TTI-101 Combination Therapy for Liver Cancer

Recruiting in Palo Alto (17 mi)

+20 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Tvardi Therapeutics, Incorporated

No Placebo Group

Breakthrough Therapy

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

The primary objectives of Cohort A Phase 1b are to evaluate the safety and tolerability of TTI-101 orally administered as a single agent to participants with locally advanced or metastatic, and unresectable Hepatocellular Carcinoma (HCC) and to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of TTI-101 as a single agent. The primary objectives of Cohort A Phase 2 are to evaluate the safety and tolerability of TTI-101 orally administered as a single agent at the RP2D to participants with locally advanced or metastatic, and unresectable HCC and to assess the preliminary efficacy of TTI-101 as a single agent in participants with locally advanced or metastatic, and unresectable HCC. The secondary objectives of Cohort A Phase 2 are to assess response, progression, survival, and pharmacokinetics. The primary objectives of Cohorts B and C Phase 1b are to evaluate the safety and tolerability of TTI-101 orally administered in combination with pembrolizumab therapy (Cohort B) and in combination with atezolizumab and bevacizumab therapy (Cohort C) to participants with locally advanced or metastatic, or unresectable HCC and to determine the MTD and/or RP2D of TTI-101 when used in combination with pembrolizumab therapy (Cohort B) and in combination with atezolizumab and bevacizumab therapy (Cohort C). The primary objectives of Cohorts B and C Phase 2 are to evaluate the safety and tolerability of TTI-101 orally administered in combination with pembrolizumab therapy (Cohort B) and in combination with atezolizumab and bevacizumab therapy (Cohort C) at the RP2D to participants with locally advanced or metastatic, and unresectable HCC and to assess the preliminary efficacy of TTI-101 in combination with pembrolizumab therapy (Cohort B) and in combination with atezolizumab and bevacizumab therapy (Cohort C) to participants with locally advanced or metastatic, and unresectable HCC. The secondary objectives of Cohorts B and C Phase 2 are to assess response, progression, survival, and pharmacokinetics.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you must stop using herbal medications 7 days before the first dose of the study treatment. Also, you cannot have had standard therapy, investigational agents, or certain other treatments within specific time frames before starting the trial. Please consult with the trial team for guidance on your specific medications.

What data supports the idea that TTI-101 Combination Therapy for Liver Cancer is an effective treatment?

The available research shows that immune checkpoint inhibitors (ICIs), which are part of the TTI-101 Combination Therapy, can improve survival rates for patients with advanced liver cancer. These drugs help the immune system fight cancer more effectively. The research suggests that combining ICIs with other therapies could lead to better and longer-lasting results. Additionally, newer drug combinations, like those including TTI-101, have been shown to maintain patients' quality of life longer than current standard treatments. This indicates that TTI-101 Combination Therapy could be a promising option for treating liver cancer. ^{1 2 3 4 5}

What safety data is available for TTI-101 combination therapy in liver cancer?

The safety data for TTI-101 combination therapy, which may include drugs like Atezolizumab, Bevacizumab, Pembrolizumab, and others, primarily involves immune checkpoint inhibitors (ICIs). These treatments are associated with immune-related adverse events (irAEs), including hepatotoxicity, which can vary in severity. Hepatotoxicity is less common but can require discontinuation of therapy and treatment with immunosuppressive agents. Older patients (≥65 years) may experience more frequent hepatic adverse events. The safety of ICIs in liver transplant recipients is still under investigation, with limited evidence available. ^{6 7 8 9 10}

Is the drug TTI-101 a promising treatment for liver cancer?

The information provided does not directly address TTI-101 or its effectiveness for liver cancer. The articles focus on other drugs and treatments for different types of cancer. ^{2 11 12 13 14}

Research Team

Eligibility Criteria

This trial is for adults with advanced, inoperable liver cancer who can swallow pills and provide informed consent. Participants must have measurable disease, good performance status, and adequate organ function. Cohort C requires no prior systemic treatment for liver cancer and agreement to use contraception. Exclusions include pregnancy, breastfeeding, recent COVID-19 recovery issues, uncontrolled medical conditions, certain past treatments including STAT inhibitors or immunotherapies (unless due to disease progression), and specific health histories.

Inclusion Criteria

I agree to use birth control.

I am fully active or restricted in physically strenuous activity but can do light work.

My cancer progressed after 2 cycles of initial anti-PD-1 or anti-PD-L1 treatment.

Exclusion Criteria

I have a history of certain medical conditions or infections.

I have not had extensive radiotherapy or a bone marrow transplant in the last 5 years.

I have had cancer spread to the lining of my brain and spinal cord.

Treatment Details

Interventions

• Atezolizumab, Bevacizumab (Monoclonal Antibodies)
• Pembrolizumab (Monoclonal Antibodies)
• TTI-101 (Other)

Trial Overview The study tests TTI-101 alone (Cohort A) or combined with pembrolizumab (Cohort B) or atezolizumab plus bevacizumab (Cohort C). It aims to find the safest dose that's also effective against unresectable hepatocellular carcinoma by observing safety/tolerability and preliminary efficacy. The trial will also assess how the body processes these drugs.

Participant Groups

Group I: Cohort C: TTI-101 in Combination with Atezolizumab and Bevacizumab Experimental Treatment 3 Interventions

Cohort C Phase 1b: Participants will receive various dose levels of TTI-101 in combination with atezolizumab and bevacizumab to determine the RP2D. Cohort C Phase 2: Enrollment in Phase 2 may commence with approval from the safety review committee. Participants will be enrolled and treated at the RP2D of TTI-101 in combination with atezolizumab and bevacizumab.

Group II: Cohort B: TTI-101 in Combination with Pembrolizumab Experimental Treatment 2 Interventions

Cohort B Phase 1b: Participants will receive various dose levels of TTI-101 in combination with pembrolizumab to determine the RP2D. Cohort B Phase 2: Enrollment in Phase 2 may commence with approval from the safety review committee. Participants will be enrolled and treated at the RP2D of TTI-101 in combination with pembrolizumab.

Group III: Cohort A: TTI-101 as a Single Agent Experimental Treatment 1 Intervention

Cohort A Phase 1b: Participants will receive various dose levels of TTI-101 as a single agent to determine the RP2D. Cohort A Phase 2: Enrollment in Phase 2 may commence with approval from the safety review committee. Participants will be enrolled and treated at the RP2D of TTI-101 as a single agent.

Who Is Running the Clinical Trial?

Tvardi Therapeutics, Incorporated

Lead Sponsor

Trials

5

Recruited

360+

Findings from Research

Immune checkpoint inhibitors (ICIs) have shown promise in improving progression-free and overall survival in patients with advanced liver cancers, such as hepatocellular carcinoma and intrahepatic cholangiocarcinoma, with an acceptable safety profile based on a review of clinical trials.

Combining ICIs with other therapies may enhance treatment effectiveness, and the development of biomarkers will be crucial for personalizing treatment strategies for patients with primary liver cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential experimental immune checkpoint inhibitors for the treatment of cancer of the liver. Hewitt, DB., Rahnemai-Azar, AA., Pawlik, TM.[2021]

The TRITICC trial is investigating the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in 28 patients with advanced biliary tract cancer who have not responded to first-line gemcitabine-based chemotherapy, aiming to improve progression-free survival.

This study will assess not only the efficacy of the treatment but also its safety and potential predictive markers for response, providing valuable insights into managing this challenging cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study protocol of an open-label, single arm phase II trial investigating the efficacy and safety of Trifluridine/Tipiracil combined with irinotecan as a second line therapy in patients with cholangiocarcinoma (TRITICC). Kehmann, L., Berres, ML., Gonzalez-Carmona, M., et al.[2023]

Recent studies presented at the 2020 Gastrointestinal Cancers Symposium indicate that various treatments have led to improved patient outcomes and enhanced quality of life.

A promising new combination therapy for advanced hepatocellular carcinoma was highlighted, suggesting potential advancements in treatment options for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient Reported Outcomes Show Newer Drug Combinations Maintain Quality of Life Longer Than Current Standard of Care Treatments. Wright, KM.[2021]

In a study of 138 patients with hepatocellular carcinoma and portal vein tumor thrombosis, those who underwent surgical resection followed by postoperative chemotherapy had the longest median survival of 13.4 months, compared to 3.5 months for conservative treatment.

Postoperative chemotherapy was identified as the most significant factor influencing survival outcomes, suggesting that combining surgery with additional chemotherapy can greatly improve prognosis for patients with resectable tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatocellular carcinoma associated with tumor thrombosis in the portal vein: the effects of different treatments. Fan, J., Wu, ZQ., Zhou, J., et al.[2008]

Nivolumab has shown promise in treating hepatocellular carcinoma and has recently received FDA approval, marking a significant advancement in systemic therapy options for this type of cancer.

In intrahepatic cholangiocarcinoma, therapies targeting FGFR2 and IDH1, along with immune checkpoint inhibitors, are leading the way in development, highlighting the potential for new treatments in hepatobiliary cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel targeted therapy strategies for biliary tract cancers and hepatocellular carcinoma. DeLeon, TT., Ahn, DH., Bogenberger, JM., et al.[2022]

In a study of 406 patients with advanced hepatocellular carcinoma (HCC) receiving immune checkpoint inhibitors (ICI), the development of treatment-related adverse events (trAE) graded ≥2 was linked to significantly longer overall survival (16.7 months vs. 11.2 months) and progression-free survival (5.5 months vs. 2.2 months).

This association persisted even after adjusting for various clinical factors, indicating that trAE can serve as an independent predictor of better outcomes in HCC patients undergoing ICI therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: Evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice. Pinato, DJ., Marron, TU., Mishra-Kalyani, PS., et al.[2021]

Immune checkpoint inhibitors targeting CTLA-4 and PD-1 have been shown to significantly improve survival rates in patients with advanced cancer, leading to their FDA approval and expanding indications.

While hepatotoxicity is a less common side effect of these therapies, it can vary in incidence and severity based on treatment type and cancer, and may necessitate stopping therapy and using immunosuppressive treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver Toxicity with Cancer Checkpoint Inhibitor Therapy. Nadeau, BA., Fecher, LA., Owens, SR., et al.[2019]

A study analyzing 9,806 liver adverse events from the FDA Adverse Event Reporting System found a significant association between immune checkpoint inhibitors (ICIs) and hepatotoxicity, particularly in patients aged 65 and older.

Nivolumab was identified as having the highest incidence of liver-related adverse events (36.17%), with conditions like abnormal liver function, hepatitis, and autoimmune hepatitis being the most commonly reported issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatotoxicity in immune checkpoint inhibitors: A pharmacovigilance study from 2014-2021. Xu, Z., Qi, G., Liu, X., et al.[2023]

In a review of 52 liver transplant recipients treated with immune checkpoint inhibitors (ICIs), 28.8% experienced acute graft rejection, which significantly impacted overall survival, with those rejecting grafts living only 3.5 months on average compared to 17.2 months for those without rejection.

The disease control rate for patients receiving ICIs was 44.2%, and those who responded to treatment had a much longer overall survival of 26.4 months, highlighting the potential efficacy of ICIs despite the associated risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitors in malignancies after liver transplantation: A systematic review and pooled analysis. Kayali, S., Pasta, A., Plaz Torres, MC., et al.[2023]

In a study of 1480 cancer patients treated with immune checkpoint inhibitors (ICIs), over 50% experienced hepatic adverse events (AEs), with 14.9% classified as severe (grade 3-4).

The presence of hepatic AEs was linked to poorer overall survival rates, with median survival dropping from 9.0 months for patients without AEs to just 3.3 months for those with severe hepatic AEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pattern and impact of hepatic adverse events encountered during immune checkpoint inhibitors - A territory-wide cohort study. Chan, SL., Yip, TC., Wong, VW., et al.[2021]

TAS-102, an oral nucleoside antitumor agent, shows enhanced therapeutic efficacy when combined with irinotecan hydrochloride (CPT-11) in a preclinical study using colorectal and gastric cancer models, significantly outperforming each drug used alone.

The combination treatment did not result in significant weight loss in the mice, suggesting a favorable safety profile while effectively inhibiting tumor growth in various cancer xenografts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with irinotecan hydrochloride on human colorectal and gastric cancer xenografts. Nukatsuka, M., Nakagawa, F., Saito, H., et al.[2020]

In a study using KRAS mutant murine models of colorectal cancer, the combination of trifluridine/tipiracil (FTD/TPI) and DC101 significantly improved tumor growth inhibition, achieving a 60.3% reduction compared to lower reductions with each treatment alone.

The combination therapy not only enhanced the effectiveness of FTD/TPI by increasing its DNA incorporation but also reduced vascular endothelial cell activity, suggesting a synergistic effect that could be beneficial for treating metastatic colorectal and gastric cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, FTD/TPI, with Ramucirumab Murine Version DC101 in a Mouse Syngeneic Cancer Transplantation Model. Tsunekuni, K., Kawakami, H., Matsuoka, K., et al.[2020]

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 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]

References

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

Potential experimental immune checkpoint inhibitors for the treatment of cancer of the liver. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Study protocol of an open-label, single arm phase II trial investigating the efficacy and safety of Trifluridine/Tipiracil combined with irinotecan as a second line therapy in patients with cholangiocarcinoma (TRITICC). [2023]

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

Patient Reported Outcomes Show Newer Drug Combinations Maintain Quality of Life Longer Than Current Standard of Care Treatments. [2021]

4. Singapore pubmed.ncbi.nlm.nih.gov

Hepatocellular carcinoma associated with tumor thrombosis in the portal vein: the effects of different treatments. [2008]

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

Novel targeted therapy strategies for biliary tract cancers and hepatocellular carcinoma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: Evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice. [2021]

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

Liver Toxicity with Cancer Checkpoint Inhibitor Therapy. [2019]

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

Hepatotoxicity in immune checkpoint inhibitors: A pharmacovigilance study from 2014-2021. [2023]

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

Immune checkpoint inhibitors in malignancies after liver transplantation: A systematic review and pooled analysis. [2023]

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

Pattern and impact of hepatic adverse events encountered during immune checkpoint inhibitors - A territory-wide cohort study. [2021]

11. Greece pubmed.ncbi.nlm.nih.gov

Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with irinotecan hydrochloride on human colorectal and gastric cancer xenografts. [2020]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, FTD/TPI, with Ramucirumab Murine Version DC101 in a Mouse Syngeneic Cancer Transplantation Model. [2020]

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

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

14. 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]