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

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase I clinical trial assessing the safety and recommended phase II dose of cabozantinib in combination with trifluridine/tipiracil (TAS102) in patients with metastatic colorectal carcinoma (mCRC).

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.

What data supports the effectiveness of the drug combination Cabozantinib + TAS-102 for colorectal cancer?

Research shows that TAS-102, a part of the treatment, has been effective in improving survival in patients with metastatic colorectal cancer, especially when combined with other drugs like bevacizumab. This suggests that combining TAS-102 with other treatments could potentially enhance its effectiveness. ^{1 2 3 4 5}

Is the combination of Cabozantinib and TAS-102 generally safe for humans?

Cabozantinib has been studied for safety in various conditions, showing that higher doses can increase the risk of side effects like hand-foot syndrome, diarrhea, and high blood pressure, but these risks can be managed by adjusting the dose. TAS-102, also known as Lonsurf, is generally considered safe but can cause side effects like low blood cell counts and fatigue. Always consult with a healthcare provider for personalized advice. ^{6 7 8 9 10}

What makes the drug combination of Cabozantinib and TAS-102 unique for colorectal cancer?

The combination of Cabozantinib and TAS-102 is unique for colorectal cancer because Cabozantinib targets multiple pathways involved in tumor growth and resistance, such as MET and VEGFR2, and has shown potent antitumor effects by reducing tumor blood supply and altering cell metabolism. This approach may help overcome resistance to other treatments and enhance the effectiveness of TAS-102, which is a chemotherapy drug. ^{6 10 11 12 13}

Research Team

Farshid Dayyani

Principal Investigator

Chao Family Comprehensive Cancer Center

Eligibility Criteria

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

Age ≥ 18 years

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

Patients must have histologically or cytologically confirmed colorectal adenocarcinoma

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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 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]

References

1. Japan pubmed.ncbi.nlm.nih.gov

Effects and risk factors of TAS-102 in real-world patients with metastatic colorectal cancer, EROTAS-R study. [2023]

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

Evaluation of Tolerability of Trifluridine/Tipiracil Combination Tablet in Patients With Advanced/Recurrent Colorectal Cancer. [2020]

3. 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]

4. United States 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. [2023]

5. Greece pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Trifluridine-Tipiracil Hydrochloride Oral Combination (TAS-102) in Patients with Unresectable Colorectal Cancer. [2020]

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

Anticancer Activity of the Combination of Cabozantinib and Temozolomide in Uterine Sarcoma. [2022]

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

Phase 1 study of cabozantinib in combination with topotecan-cyclophosphamide for patients with relapsed Ewing sarcoma or osteosarcoma. [2023]

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

Phase I trial of the multi-kinase inhibitor cabozantinib, a CYP3A4 substrate, plus CYP3A4 interacting antiretroviral therapy in people living HIV and cancer (AMC087). [2023]

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

Cabozantinib exposure-response analyses of efficacy and safety in patients with advanced hepatocellular carcinoma. [2020]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Pharmacokinetics and Pharmacodynamics of Cabozantinib. [2022]

11. United States 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. [2020]

12. England pubmed.ncbi.nlm.nih.gov

Cabozantinib (XL184) for the treatment of locally advanced or metastatic progressive medullary thyroid cancer. [2019]

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

Cabozantinib Exhibits Potent Antitumor Activity in Colorectal Cancer Patient-Derived Tumor Xenograft Models via Autophagy and Signaling Mechanisms. [2021]