A Study of TTI-101 as Monotherapy and in Combination in Participants With Locally Advanced or Metastatic, and Unresectable Hepatocellular Carcinoma

NCT05440708 | Recruiting Phase 1 FDA Drug

• 1 other identifier: TVD-101-001H
• Study Type: interventional
• Target: 193
• Locations: 1 country
• Sites: 21

Brief Summary

The primary objectives of Cohort A Phase 1b and exploratory expansion 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.

Conditions

Hepatocellular Carcinoma

Keywords

Hepatocellular carcinoma; TTI-101; Pembrolizumab; Atezolizumab; Bevacizumab; revert

Outcome Measures

Primary Outcomes (3)

• Incidence of Adverse Events (AE)

  An AE is any untoward medical occurrence in a participant or clinical study participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Any clinically significant changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs and physical examinations will be recorded as AEs.

  Up to approximately 20 months

• Incidence of Serious Adverse Events (SAE)

  Up to approximately 18 months

• Phase 2: Overall Response Rate (ORR) to TTI-101

  ORR (calculated as Partial Response \[PR\] + Complete Response \[CR\]) using RECIST Version 1.1.

  Up to approximately 18 months

Secondary Outcomes (17)

• Phase 1b: Overall Response Rate (ORR) to TTI-101

  Up to approximately 18 months

• Duration of Response (DoR) to TTI-101

  Up to approximately 18 months

• Disease Control Rate (DCR) to TTI-101

  Up to approximately 18 months

• Duration of Disease Control (DDC) to TTI-101

  Up to approximately 18 months

• Time to Tumor Progression (TTP) to TTI-101

  Up to approximately 18 months

Study Arms (3)

Cohort A: TTI-101 as a Single Agent

EXPERIMENTAL

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.

Drug: TTI-101

Cohort B: TTI-101 in Combination with Pembrolizumab

EXPERIMENTAL

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.

Drug: TTI-101; Drug: Pembrolizumab

Cohort C: TTI-101 in Combination with Atezolizumab and Bevacizumab

EXPERIMENTAL

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.

Drug: TTI-101; Drug: Atezolizumab; Drug: Bevacizumab

Interventions

Pembrolizumab DRUG

Intravenous (IV) infusion

Also known as: Keytruda®

Cohort B: TTI-101 in Combination with Pembrolizumab

TTI-101 DRUG

Oral tablet

Cohort A: TTI-101 as a Single Agent; Cohort B: TTI-101 in Combination with Pembrolizumab; Cohort C: TTI-101 in Combination with Atezolizumab and Bevacizumab

Atezolizumab DRUG

Intravenous (IV) infusion

Also known as: Tecentriq®

Cohort C: TTI-101 in Combination with Atezolizumab and Bevacizumab

Bevacizumab DRUG

Intravenous (IV) infusion

Also known as: Avastin®

Cohort C: TTI-101 in Combination with Atezolizumab and Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able to understand and willing to provide informed consent and able to comply with the study procedures and restrictions.
• Age ≥18 years at the time of informed consent.
• Have histologically or radiographically (Liver Imaging Reporting and Data Systems category 5) confirmed diagnosis of locally advanced or metastatic, and unresectable HCC. Participants without cirrhosis require histological confirmation.
• Cohorts A and B only: Willing to provide a representative fresh tumor tissue specimen prior to enrollment. The fresh tumor specimen must be obtained after progression on the prior therapy. No biopsy is required for participants in Cohort C.
• Measurable disease as per RECIST Version 1.1. Participants who received prior local therapy are eligible provided the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST Version 1.1.
• Able to swallow tablets.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Has adequate hematologic and organ function as defined by the following local laboratory values at screening:
• Absolute neutrophil count (ANC) ≥1.5 × 10\^9/L (1500/μL) without granulocyte colony-stimulating factor support.
• Lymphocyte count ≥0.5 × 10\^9/L (500/μL).
• Platelet count ≥75 × 10\^9/L (75,000/μL) without transfusion.
• Hemoglobin ≥90 g/L (9 g/dL). Participants may be transfused to meet this criterion.
• Serum albumin ≥28 g/L (2.8 g/dL).
• AST, ALT, and alkaline phosphatase (ALP) ≤5 × upper limit of normal (ULN).
• Serum bilirubin ≤2 mg/dL.

You may not qualify if:

• Pregnant or breastfeeding.
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• History of leptomeningeal disease.
• Previous treatment of the current malignancy with a signal transducer and activator of transcription (STAT) inhibitor.
• Previous therapy with:
• Standard therapy including chemotherapy, immunotherapy, biologic therapy, or any other anticancer therapy within 28 days (or 5 elimination half-lives for non-cytotoxics, whichever is shorter) of Cycle 1 Day 1 (6 weeks for nitrosoureas or mitomycin).
• Any investigational agent within 28 days (or 5 elimination half-lives for a non-cytotoxic investigational therapy, whichever is shorter) of Cycle 1 Day 1 or 5 half-lives for a small molecule/targeted therapy.
• Extensive prior radiotherapy to more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years from enrollment.
• Herbal preparations are not allowed throughout the study. These herbal medications include but are not limited to St. John's wort, kava, ephedra (mahung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Participants should stop using herbal medications 7 days prior to the first dose of study treatment.
• Is not fully recovered from all coronavirus disease 2019 (COVID-19)-related symptoms for 2 weeks prior to Cycle 1 Day 1, if previously tested positive for COVID-19.
• Ongoing toxicity (except alopecia) due to a prior therapy, unless returned to baseline or Grade 1 or less.
• Has had major surgery within 3 weeks prior to starting investigational product (IP) or has not recovered from major side effects due to surgery.
• Significantly impaired cardiac function such as unstable angina pectoris, congestive heart failure with New York Heart Association Class III or IV, myocardial infarction within the last 12 months prior to study entry; serious arrhythmia (including QTc prolongation of \>450 ms for males and \>470 ms for females and/or pacemaker) or prior diagnosis of congenital long QT syndrome or left ventricular ejection fraction \<50% on screening echocardiogram.
• Pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Participants with indwelling catheters for control of effusions or ascites are allowed.
• History of cerebrovascular accident or stroke within the previous 2 years.

Sponsors & Collaborators

• Tvardi Therapeutics, Incorporated: lead

Study Sites (21)

The Kirklin Clinic of University of Alabama Birmingham Hospital

Birmingham, Alabama, 35233, United States

RECRUITING

University of California San Diego

La Jolla, California, 92093, United States

COMPLETED

Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

RECRUITING

University of California Irvine Medical Center

Orange, California, 92868, United States

RECRUITING

University of Colorado Hospital - Anschutz Medical Campus

Aurora, Colorado, 80045, United States

RECRUITING

Georgetown Lombardi Comprehensive Cancer Center

Washington D.C., District of Columbia, 20007, United States

COMPLETED

Moffitt Cancer Center

Tampa, Florida, 33612, United States

RECRUITING

The Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21231, United States

RECRUITING

University of Michigan Rogel Cancer Center

Ann Arbor, Michigan, 48109, United States

RECRUITING

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

RECRUITING

Washington University in St. Louis

St Louis, Missouri, 63129, United States

RECRUITING

Memorial Sloan Kettering Cancer Center - New York

New York, New York, 10065, United States

RECRUITING

Cleveland Clinic Lerner College of Medicine

Cleveland, Ohio, 44195, United States

RECRUITING

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

RECRUITING

Harold C. Simmons Comprehensive Cancer Center

Dallas, Texas, 75390, United States

RECRUITING

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030-4000, United States

RECRUITING

DHR Health Institute for Research and Development

McAllen, Texas, 78504, United States

RECRUITING

University of Texas Health Science Center - San Antonio

San Antonio, Texas, 78229, United States

RECRUITING

Virginia Mason Medical Center

Seattle, Washington, 98101, United States

RECRUITING

Summit Cancer Centers - North Spokane

Spokane, Washington, 99208, United States

RECRUITING

Froedtert and Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

COMPLETED

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

C188-9 compound; pembrolizumab; atezolizumab; Bevacizumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Central Study Contacts

Kari Anne Rowland, MS

CONTACT

Please email; clinicaltrials@tvardi.com

Sara Manning

CONTACT

Please email; clinicaltrials@tvardi.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 27, 2022
• First Posted: July 1, 2022
• Study Start: March 23, 2023
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): March 10, 2027
• Last Updated: April 27, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (21)