TTI-101 Combination Therapy for Liver Cancer

Recruiting at 20 trial locations

Overseen By Sara Manning

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Tvardi Therapeutics, Incorporated

Must not be taking: Herbal medications, Aspirin, Anticoagulants

Disqualifiers: Pregnancy, Fibrolamellar HCC, HIV, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

178 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called TTI-101 for liver cancer that cannot be surgically removed and has spread locally or to other parts of the body. The trial tests the safety and effectiveness of TTI-101, both alone and in combination with other drugs like pembrolizumab, atezolizumab, and bevacizumab. Individuals with liver cancer that has progressed after certain treatments or who are new to specific therapies may be eligible. The trial examines how well these treatments work together and their effects on cancer progression and survival rates. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in liver cancer treatment.

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.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications, but you must stop using herbal medications 7 days before starting the study treatment. Also, you cannot have had certain cancer treatments or investigational agents within 28 days before the trial.

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

Research shows that TTI-101, when used alone, has been well-tolerated by patients with advanced solid tumors, including liver cancer. A previous study reported no severe side effects related to the treatment and observed no dose-limiting toxicities, suggesting the treatment is relatively safe for humans.

Early data indicate that TTI-101 combined with pembrolizumab is also well-tolerated. However, the combination with atezolizumab and bevacizumab remains under study. Both pembrolizumab and the atezolizumab-bevacizumab combination already treat various cancers, establishing their safety records.

As this trial is in its early stages, more data will confirm the safety of these combinations. Participants can consider this information when deciding whether to join the study. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about TTI-101 for liver cancer because it offers a fresh approach to treatment by targeting the STAT3 protein, which plays a key role in cancer cell growth and survival. Unlike traditional liver cancer treatments, which often include targeted therapies like sorafenib or immunotherapies like nivolumab, TTI-101 uniquely blocks the STAT3 signaling pathway, potentially curbing cancer progression more effectively. Additionally, when TTI-101 is combined with pembrolizumab, atezolizumab, or bevacizumab, it might enhance these drugs' effectiveness, offering new hope for patients with advanced liver cancer. This innovative mechanism could lead to more personalized and effective treatment options, addressing a critical need in liver cancer care.

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

Research shows that TTI-101 may help treat liver cancer. In studies with mice, it stopped tumors from growing and even helped heal liver damage. In humans, TTI-101 demonstrated its ability to fight tumors, benefiting 54% of people with advanced liver cancer and other solid tumors. In this trial, participants in Cohort A will receive TTI-101 as a single agent. Cohort B participants will receive TTI-101 with pembrolizumab, where some liver cancer patients have experienced partial tumor shrinkage. Cohort C participants will receive TTI-101 with atezolizumab and bevacizumab, which has also led to partial tumor shrinkage in similar patients. Overall, these findings suggest that TTI-101, whether used alone or with other drugs, could effectively treat advanced liver cancer. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1b Treatment

Participants receive TTI-101 as a single agent or in combination with pembrolizumab, atezolizumab, and bevacizumab to determine the maximum tolerated dose and recommended Phase 2 dose

Up to 20 months

Phase 2 Treatment

Participants receive TTI-101 at the recommended Phase 2 dose as a single agent or in combination with pembrolizumab, atezolizumab, and bevacizumab to evaluate safety, tolerability, and preliminary efficacy

Up to 18 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab, Bevacizumab
• Pembrolizumab
• TTI-101

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.

How Is the Trial Designed?

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.

TTI-101 is already approved in United States for the following indications:

Approved in United States as TTI-101 for:

• Orphan Drug designation for Idiopathic Pulmonary Fibrosis and Hepatocellular Carcinoma

Who Is Running the Clinical Trial?

Tvardi Therapeutics, Incorporated

Lead Sponsor

Trials

5

Recruited

360+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05440708

NCT05440708 | A Study of TTI-101 as Monotherapy and in ... 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11911802/

Phase I Trial of TTI-101, a First-in-Class Oral Inhibitor of ... Confirmed partial responses were noted in patients with hepatocellular carcinoma (HCC) and other solid tumors that had relapsed or were refractory to standard ...

3. targetedonc.com targetedonc.com/view/treatment-with-tti-101-alone-or-with-standard-targeted-therapy-in-advanced-hcc-commences

Treatment With TTI-101 Alone or With Standard ... Further, phase 1 data from the REVERT-Liver Cancer study showed that TTI-101 monotherapy was tolerable for patients with advanced solid ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.TPS3158

First-in-man phase I clinical trial evaluating TTI-101, an ... This single-site Phase I trial (NCT03195699) is evaluating TTI-101 as monotherapy in patients with advanced solid tumors who are refractory to prior therapies.

5. tvarditherapeutics.com tvarditherapeutics.com/liver-cancer-clinical-trial/

REVERT Liver Cancer Clinical Trial The REVERT LIVER CANCER clinical trial is evaluating the safety and effectiveness of TTI-101 orally administered in adults with hepatocellular carcinoma (HCC)

6. onclive.com onclive.com/view/novel-stat3-inhibitor-tt1-101-is-safe-and-shows-antitumor-activity-in-r-r-hcc-and-other-solid-tumors

Novel STAT3 Inhibitor TT1-101 Is Safe and Shows ... Treatment with TT1-101, was well tolerated and showed clinically meaningful antitumor activity, including confirmed partial responses (cPRs) ...