Combination Chemotherapy for Colorectal Cancer

Overseen By Cancer Connect

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Wisconsin, Madison

Must not be taking: CYP3A4 inducers/inhibitors, TAS102

Disqualifiers: BRAF V600 mutations, 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

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

Compensation: Varies

Number of Visits: Unknown

Duration: up to 2 years

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is being done to see if combining liposomal irinotecan with TAS102 and bevacizumab confers clinical benefit for patients with treatment refractory metastatic colorectal cancer.

Will I have to stop taking my current medications?

The trial requires that you stop using strong inducers or inhibitors of CYP3A4 (a type of enzyme that affects drug metabolism) at least 2 weeks before starting the study treatment.

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

Research shows that the combination of trifluridine/tipiracil and bevacizumab is effective for patients with metastatic colorectal cancer, improving survival rates and showing antitumor activity in various studies. ^{1 2 3 4 5}

Is the combination chemotherapy for colorectal cancer safe for humans?

The combination of trifluridine/tipiracil (TAS-102) and bevacizumab has been studied in patients with metastatic colorectal cancer and is generally considered to have controllable safety, though it can cause side effects like nausea and vomiting. These treatments have been evaluated in various studies, showing that while they can be effective, they may also lead to common treatment-related adverse events (unwanted effects). ^{1 6 7 8 9}

What makes the drug combination of Bevacizumab, Liposomal irinotecan, and TAS102 unique for treating colorectal cancer?

This drug combination is unique because it combines TAS-102 (trifluridine and tipiracil) with bevacizumab, which has shown enhanced activity against colorectal cancer compared to using either drug alone. It is particularly beneficial for patients with metastatic colorectal cancer who have not responded to standard therapies, offering a feasible late-line treatment option that can prolong survival. ^{2 3 5 8 10}

Research Team

Dustin Deming, M.D.

Principal Investigator

UW Carbone Cancer Center

Eligibility Criteria

This trial is for adults over 18 with metastatic colorectal cancer that's resistant to standard treatments. They must have tried certain chemotherapies and, if applicable, targeted therapies based on their cancer's genetic features. People can't join if they have specific mutations (BRAF V600), high microsatellite instability, or are using strong CYP3A4 affecting drugs.

Inclusion Criteria

My colorectal cancer is confirmed and cannot be removed by surgery.

My cancer is not caused by a mismatch repair deficiency.

I am 18 years old or older.

Exclusion Criteria

My cancer is not caused by mismatch repair deficiency or high microsatellite instability.

My cancer does not have the BRAF V600 mutation.

I have stopped using certain strong medications 2 weeks before starting therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive liposomal irinotecan, TAS102, and bevacizumab for metastatic colorectal cancer

up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Bevacizumab
• Liposomal irinotecan
• TAS102

Trial Overview The study tests a combination of three drugs: Liposomal Irinotecan, TAS102, and Bevacizumab in patients with advanced colorectal cancer who haven't responded to previous treatments. It aims to see if this mix offers any benefit over existing options.

Participant Groups

Group I: Participants with Metastatic or Unresectable Colorectal Cancer Experimental Treatment 3 Interventions

Male and females aged 18 years and older with histologically confirmed metastatic or unresectable (not amenable to curative therapy) colorectal cancer.

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

University of Wisconsin, Madison

Lead Sponsor

Trials

1,249

Recruited

3,255,000+

Ipsen

Industry Sponsor

Trials

358

Recruited

74,600+

David Loew

Ipsen

Chief Executive Officer since 2020

BA in Business Administration and MBA from the University of St. Gallen, Switzerland

Sandra Silvestri

Ipsen

Chief Medical Officer since 2023

MD, PhD

Findings from Research

The maximum tolerated dose (MTD) for the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan was established at FTD/TPI 25 mg/m2 twice daily plus irinotecan 180 mg/m2, with manageable side effects including fatigue and neutropenia.

In a cohort of 24 patients with previously treated metastatic colorectal cancer, the triplet combination of FTD/TPI, irinotecan, and bevacizumab showed promising results, with 12% achieving partial responses and a median progression-free survival of 7.9 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Trifluridine/Tipiracil Plus Irinotecan and Bevacizumab in Advanced Gastrointestinal Tumors. Varghese, AM., Cardin, DB., Hersch, J., et al.[2022]

In a study of 19 patients with metastatic colorectal cancer, the combination of biweekly TAS-102 and bevacizumab resulted in a median progression-free survival of 5.6 months and overall survival of 11.5 months, indicating its efficacy as a third-line treatment.

The treatment was generally safe, with only one patient experiencing severe neutropenia (grade 3 or more), suggesting that this combination therapy may effectively manage cancer while minimizing serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective Multicenter Phase II Study of Biweekly TAS-102 and Bevacizumab for Metastatic Colorectal Cancer. Ishizaki, T., Mazaki, J., Enomoto, M., et al.[2021]

In a phase 3 study involving 856 patients with unresectable metastatic colorectal cancer, trifluridine-tipiracil plus bevacizumab showed similar progression-free survival compared to capecitabine plus bevacizumab, with median times of 9.4 months and 9.3 months respectively.

The safety profiles of the two treatments differed significantly, with trifluridine-tipiracil plus bevacizumab leading to higher rates of neutropenia and anemia, while capecitabine plus bevacizumab was associated with more cases of hand-foot syndrome, indicating that both treatments have distinct safety considerations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study. André, T., Falcone, A., Shparyk, Y., et al.[2023]

In a phase II/III trial involving 397 patients with metastatic colorectal cancer, the combination of trifluridine/tipiracil (FTD/TPI) and bevacizumab did not show noninferiority compared to the standard treatment of fluoropyrimidine and irinotecan plus bevacizumab, with a median overall survival of 14.8 months versus 18.1 months, respectively.

Patients receiving FTD/TPI plus bevacizumab experienced a higher rate of grade ≥3 adverse events, particularly neutropenia (65.8% vs. 41.6% in the control group), indicating potential safety concerns with this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trifluridine/tipiracil+bevacizumab (BEV) vs. fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial. Kuboki, Y., Terazawa, T., Masuishi, T., et al.[2023]

In the TASCO1 trial involving 153 patients with unresectable metastatic colorectal cancer, the combination of trifluridine/tipiracil and bevacizumab (TT-B) resulted in a median overall survival of 22.3 months, compared to 17.7 months for capecitabine plus bevacizumab (C-B).

The safety profile of TT-B was consistent with previous studies, indicating it is a promising treatment option for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line trifluridine/tipiracil + bevacizumab in patients with unresectable metastatic colorectal cancer: final survival analysis in the TASCO1 study. Van Cutsem, E., Danielewicz, I., Saunders, MP., et al.[2022]

In a study of 57 patients with metastatic unresectable colorectal cancer treated with the combination of TAS-102 and bevacizumab, the incidence of nausea was 57.9% and vomiting was 17.5%, indicating that these side effects are common even after multiple treatment cycles.

Patients who had previously experienced nausea and vomiting from other treatments were found to be at a higher risk for similar side effects when treated with TAS-102 and bevacizumab, suggesting that prior treatment history is an important factor to consider in managing these symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emetogenicity and Risk Factors of Nausea and Vomiting in Patients With Metastatic Colorectal Cancer Receiving Trifluridine/Tipiracil and Bevacizumab Chemotherapy. Matsuoka, S., Fujii, H., Iihara, H., et al.[2023]

Trifluridine/tipiracil (TAS-102) has a favorable safety profile for patients with metastatic colorectal cancer (mCRC), showing a low incidence of common adverse events like nausea, diarrhea, and fatigue, which can help improve patient adherence to treatment.

Oncology nurses play a crucial role in educating patients about managing treatment-related adverse events, which is essential for maintaining adherence to this oral chemotherapy regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic Colorectal Cancer: Management With Trifluridine/Tipiracil . White, T., Larson, H., Minnella, A., et al.[2017]

In a phase 1/2 trial involving 25 patients with heavily treated metastatic colorectal cancer, the combination of TAS-102 and bevacizumab showed promising activity, with a 16-week progression-free survival rate of 42.9%.

The treatment was found to have manageable safety, with the most common severe side effects being neutropenia and leucopenia, but no treatment-related deaths were reported, indicating that this combination could be a viable option for patients who have not responded to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study. Kuboki, Y., Nishina, T., Shinozaki, E., et al.[2022]

In a Phase II study involving 39 elderly patients (average age 76) with untreated metastatic colorectal cancer, the combination of TAS-102 (FTD/TPI) and bevacizumab (Bev) demonstrated a median progression-free survival of 9.4 months and a median overall survival of 22.4 months, indicating strong efficacy.

The treatment was generally well-tolerated, although it did lead to significant grade 3-4 adverse events, particularly neutropenia (71.8%) and leukopenia (51.3%), suggesting that while effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trifluridine/tipiracil plus bevacizumab as a first-line treatment for elderly patients with metastatic colorectal cancer (KSCC1602): A multicenter phase II trial. Oki, E., Makiyama, A., Miyamoto, Y., et al.[2021]

The combination of trifluridine/tipiracil (TAS-102) and bevacizumab is a feasible treatment option for patients with recurrent colorectal cancer, as demonstrated in two case studies.

No severe adverse events (≥Grade 3) were reported, aside from hematotoxicity, indicating a relatively safe profile for this late-line chemotherapy regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Two Cases of Metastatic Colorectal Cancer Treated with TAS-102 plus Bevacizumab]. Maeda, F., Gan, S., Yamada, A., et al.[2021]

References

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

Phase I Study of Trifluridine/Tipiracil Plus Irinotecan and Bevacizumab in Advanced Gastrointestinal Tumors. [2022]

2. Greece pubmed.ncbi.nlm.nih.gov

Prospective Multicenter Phase II Study of Biweekly TAS-102 and Bevacizumab for Metastatic Colorectal Cancer. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Trifluridine/tipiracil+bevacizumab (BEV) vs. fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial. [2023]

5. England pubmed.ncbi.nlm.nih.gov

First-line trifluridine/tipiracil + bevacizumab in patients with unresectable metastatic colorectal cancer: final survival analysis in the TASCO1 study. [2022]

6. Greece pubmed.ncbi.nlm.nih.gov

Emetogenicity and Risk Factors of Nausea and Vomiting in Patients With Metastatic Colorectal Cancer Receiving Trifluridine/Tipiracil and Bevacizumab Chemotherapy. [2023]

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

Metastatic Colorectal Cancer: Management With Trifluridine/Tipiracil . [2017]

8. England pubmed.ncbi.nlm.nih.gov

TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study. [2022]

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

Trifluridine/tipiracil plus bevacizumab as a first-line treatment for elderly patients with metastatic colorectal cancer (KSCC1602): A multicenter phase II trial. [2021]

10. Japan pubmed.ncbi.nlm.nih.gov

[Two Cases of Metastatic Colorectal Cancer Treated with TAS-102 plus Bevacizumab]. [2021]