Trifluridine/Tipiracil + Talazoparib for Gastroesophageal Cancer

Overseen By Sarah Chatley, BS

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Roswell Park Cancer Institute

Must not be taking: PARP inhibitors, FTD/TPI

Disqualifiers: CNS disease, Cardiac disease, Infection, others

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

Compensation: Varies

Number of Visits: 14

Duration: Ongoing, cycles of 14 days

45 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial investigates the side effects and best dose of talazoparib when given together with trifluridine/tipiracil for the treatment of patients with colorectal or gastroesophageal cancer that has spread to nearby tissue or lymph nodes (locally advanced) or other places in the body (metastatic). Drugs used in the chemotherapy, such as trifluridine/tipiracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving talazoparib with trifluridine/ tipiracil may inhibit certain enzymes in the cells that are responsible for tumor cell growth.

Will I have to stop taking my current medications?

The trial requires that you stop any systemic cancer treatments at least 2 weeks before starting the study drugs, or 6 weeks if you were taking mitomycin C or nitrosourea. Other medications are not specifically mentioned, so it's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug Trifluridine/Tipiracil + Talazoparib for gastroesophageal cancer?

Trifluridine/tipiracil has been shown to improve overall survival and disease control in patients with metastatic gastric and gastroesophageal junction cancer who have been treated with at least two prior therapies, as demonstrated in the TAGS trial. This drug combination did not negatively impact quality of life and was generally well-tolerated, providing a valuable treatment option for these patients. ^{1 2 3 4 5}

Is the combination of Trifluridine/Tipiracil and Talazoparib safe for humans?

Talazoparib has been shown to have a manageable safety profile in patients with certain types of breast and prostate cancer, meaning it is generally safe for use in humans. However, specific safety data for the combination of Trifluridine/Tipiracil and Talazoparib in gastroesophageal cancer is not available from the provided research. ^{6 7 8 9 10}

How is the drug Trifluridine/Tipiracil + Talazoparib unique for treating gastroesophageal cancer?

This drug combination is unique because it combines Trifluridine/Tipiracil, which has shown to improve survival in patients with advanced gastric cancer after multiple prior treatments, with Talazoparib, a PARP inhibitor that may enhance the effectiveness of cancer treatment by preventing cancer cells from repairing themselves. ^{1 2 3 11 12}

Research Team

Christos Fountzilas, MD, FACP

Principal Investigator

Roswell Park Cancer Institute

Eligibility Criteria

This trial is for adults with advanced or metastatic colorectal or gastroesophageal cancer who have tried at least one treatment without success. They must be able to perform daily activities with ease (ECOG status 0-1), have a life expectancy of more than 3 months, and meet specific blood count and organ function criteria. Pregnant women, those with certain infections like HIV or hepatitis B, or patients with other serious health conditions are excluded.

Inclusion Criteria

Platelet count >= 100,000/mm^3 without transfusion or growth factor support

Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

I am fully active or can carry out light work.

Exclusion Criteria

I need fluid removed from my abdomen weekly or have a permanent catheter.

I have a condition that might affect how my body absorbs certain medications.

I haven't had a GI blockage or tear in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive trifluridine/tipiracil PO BID and talazoparib tosylate PO QD on days 1-5. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Ongoing, cycles of 14 days

Visits every 14 days for treatment cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Pharmacokinetics and Pharmacodynamics Evaluation

Evaluation of pharmacokinetic parameters and pharmacodynamic markers of activity

Up to 28 days prior to first drug dose, on treatment and between cycle 1-day 8 and cycle 1 day 12

Treatment Details

Interventions

• Talazoparib Tosylate
• Trifluridine and Tipiracil Hydrochloride

Trial Overview The study is testing the combination of two drugs: trifluridine/tipiracil and talazoparib. Trifluridine/tipiracil is a chemotherapy drug that kills cancer cells or stops them from growing. Talazoparib blocks enzymes needed by tumor cells to grow. The goal is to find the best dose of talazoparib that can be given safely with trifluridine/tipiracil.

Participant Groups

Group I: Treatment Arm Experimental Treatment 2 Interventions

Patients receive trifluridine/tipiracil PO BID and talazoparib tosylate PO QD on days 1-5. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Talazoparib Tosylate is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Talzenna for:

• Germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer
• Metastatic castration-resistant prostate cancer (mCRPC) in adults

Approved in United States as Talzenna for:

• Germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer
• HRR Gene-mutated metastatic castration-resistant prostate cancer (mCRPC)

Approved in Canada as Talzenna for:

• BRCA-mutated breast cancer

Who Is Running the Clinical Trial?

Roswell Park Cancer Institute

Lead Sponsor

Trials

427

Recruited

40,500+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Findings from Research

Trifluridine/tipiracil (Lonsurf®) has been shown to significantly improve overall survival in patients with metastatic gastric cancer who have previously undergone at least two treatment regimens, as demonstrated in the phase III TAGS trial.

The treatment not only enhances survival and progression-free survival but also maintains health-related quality of life, with manageable side effects primarily related to blood cell counts and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trifluridine/Tipiracil: A Review in Metastatic Gastric Cancer. Kang, C., Dhillon, S., Deeks, ED.[2020]

In the phase III TAGS trial involving 507 patients with metastatic gastric/gastroesophageal junction cancer, trifluridine/tipiracil significantly improved overall survival (4.6-6.1 months) and progression-free survival (1.9-2.3 months) compared to placebo, regardless of the type of prior therapy received.

The safety profile of trifluridine/tipiracil was consistent across different treatment subgroups, with similar rates of severe adverse events, indicating it is a safe option for patients who have undergone multiple prior treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of prior therapies on outcomes with trifluridine/tipiracil in patients with metastatic gastric/gastroesophageal junction cancer in a randomized phase III trial (TAGS). Shitara, K., George, B., Taieb, J., et al.[2023]

Trifluridine/tipiracil (TAS-102) has been approved for treating metastatic gastric and gastroesophageal junction adenocarcinoma after showing significant improvement in overall survival (5.7 months) compared to placebo (3.6 months) in a Phase III trial with patients who had undergone at least two lines of chemotherapy.

The treatment demonstrated a disease control rate of over 50% after eight weeks and did not impair quality of life, while the most common serious side effect was neutropenia, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Evaluation of the Safety and Efficacy of Trifluridine/Tipiracil in the Treatment of Advanced Gastric/Gastroesophageal Junction Adenocarcinoma: Evidence to Date. Wheelden, M., Yee, NS.[2020]

In a phase II trial involving 42 patients with unresectable advanced/recurrent esophageal squamous cell carcinoma, trifluridine/tipiracil (FTD/TPI) demonstrated modest efficacy, with a 3-month progression-free survival rate of 15.4% and a median overall survival of 4.5 months.

The treatment was associated with significant toxicities, including neutropenia (47.6%) and leukocytopenia (35.7%), but no treatment-related deaths occurred, indicating that while FTD/TPI is feasible, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II study of trifluridine/tipiracil for esophageal squamous carcinoma refractory/intolerant to 5-fluorouracil, platinum compounds, and taxanes: the ECTAS study. Mori, Y., Kikuchi, O., Horimatsu, T., et al.[2022]

In the TAGS study, trifluridine/tipiracil (FTD/TPI) significantly improved overall survival (OS) in patients with metastatic gastric cancer and esophagogastric junction cancer, showing a median OS of 6.8 months for third-line treatment compared to 3.2 months for placebo.

FTD/TPI also demonstrated a safety profile consistent across treatment lines, with significant improvements in progression-free survival (PFS) and time to deterioration in performance status, indicating its efficacy as a viable treatment option in both third-line and fourth-line settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trifluridine/tipiracil versus placebo for third or later lines of treatment in metastatic gastric cancer: an exploratory subgroup analysis from the TAGS study. Tabernero, J., Shitara, K., Zaanan, A., et al.[2022]

Talazoparib is an oral PARP inhibitor recently approved in the USA for treating adults with specific types of breast cancer, particularly those with BRCA mutations, highlighting its targeted efficacy in a defined patient population.

The drug is also being explored for use in other cancers, including metastatic castration-resistant prostate cancer and early triple negative breast cancer, indicating its potential versatility in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talazoparib: First Global Approval. Hoy, SM.[2020]

Talazoparib tosylate is an FDA and EMA-approved oral PARP inhibitor specifically effective for treating breast cancer in patients with germline BRCA mutations, showing superior efficacy compared to other PARP inhibitors and standard chemotherapy.

The drug works through a mechanism called synthetic lethality, which means it targets cancer cells' weaknesses, providing significant clinical benefits for patients with advanced or metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talazoparib to treat BRCA-positive breast cancer. Guney Eskiler, G.[2019]

Talazoparib, a PARP inhibitor, has been approved for treating metastatic breast cancer in patients with germline BRCA1/2 mutations, showing superior progression-free survival compared to standard chemotherapy in a phase III trial.

The review discusses talazoparib's safety profile and explores its potential effectiveness when combined with standard cytotoxic drugs and novel therapies, highlighting its role in enhancing treatment options for this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence to date: talazoparib in the treatment of breast cancer. Exman, P., Barroso-Sousa, R., Tolaney, SM.[2020]

Biologic therapies, particularly those targeting HER2 and VEGF, are showing promise in treating esophageal and gastric cancers, with trastuzumab and ramucirumab currently recommended by the NCCN for specific patient groups.

Recent studies indicate that other agents like pertuzumab, apatinib, and pembrolizumab may improve overall and progression-free survival, suggesting a growing role for targeted biologic therapies in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biologic therapy in esophageal and gastric malignancies: current therapies and future directions. Samson, P., Lockhart, AC.[2020]

In the TALAPRO-1 study involving 97 men with metastatic castration-resistant prostate cancer (mCRPC), talazoparib significantly improved health-related quality of life (HRQoL) and reduced pain levels, particularly in patients with BRCA1/2 mutations.

The study found that 84% of all patients and 83% of those with BRCA1/2 mutations did not experience a deterioration in worst pain after 12 months of treatment, indicating a high probability of maintaining pain relief while receiving talazoparib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Harboring DNA Damage Response Alterations Treated with Talazoparib: Results from TALAPRO-1. Saad, F., de Bono, J., Barthélémy, P., et al.[2023]

The TRiflUridine/tipiracil in Second-line sTudY (JapicCTI-173618) is a phase II/III clinical trial involving 524 patients with metastatic colorectal cancer, designed to compare the efficacy and safety of trifluridine/tipiracil plus bevacizumab against standard irinotecan, fluoropyrimidine, and bevacizumab regimens.

The primary goal of the study is to demonstrate that trifluridine/tipiracil plus bevacizumab is non-inferior in overall survival compared to standard treatments, while also focusing on maintaining quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and design of the TRUSTY study: a randomised, multicentre, open-label phase II/III study of trifluridine/tipiracil plus bevacizumab versus irinotecan, fluoropyrimidine plus bevacizumab as second-line treatment in patients with metastatic colorectal cancer progressive during or following first-line oxaliplatin-based chemotherapy. Yoshino, T., Oki, E., Nozawa, H., et al.[2022]

The TAGS trial demonstrated that trifluridine/tipiracil (Lonsurf®) is both effective and safe for treating patients with metastatic gastric cancer after gastrectomy, highlighting its potential in late-line chemotherapy.

In a specific case, a patient achieved a remarkable 38 months of survival after using trifluridine/tipiracil as a fifth-line treatment following recurrence, showcasing its efficacy even in advanced stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Long-Term Survivor with Recurrent Gastric Cancer Using Trifluridine/Tipiracil as a Late-Line Chemotherapy]. Hamada, S., Komatsu, S., Shibata, R., et al.[2021]

References

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

Trifluridine/Tipiracil: A Review in Metastatic Gastric Cancer. [2020]

2. Germany pubmed.ncbi.nlm.nih.gov

Effects of prior therapies on outcomes with trifluridine/tipiracil in patients with metastatic gastric/gastroesophageal junction cancer in a randomized phase III trial (TAGS). [2023]

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

Clinical Evaluation of the Safety and Efficacy of Trifluridine/Tipiracil in the Treatment of Advanced Gastric/Gastroesophageal Junction Adenocarcinoma: Evidence to Date. [2020]

4. Japan pubmed.ncbi.nlm.nih.gov

Multicenter phase II study of trifluridine/tipiracil for esophageal squamous carcinoma refractory/intolerant to 5-fluorouracil, platinum compounds, and taxanes: the ECTAS study. [2022]

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

Trifluridine/tipiracil versus placebo for third or later lines of treatment in metastatic gastric cancer: an exploratory subgroup analysis from the TAGS study. [2022]

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

Talazoparib: First Global Approval. [2020]

7. Spain pubmed.ncbi.nlm.nih.gov

Talazoparib to treat BRCA-positive breast cancer. [2019]

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

Evidence to date: talazoparib in the treatment of breast cancer. [2020]

9. China pubmed.ncbi.nlm.nih.gov

Biologic therapy in esophageal and gastric malignancies: current therapies and future directions. [2020]

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

Patient-reported Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Harboring DNA Damage Response Alterations Treated with Talazoparib: Results from TALAPRO-1. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Rationale and design of the TRUSTY study: a randomised, multicentre, open-label phase II/III study of trifluridine/tipiracil plus bevacizumab versus irinotecan, fluoropyrimidine plus bevacizumab as second-line treatment in patients with metastatic colorectal cancer progressive during or following first-line oxaliplatin-based chemotherapy. [2022]

12. Japan pubmed.ncbi.nlm.nih.gov

[Long-Term Survivor with Recurrent Gastric Cancer Using Trifluridine/Tipiracil as a Late-Line Chemotherapy]. [2021]