Regorafenib + Pembrolizumab for Colorectal Cancer

Not currently recruiting at 3 trial locations

Overseen By Richard D. Kim, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Southern California

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Hypertension, Brain metastasis, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 21 days per course, repeated

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, regorafenib and pembrolizumab, to evaluate their effectiveness against colorectal cancer that has spread. Regorafenib, a chemotherapy drug, attacks cancer cells, while pembrolizumab, an antibody, aids the immune system in fighting cancer. The trial aims to determine the best doses and identify any side effects from using these drugs together. It seeks participants with advanced colorectal cancer who have not responded well to treatments like oxaliplatin or irinotecan and can still take oral medication. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking cancer research.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot take certain medications like strong CYP3A4 inhibitors or inducers, and you cannot have had certain treatments like chemotherapy or immunotherapy within 2 weeks before starting the trial. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that regorafenib has been studied in patients with advanced colorectal cancer and has helped them live longer. Several studies have tested it, and it is already approved for use in the later stages of this cancer. However, like any treatment, it can have side effects. Some patients have reported fatigue, pain or swelling in their hands and feet, and high blood pressure.

Pembrolizumab, a monoclonal antibody, helps the immune system fight cancer cells. It is generally well-tolerated, but some people might experience fatigue, develop a skin rash, or have diarrhea.

Researchers are testing the combination of regorafenib and pembrolizumab to see if they work better together. While these treatments are approved separately for some cancers, testing them together is still ongoing. Current studies aim to find the best dose and identify any new side effects when used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining regorafenib and pembrolizumab for colorectal cancer because this duo offers a unique approach compared to standard treatments. Regorafenib is a multikinase inhibitor that targets several pathways crucial for cancer cell growth, while pembrolizumab is an immunotherapy that helps the immune system recognize and attack cancer cells. This combination not only targets cancer directly but also boosts the body's natural defenses, potentially leading to more effective and sustained responses than traditional chemotherapy options.

What evidence suggests that this trial's treatments could be effective for colorectal cancer?

Research has shown that using pembrolizumab and regorafenib together may help treat metastatic colorectal cancer. The FDA has already approved regorafenib for this type of cancer, proving its effectiveness. Studies indicate that regorafenib can enhance the effectiveness of pembrolizumab, an immunotherapy drug, by boosting the immune system's ability to fight cancer. This trial will evaluate the combination of pembrolizumab and regorafenib, which some studies have shown can prevent colon cancer recurrence. These findings suggest that this treatment could be effective for metastatic colorectal cancer. ^{1 4 6 7 8}

Who Is on the Research Team?

Heinz-Josef Lenz

Principal Investigator

University of Southern California

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic colorectal cancer who have not responded to standard treatments. They must be able to take oral medication, have certain blood and liver function levels within specific ranges, and agree to use contraception during and after the trial. Those with severe heart conditions, uncontrolled hypertension, active infections or autoimmune diseases are excluded.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

Aspartate transaminase (AST), alanine transaminase (ALT) =< 2.5-times the upper limit of normal (=< 5-times in patients with liver metastasis)

My colorectal cancer is advanced, and I can't tolerate standard treatments.

Exclusion Criteria

I take medication to control my seizures.

I haven't had severe bleeding in the last 4 weeks.

I haven't received any live vaccines in the last 30 days and won't during the trial.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab IV on day 1 and regorafenib PO daily on days 1-14, with courses repeating every 21 days

21 days per course, repeated

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 30 months

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Regorafenib

Trial Overview The study is testing the combination of two drugs: Regorafenib (a chemotherapy drug) and Pembrolizumab (an immunotherapy monoclonal antibody). The goal is to find out if this combo is more effective in stopping the growth or spread of colorectal cancer cells compared to current treatments.

How Is the Trial Designed?

Group I: Treatment (pembrolizumab, regorafenib) Experimental Treatment 2 Interventions

Participants receive pembrolizumab IV over 30 minutes on day 1 and regorafenib PO QD on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

University of Southern California

Lead Sponsor

Trials

956

Recruited

1,609,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Regorafenib, a multikinase inhibitor used for advanced solid tumors, was associated with a range of adverse events (AEs) in a meta-analysis of 2,065 patients, with the most common being hand-foot skin reaction (54%), diarrhea (33%), and fatigue (32%).

The analysis revealed that regorafenib significantly increases the risk of developing AEs compared to placebo, highlighting the importance of monitoring these effects to improve patient safety and treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events risk associated with regorafenib in the treatment of advanced solid tumors: meta-analysis of randomized controlled trials. Yin, X., Yin, Y., Shen, C., et al.[2022]

In a phase II trial involving 48 patients with microsatellite stable colorectal cancer, the combination of regorafenib and avelumab showed a best response of stable disease in 53.5% of patients, with a median progression-free survival of 3.6 months and overall survival of 10.8 months.

The study found that higher infiltration of CD8+ T cells in tumors was linked to better outcomes, suggesting that assessing immune cell presence could help identify patients who might benefit more from this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib-Avelumab Combination in Patients with Microsatellite Stable Colorectal Cancer (REGOMUNE): A Single-arm, Open-label, Phase II Trial. Cousin, S., Cantarel, C., Guegan, JP., et al.[2022]

Regorafenib significantly improves median overall survival and progression-free survival in patients with previously treated metastatic colorectal cancer (mCRC), as shown in the CORRECT trial with a regimen of 160 mg daily for 3 weeks of each 4-week cycle.

The drug has a generally acceptable tolerability profile and does not compromise health-related quality of life, making it a valuable addition to treatment options for patients with progressive mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: a review of its use in previously treated patients with progressive metastatic colorectal cancer. Carter, NJ.[2021]

Regorafenib is an oral multi-kinase inhibitor that has shown significant survival benefits in metastatic colorectal cancer and has been FDA approved for this use since 2012.

The drug also improves progression-free survival in patients with metastatic gastrointestinal stromal tumors and advanced hepatocellular carcinoma, leading to its FDA approval for these conditions as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib. Ettrich, TJ., Seufferlein, T.[2018]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In a study of 72 patients with microsatellite stable metastatic colorectal cancer, regorafenib or fruquintinib combined with sintilimab showed a median progression-free survival of 4.2 months and an overall survival of 10.5 months, indicating these combinations are viable third-line treatment options.

The treatment was generally well-tolerated, with only 15.3% of patients experiencing severe adverse events, and patients without liver metastasis showed better response rates and overall survival, suggesting they may benefit more from this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microsatellite stable metastatic colorectal cancer without liver metastasis may be preferred population for regorafenib or fruquintinib plus sintilimab as third-line or above therapy:A real-world study. Nie, C., Lv, H., Chen, B., et al.[2022]

In a study of 23 patients with metastatic colorectal cancer who had previously undergone multiple treatments, regorafenib showed some efficacy, with 34.8% achieving stable disease and 8.7% showing partial response, although 56.5% experienced disease progression.

Regorafenib treatment was associated with significant side effects, with 65% of patients experiencing severe toxicity, primarily hand-foot syndrome and fatigue, leading to dose reductions in 86.9% of cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and early outcomes of regorafenib in multiply pre-treated metastatic colorectal adenocarcinoma-experience from a tertiary cancer centre in India. Zanwar, S., Ostwal, V., Gupta, S., et al.[2022]

Regorafenib is an effective oral multikinase inhibitor approved by the FDA for treating metastatic colorectal cancer in patients who have not responded to standard chemotherapy and other targeted therapies, showing significant efficacy compared to placebo in the CORRECT trial.

While regorafenib has a greater antiangiogenic effect than sorafenib, it is associated with common severe side effects such as hand-foot skin reactions, diarrhea, hypertension, and fatigue, which require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of regorafenib-related toxicities: a review. Krishnamoorthy, SK., Relias, V., Sebastian, S., et al.[2022]

Regorafenib significantly improves overall survival by up to 2.5 months and progression-free survival by up to 1.5 months in patients with metastatic colorectal cancer (mCRC) who have not responded to standard therapies, based on phase 3 studies.

The treatment is generally well-tolerated, with most side effects being mild to moderate, and it does not negatively impact health-related quality of life compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review in Metastatic Colorectal Cancer. Dhillon, S.[2019]

Regorafenib has shown statistically significant improvements in overall survival, progression-free survival, and disease control in patients with metastatic colorectal cancer, based on results from two phase III trials (CORRECT and CONCUR) and two real-world studies (REBECCA and CONSIGN).

Despite these positive outcomes, there are concerns that the clinical benefits of regorafenib may not be meaningful for all patients, and some subgroups may not experience the same level of benefit, highlighting the need for further investigation into its efficacy across different patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is regorafenib providing clinically meaningful benefits to pretreated patients with metastatic colorectal cancer? García-Alfonso, P., Feliú, J., García-Carbonero, R., et al.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03657641

Regorafenib and Pembrolizumab in Treating Participants ... This phase I/II studies the side effects and best dose of regorafenib when given together with pembrolizumab in treating participants with colorectal cancer ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5844550/

Is it an attractive option or merely a “me too” drug? - PMC The findings from this study led to the US FDA approval of regorafenib in September 2012 for the treatment of patients with mCRC who have been previously ...

3. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1446945/full

Efficacy and safety of regorafenib for the treatment ... This is a retrospective study of a cohort of patients with mCRC treated with regorafenib in Hospital Universitario Ramón y Cajal, in Madrid, Spain.

4. journalofoncology.org journalofoncology.org/articles/is-the-combination-of-pembrolizumab-and-regorafenib-the-beginning-of-a-new-era-in-the-treatment-of-metastatic-colorectal-cancer/jos.galenos.2025.2025-3-23

Is the Combination of Pembrolizumab and Regorafenib ... An ongoing phase II trial (NCT06006923) is evaluating the safety and efficacy of regorafenib combined with pembrolizumab in MSIH colorectal ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8436536/

Regorafenib enhances anti-PD1 immunotherapy efficacy in ... This study highlights the synergistic immunomodulatory effects of REG and aPD1 combination therapy in mediating a sustained inhibition of colon cancer regrowth.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7170555/

Safety and efficacy of regorafenib in patients with treatment ... Regorafenib improved overall survival in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies in two randomised, phase III trials.

7. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04776148/

Clinical Trial: NCT04776148 The purpose of this study is to assess the safety and efficacy of lenvatinib (MK-7902/E7080) in combination with pembrolizumab (MK-3475) in ...

8. aacrjournals.org aacrjournals.org/cancerres/article/72/8_Supplement/2337/579135/Abstract-2337-Regorafenib-BAY-73-4506-Anti

Abstract 2337: Regorafenib (BAY 73-4506): Anti-metastatic ... In summary, these results suggest that regorafenib may exert its anti-tumor activity in colorectal cancer by inhibition of multiple kinases ...