for each patient.
Up to 24 months (beginning at start of post lead-in phase)
Progression-free Survival (PFS), Lead-In Phase
Time Frame: Up to 24 months
Median number of months from time of randomization to the date of disease progression or death from any cause. Per RECISIT v1.1: Progressive Disease (PD):≥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). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.
Up to 24 months
Overall Survival (OS)
Time Frame: Up to 48 months (lead-in phase)
Median number of months from start of treatment to death from any cause.
Up to 48 months (lead-in phase)
Overall Survival (OS)
Time Frame: Up to 24 months (beginning at start of post lead-in phase)
Median number of months from time of randomization to death from any cause.
Up to 24 months (beginning at start of post lead-in phase)
Objective Response Rate (ORR), Randomized Phase
Time Frame: Up to 12 months (beginning at start of post lead-in phase)
Percentage of patients with partial response (PR) or complete response (CR) to the treatment per RECIST 1.1. criteria. v1.1. Per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or nontarget) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Up to 12 months (beginning at start of post lead-in phase)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Anwaar Saeed

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Bayer

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Anwaar H Saeed, MD, UPMC Hillman Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 26, 2024

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 11, 2025

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 12, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 17, 2023

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 17, 2023

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 23, 2023

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 20, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 16, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • HCC 23-041

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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