Cabozantinib + TAS-102 for Colorectal Cancer

Overseen By Chao Family Comprehensive Cancer Center University of California, Irvine

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of California, Irvine

Must not be taking: Anticoagulants, Kinase inhibitors

Disqualifiers: Brain metastases, Cardiovascular disorders, 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: 8

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments: cabozantinib, a cancer drug, and TAS-102 (Lonsurf), a chemotherapy drug. The aim is to find a safe dose for individuals with metastatic colorectal cancer, which has spread beyond the colon. The primary goal is to assess how patients tolerate this combination and determine the optimal dosage for future studies. This trial may suit those with colorectal cancer that has spread, cannot be treated with surgery or radiation, and have not responded to other treatments. Participants must be able to swallow tablets and have a life expectancy of at least three months. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on certain investigational drugs or specific anticoagulants like warfarin. It's best to discuss your current medications with the trial team to see if they are allowed.

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

Research has shown that the combination of cabozantinib and TAS-102 is generally well-tolerated. In studies with patients who have advanced colorectal cancer, this combination proved practical and manageable.

One study found that 75% of patients had their disease under control, indicating effective management of their condition. About 42% of the patients experienced a significant drop in their cancer marker levels, showing the treatment worked as intended without causing excessive problems.

However, like any treatment, side effects may occur. Some patients required medications to boost their blood cell counts, suggesting the treatment can affect blood levels. Overall, most people managed the treatment at regular doses without severe issues.

Keep in mind, this treatment is still under investigation, so not all effects are fully known. However, these early findings suggest it is safe enough for further research. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for colorectal cancer?

Researchers are excited about Cabozantinib combined with TAS-102 for colorectal cancer because this duo tackles the disease differently than standard treatments. While typical therapies often rely on traditional chemotherapy or targeted therapies that focus on specific proteins, Cabozantinib inhibits multiple pathways that cancer cells use to grow and spread, potentially offering a more comprehensive approach. Additionally, TAS-102, with its unique combination of trifluridine and tipiracil, targets cancer cell DNA, disrupting replication. This combination aims to enhance treatment efficacy by attacking the cancer from multiple angles, which could be promising for patients who haven't responded well to existing options.

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

Research has shown that using cabozantinib with TAS-102, which participants in this trial will receive, may be promising for treating metastatic colorectal cancer (mCRC). In one study, 75% of patients experienced either stabilization or improvement in their cancer. Additionally, 42% of patients saw a significant drop in their cancer marker, CEA, by more than 30%. Patients who received only TAS-102 in previous studies showed an average survival time of 8.6 to 14.4 months, with cancer not worsening for 3.7 to 6.8 months. These findings suggest that combining cabozantinib with TAS-102 could enhance treatment effectiveness for mCRC. ^{1 2 3 5 6}

Who Is on the Research Team?

Farshid Dayyani

Principal Investigator

Chao Family Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced colorectal cancer that's spread and can't be cured by surgery or radiation. They must have tried other treatments without success, be in fairly good health otherwise, and agree to use contraception. People who've had certain recent treatments, severe allergies to the drugs being tested, brain metastases not stable for at least 4 weeks, or uncontrolled illnesses cannot join.

Inclusion Criteria

You are expected to live for at least 3 more months.

Patients must have histologically or cytologically confirmed colorectal adenocarcinoma

Performance status: ECOG performance status ≤2

Exclusion Criteria

Receipt of any type of small molecule kinase inhibitor within 2 weeks before first dose of study treatment

Has severe hypersensitivity (Grade ≥ 3) to TAS-102 or cabozantinib and/or any of their excipients

Pregnant or lactating females

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib daily and TAS-102 on specified days in a 28-day cycle, with peg-filgrastim administered on Day 13

12 months

Tumor assessments every 8 weeks during the first year

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Participants are monitored for overall survival and progression-free survival

Up to 18 months after last patient enrollment

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• TAS-102

Trial Overview The study tests combining Cabozantinib with TAS-102 (trifluridine/tipiracil) to find a safe dosage and see how well it works as a last-resort treatment for metastatic colorectal carcinoma (mCRC). It's an early-phase trial designed to establish safety profiles before moving on to larger trials.

How Is the Trial Designed?

Group I: Cabozantinib in Combination with TAS-102 (trifluridine/tipiracil) Experimental Treatment 2 Interventions

Subjects will receive cabozantinib in combination with TAS-102. Patients will receive cabozantinib on Days 1 - 28 and TAS-102 on Days 1-5 and Days 8-12, for a cycle length of 28 days.

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

Approved in European Union as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in United States as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Canada as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Japan as Cabometyx for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

University of California, Irvine

Lead Sponsor

Trials

580

Recruited

4,943,000+

Published Research Related to This Trial

In a study of 70 patients with metastatic colorectal cancer who had previously failed multiple therapies, TAS-102 demonstrated a median progression-free survival (PFS) of 6.0 months and an overall survival (OS) of 10.0 months, indicating its effectiveness in a real-world setting.

Combining TAS-102 with bevacizumab resulted in significantly better disease control rates (75.9% vs. 40-50% for other combinations), PFS (6.3 months vs. 3.0 months), and OS (12.0 months vs. 6.0-6.5 months), suggesting that this combination therapy may enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Exploration of Trifluridine/Tipiracil Monotherapy and in Combination With Bevacizumab or Immune Checkpoint Inhibitors for Patients With Metastatic Colorectal Cancer: A Real-World Study. Nie, C., Xu, W., Chen, B., et al.[2023]

Cabozantinib and temozolomide both significantly reduced the growth and viability of uterine sarcoma cells, with the combination of the two drugs showing even greater effectiveness in promoting cell death and inhibiting tumor growth.

In mouse models, the combined treatment of cabozantinib and temozolomide led to a significant reduction in tumor size, indicating a synergistic effect that supports further clinical trials for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticancer Activity of the Combination of Cabozantinib and Temozolomide in Uterine Sarcoma. Noh, JJ., Cho, YJ., Ryu, JY., et al.[2022]

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 study involving 111 patients with recurrent ovarian cancer, cabozantinib showed a median progression-free survival (PFS) of 5.3 months, which was similar to the 5.5 months achieved with weekly paclitaxel, indicating comparable initial treatment effectiveness.

However, cabozantinib had worse outcomes in overall survival (OS), event-free survival (EFS), and overall response rate (ORR) compared to paclitaxel, along with increased gastrointestinal side effects, leading to the conclusion that cabozantinib is not recommended for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II study of cabozantinib versus weekly paclitaxel in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study. Matulonis, UA., Sill, MW., Makker, V., et al.[2020]

In the Phase III CELESTIAL trial, cabozantinib significantly improved overall survival (OS) and progression-free survival (PFS) in hepatocellular carcinoma patients compared to placebo, with the most effective dose being 60 mg daily.

While the 60 mg dose provided the best efficacy outcomes, it also increased the risk of adverse events (AEs); lower doses (20 or 40 mg) reduced the likelihood of AEs like palmar-plantar erythrodysaesthesia and diarrhea, suggesting a balance between maximizing efficacy and minimizing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib exposure-response analyses of efficacy and safety in patients with advanced hepatocellular carcinoma. Nguyen, L., Chapel, S., Tran, BD., et al.[2020]

In a Phase 1 study involving 12 patients with relapsed osteosarcoma and Ewing sarcoma, the combination of cabozantinib, topotecan, and cyclophosphamide showed acceptable toxicity levels, with manageable dose-limiting toxicities observed.

The treatment resulted in one partial response and stable disease in seven patients, suggesting that this combination therapy may provide potential disease control in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of cabozantinib in combination with topotecan-cyclophosphamide for patients with relapsed Ewing sarcoma or osteosarcoma. Campbell, K., Posner, A., Chen, N., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11265208/

A Phase 1 Study of Cabozantinib and Trifluridine/Tipiracil ... The prognosis for patients with advanced metastatic colorectal adenocarcinoma (mCRC) remains poor, with a 5-year overall survival of 14.7%. Trifluridine and ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S153300282300107X

A Phase 1 Study of Cabozantinib and Trifluridine/Tipiracil ... The prognosis for patients with advanced metastatic colorectal adenocarcinoma (mCRC) remains poor, with a 5-year overall survival of 14.7%.1 Trifluridine and ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.4_suppl.98

Phase 1 dose-finding trial of cabozantinib (cabo) and ... The disease control rate was 75%. 5/12 (42%) pts had a CEA decline > 30%. Conclusions: The combination of Cabo and FTD/TPI is feasible and ...

4. academic.oup.com academic.oup.com/oncolo/article/29/5/e601/7609538

Efficacy and Safety of Trifluridine/Tipiracil-Containing ... Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory ...

5. clinicaltrials.icts.uci.edu clinicaltrials.icts.uci.edu/trial/NCT04868773

Study of Cabozantinib Plus TAS102 in mCRC as Salvage ... This is a phase I clinical trial assessing the safety and recommended phase II dose of cabozantinib in combination with trifluridine/tipiracil ( ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38103947/

A Phase 1 Study of Cabozantinib and Trifluridine/Tipiracil in ... Conclusion: The combination of cabozantinib and FTD/TPI is feasible and tolerable at standard doses with the use of growth factors and showed encouraging ...