5FU/LV + Regorafenib for Colorectal Cancer

Overseen By Safiya Joseph

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: The Methodist Hospital Research Institute

Must not be taking: Corticosteroids, Immunosuppressants, Antivirals, others

Disqualifiers: Cardiac issues, Uncontrolled hypertension, Active infection, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 24-48 weeks

56 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a non-inferiority randomized phase II trial investigating the efficacy and safety of 5FU/LV in combination with regorafenib for patients with metastatic colorectal cancer in the third-line setting. Patients will be randomly assigned in a 1:1 ratio between 5FU/LV combined with regorafenib or trifluridine-tipiracil (FTD-TPI) plus bevacizumab. Arm 1 (Treatment Arm) will consist of the 5FU/LV administered to 26 patients as (LV \[400 mg/m² IV over 120 minutes\], followed by 5FU \[400 mg/m² IV bolus then 2400 mg/m² IV infusion over 46 hours\] in 2-week cycles) and regorafenib will be administered dose of 80-120 mg per day with weekly 40 mg per day increases to a maximum of 120 mg per day for 3 weeks on /1 week off until disease progression, up to 12 cycles of treatment. Arm 2 (Control Arm) received by an additional 26 patients, will be given as FTD-TPI, administered orally, BID, at a starting dose of 35 mg/m2 of body-surface area, on days 1 through 5 and on days 8 through 12 every 28 days. Bevacizumab, at a dose of 5 mg per kilogram of body weight, will be administered intravenously on days 1 and 15. The 28-day treatment cycle continued until disease progression or unacceptable toxic effects occurred or consent was withdrawn, up to 12 cycles of treatment.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on certain treatments like corticosteroids or have recently received other investigational agents, you may not be eligible. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Regorafenib for colorectal cancer?

Research shows that Regorafenib, when used for metastatic colorectal cancer, can improve overall survival (the length of time patients live after treatment) and progression-free survival (the time during which the cancer does not get worse). This has been demonstrated in several studies, including large Phase III trials. ^{1 2 3 4 5}

What is the safety profile of 5FU/LV + Regorafenib for colorectal cancer?

Regorafenib, used for metastatic colorectal cancer, has been associated with side effects like hand-foot skin reaction, high blood pressure, fatigue, diarrhea, and liver issues. These side effects often occur early in treatment and can be managed with dose adjustments and close monitoring by healthcare providers. ^{5 6 7 8 9}

How does the drug 5FU/LV + Regorafenib differ from other treatments for colorectal cancer?

The combination of 5FU/LV (chemotherapy drugs) with Regorafenib (a multikinase inhibitor) is unique because Regorafenib targets multiple pathways involved in cancer growth and blood vessel formation, offering survival benefits in metastatic colorectal cancer that has progressed after standard therapies. This combination may provide a novel approach by enhancing the effects of chemotherapy with Regorafenib's ability to inhibit cancer cell growth and angiogenesis (formation of new blood vessels). ^{1 3 10 11 12}

Research Team

Maen Abdelrahim, MD, PhD, Pharm B

Principal Investigator

The Methodist Hospital Research Institute

Abdullah Esmail, MD

Principal Investigator

Houston Methodist Neal Cancer Center

Eligibility Criteria

This trial is for patients with metastatic colorectal cancer who are undergoing their third round of treatment. Participants must be eligible for the third-line setting and able to take oral medication, as well as receive intravenous treatments.

Inclusion Criteria

My colorectal cancer has spread and this was confirmed by a lab test.

Subjects must be able to understand and be willing to sign the written informed consent form

A minimum of one measurable disease per RECISTv1.1

Exclusion Criteria

Hepatic laboratory values exceeding specified limits

Clinically significant laboratory abnormalities that would compromise patient safety or the outcome of the study

I have serious heart problems that are not under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 5FU/LV in combination with regorafenib or FTD-TPI plus bevacizumab until disease progression or unacceptable toxicity, up to 12 cycles

24-48 weeks

Bi-weekly visits for Arm 1, monthly visits for Arm 2

Follow-up

Participants are monitored for safety and effectiveness after treatment

18 months

Treatment Details

Interventions

• 5FU/LV
• Regorafenib

Trial Overview The study compares two treatments: one combines chemotherapy (5FU/LV) with regorafenib, while the other uses trifluridine-tipiracil (FTD-TPI) plus bevacizumab. Patients will be randomly assigned to either group and treated in cycles up to 12 times or until disease progression.

Participant Groups

Group I: 5FU/LV in combination with regorafenib Experimental Treatment 2 Interventions

5FU/LV will be administered to 26 patients as (LV \[400 mg/m² IV over 120 minutes\], followed by 5FU \[400 mg/m² IV bolus then 2400 mg/m² IV infusion over 46 hours\] in 2-week cycles) and regorafenib will be administered dose of 80-120 mg per day with weekly 40 mg per day increases to a maximum of 120 mg per day for 3 weeks on /1 week off until disease progression, up to 12 cycles of treatment.

Group II: trifluridine-tipiracil (FTD-TPI) plus bevacizumab Active Control 2 Interventions

an additional 26 patients, will be given as FTD-TPI, administered orally, trice daily, at a starting dose of 35 mg/m2 of body-surface area, on days 1 through 5 and on days 8 through 12 every 28 days. Bevacizumab, at a dose of 5 mg per kilogram of body weight, will be administered intravenously on days 1 and 15. The 28-day treatment cycle continued until disease progression or unacceptable toxic effects occurred or consent was withdrawn, up to 12 cycles of treatment.

Who Is Running the Clinical Trial?

The Methodist Hospital Research Institute

Lead Sponsor

Trials

299

Recruited

82,500+

Findings from Research

In a study of 43 patients aged 70 and older with metastatic colorectal cancer, regorafenib showed a disease control rate of 31.4% after 2 months, indicating it can be an effective treatment option for older patients who have failed previous therapies.

However, the treatment was associated with significant toxicities, with 35 out of 42 patients experiencing grade 3-4 adverse events, particularly fatigue, hypertension, and hand-foot skin reactions, suggesting that careful monitoring is needed, especially for patients over 80 or with impaired autonomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-arm phase II trial to evaluate efficacy and tolerance of regorafenib monotherapy in patients over 70 with previously treated metastatic colorectal adenocarcinoma FFCD 1404 - REGOLD. Aparicio, T., Darut-Jouve, A., Khemissa Akouz, F., et al.[2021]

Regorafenib is an effective treatment for patients with metastatic colorectal cancer who have previously undergone multiple chemotherapy regimens, showing a significant improvement in overall survival compared to placebo (6.4 months vs 4 months).

The treatment is associated with manageable side effects, with the most common severe adverse events being hand-foot syndrome (17%) and asthenia (10%), indicating that while it is effective, monitoring for these side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Regorafenib approved in Metastatic Colorectal cancer]. André, T., Dumont, SN.[2022]

Regorafenib is the first approved tyrosine kinase inhibitor for metastatic colorectal cancer, showing significant improvements in progression-free and overall survival in patients who had previously undergone multiple lines of chemotherapy and targeted therapies, based on results from two phase III trials.

While regorafenib has a safety profile similar to other tyrosine kinase inhibitors, it is associated with specific adverse events like hand-foot skin reaction and hypertension, which can be managed effectively through patient education and timely dose adjustments, allowing patients to continue benefiting from the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving patient outcomes with regorafenib for metastatic colorectal cancer - patient selection, dosing, patient education, prophylaxis, and management of adverse events. Hofheinz, RD., Arnold, D., Kubicka, S., et al.[2015]

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]

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 study involving 181 patients with metastatic colorectal cancer, the combination of regorafenib and FOLFIRI resulted in a modest increase in progression-free survival (PFS) compared to FOLFIRI alone, with a median PFS of 6.1 months versus 5.3 months.

While the addition of regorafenib improved the response rate (34% vs 21%), it did not significantly extend overall survival, and patients experienced increased rates of serious side effects such as diarrhea and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer. Sanoff, HK., Goldberg, RM., Ivanova, A., et al.[2019]

Regorafenib is an FDA-approved oral medication that targets multiple kinases involved in cancer growth and has shown survival benefits in patients with metastatic colorectal cancer after standard treatments have failed.

In addition to colorectal cancer, regorafenib significantly improves progression-free survival in patients with metastatic gastrointestinal stromal tumors (GIST) and is currently being tested in various other cancers, including renal cell carcinoma and hepatocellular carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib. Ettrich, TJ., Seufferlein, T.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

Regorafenib in the treatment of metastatic colorectal cancer. [2018]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Single-arm phase II trial to evaluate efficacy and tolerance of regorafenib monotherapy in patients over 70 with previously treated metastatic colorectal adenocarcinoma FFCD 1404 - REGOLD. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Regorafenib in Patients with Antiangiogenic-Naïve and Chemotherapy-Refractory Advanced Colorectal Cancer: Results from a Phase IIb Trial. [2020]

4. Pakistan pubmed.ncbi.nlm.nih.gov

Factors Affecting the Efficacy of Regorafenib in Metastatic Colorectal Cancer: Is Tumour Sidedness Important? [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Effectiveness, Toxicity, and Survival Predictors of Regorafenib in Metastatic Colorectal Cancer: A Multicenter Study of Routinely Collected Data. [2023]

6. France pubmed.ncbi.nlm.nih.gov

[Regorafenib approved in Metastatic Colorectal cancer]. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Improving patient outcomes with regorafenib for metastatic colorectal cancer - patient selection, dosing, patient education, prophylaxis, and management of adverse events. [2015]

8. United States pubmed.ncbi.nlm.nih.gov

Regorafenib-induced retinal and gastrointestinal hemorrhage in a metastatic colorectal cancer patient with liver dysfunction: A case report. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Adverse events risk associated with regorafenib in the treatment of advanced solid tumors: meta-analysis of randomized controlled trials. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Regorafenib. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer. [2019]

12. Germany pubmed.ncbi.nlm.nih.gov

Regorafenib. [2015]