RECRUITING

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

Conditions

Hepatocellular Carcinoma TTI-101 Pembrolizumab Atezolizumab Bevacizumab revert

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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.

Official Title

REVERT- Liver Cancer: A Phase 1b/2 Multicenter, Open-label Study to Evaluate the Safety and Efficacy of TTI-101 as Monotherapy and in Combination in Participants With Locally Advanced or Metastatic, and Unresectable Hepatocellular Carcinoma

Quick Facts

Study Start:2023-03-23

Study Completion:2025-03

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT05440708

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
1. Able to understand and willing to provide informed consent and able to comply with the study procedures and restrictions. 2. Age ≥18 years at the time of informed consent. 3. 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. 4. 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. 5. 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. 6. Able to swallow tablets. 7. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 8. 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. * Adequate renal function defined as either: * creatinine clearance ≥40 mL/min calculated using the Cockcroft-Gault formula, or * 24-hour urine collection. 9. Prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT) ≤2 × ULN, except for participants receiving anticoagulation therapy. 10. Child-Pugh class A or B7 within 7 days prior to enrollment. 11. Females of childbearing potential (ie, ovulating, premenopausal, and not surgically sterile) must: * Have a negative serum pregnancy test at screening. * Not be breastfeeding or lactating. * Agree to use a highly effective method of birth control for the duration of the study and for at least 30 days after the last dose in the study. Effective forms of birth control include barrier methods used in conjunction with a spermicidal agent (according to standard local practices), nonhormonal intrauterine devices, or permanent sterilization. 12. Males must: * Agree to use a condom for at least 30 days after the last dose in the study even if vasectomized in order to prevent delivery of the drug via seminal fluid. * Agree to abstain from sperm donation through 30 days after administration of the last dose of the study treatment. * Unless surgically sterile, males with female partners of childbearing potential must agree to use 2 methods of acceptable birth control for at least 30 days after the last dose in the study. Effective forms of birth control include barrier methods used in conjunction with a spermicidal agent (according to standard local practices), nonhormonal intrauterine devices in female partners, or permanent sterilization. 13. In addition to the general inclusion criteria, participants enrolled in Cohort A must have demonstrated objective progression on up to 3 prior lines of systemic antitumor drug therapy. 14. In addition to the general inclusion criteria, participants enrolled in Cohort B must have demonstrated objective progression following at least 2 cycles of first-line anti-PD-1 or anti-PD-L1 monotherapy or combination therapy. Participants may have received no more than one line of prior systemic therapy. 15. Agree to use contraception as specified in the general inclusion criteria for at least 4 months following the last dose of pembrolizumab in accordance with the approved prescribing information. 16. In addition to the general inclusion criteria, participants enrolled in Cohort C must be naïve to systemic treatment for locally advanced or metastatic, and unresectable HCC. 17. Must have had an evaluation (gastroduodenoscopy) for the presence of varices within 6 months prior to initiation of bevacizumab therapy. 18. Agree to use contraception as specified in the general inclusion criteria for at least 5 months after the last dose of atezolizumab and at least 6 months after the last dose of bevacizumab in accordance with the approved prescribing information.	1. Pregnant or breastfeeding. 2. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC. 3. History of leptomeningeal disease. 4. Previous treatment of the current malignancy with a signal transducer and activator of transcription (STAT) inhibitor. 5. Previous therapy with: 1. 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). 2. 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. 6. Extensive prior radiotherapy to more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years from enrollment. 7. 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. 8. 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. 9. Ongoing toxicity (except alopecia) due to a prior therapy, unless returned to baseline or Grade 1 or less. 10. Has had major surgery within 3 weeks prior to starting investigational product (IP) or has not recovered from major side effects due to surgery. 11. 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 \>470 ms and/or pacemaker) or prior diagnosis of congenital long QT syndrome or left ventricular ejection fraction \<50% on screening echocardiogram. 12. 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. 13. History of cerebrovascular accident or stroke within the previous 2 years. 14. History of hepatic encephalopathy. 15. Uncontrolled or symptomatic hypercalcemia (ionized calcium \>1.5 mmol/L, calcium \>12 mg/dL, or corrected serum calcium \>ULN). 16. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation). 17. History of Grade 3 or 4 allergic reactions attributed to compounds of similar chemical or biologic composition as TTI-101 (hydroxyl-naphthalene sulfonamides). 18. Known active metastases in the central nervous system (unless stable by brain imaging studies for at least 1 month without evidence of cerebral edema and no requirements for corticosteroids or anticonvulsants). 19. History of difficulty swallowing oral medications, malabsorption, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IP. 20. Has a known history of human immunodeficiency virus (HIV) infection. 21. Participants with chronic hepatitis B virus (HBV) infection, unless screening viral load \<500 IU/mL on stable doses of antiviral therapy. Note: Participants with chronic hepatitis C virus (HCV) infection are allowed to enroll into the study but do not have a defined maximum viral load requirement for study entry. Participants with both HBV and HCV infection are excluded unless they have negative HCV ribonucleic acid (RNA). 22. History of malignancy other than HCC within 3 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (eg, 5-year overall survival \[OS\] rate \>90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. 23. Has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate participation in the clinical study, or compromise compliance with the protocol such as: * Chronic pancreatitis. * Active untreated or uncontrolled fungal, bacterial, or viral infections (including COVID-19), sepsis, etc. * Acute and chronic, active infectious disorders including viral and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy. 24. Is unable to understand and to comply with study instructions and requirements.

Inclusion Criteria

Exclusion Criteria

1. Able to understand and willing to provide informed consent and able to comply with the study procedures and restrictions.
2. Age ≥18 years at the time of informed consent.
3. 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.
4. 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.
5. 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.
6. Able to swallow tablets.
7. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. 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.
* Adequate renal function defined as either:
* creatinine clearance ≥40 mL/min calculated using the Cockcroft-Gault formula, or
* 24-hour urine collection.
9. Prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT) ≤2 × ULN, except for participants receiving anticoagulation therapy.
10. Child-Pugh class A or B7 within 7 days prior to enrollment.
11. Females of childbearing potential (ie, ovulating, premenopausal, and not surgically sterile) must:
* Have a negative serum pregnancy test at screening.
* Not be breastfeeding or lactating.
* Agree to use a highly effective method of birth control for the duration of the study and for at least 30 days after the last dose in the study. Effective forms of birth control include barrier methods used in conjunction with a spermicidal agent (according to standard local practices), nonhormonal intrauterine devices, or permanent sterilization.
12. Males must:
* Agree to use a condom for at least 30 days after the last dose in the study even if vasectomized in order to prevent delivery of the drug via seminal fluid.
* Agree to abstain from sperm donation through 30 days after administration of the last dose of the study treatment.
* Unless surgically sterile, males with female partners of childbearing potential must agree to use 2 methods of acceptable birth control for at least 30 days after the last dose in the study. Effective forms of birth control include barrier methods used in conjunction with a spermicidal agent (according to standard local practices), nonhormonal intrauterine devices in female partners, or permanent sterilization.
13. In addition to the general inclusion criteria, participants enrolled in Cohort A must have demonstrated objective progression on up to 3 prior lines of systemic antitumor drug therapy.
14. In addition to the general inclusion criteria, participants enrolled in Cohort B must have demonstrated objective progression following at least 2 cycles of first-line anti-PD-1 or anti-PD-L1 monotherapy or combination therapy. Participants may have received no more than one line of prior systemic therapy.
15. Agree to use contraception as specified in the general inclusion criteria for at least 4 months following the last dose of pembrolizumab in accordance with the approved prescribing information.
16. In addition to the general inclusion criteria, participants enrolled in Cohort C must be naïve to systemic treatment for locally advanced or metastatic, and unresectable HCC.
17. Must have had an evaluation (gastroduodenoscopy) for the presence of varices within 6 months prior to initiation of bevacizumab therapy.
18. Agree to use contraception as specified in the general inclusion criteria for at least 5 months after the last dose of atezolizumab and at least 6 months after the last dose of bevacizumab in accordance with the approved prescribing information.

1. Pregnant or breastfeeding.
2. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
3. History of leptomeningeal disease.
4. Previous treatment of the current malignancy with a signal transducer and activator of transcription (STAT) inhibitor.
5. Previous therapy with:
1. 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).
2. 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.
6. Extensive prior radiotherapy to more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years from enrollment.
7. 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.
8. 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.
9. Ongoing toxicity (except alopecia) due to a prior therapy, unless returned to baseline or Grade 1 or less.
10. Has had major surgery within 3 weeks prior to starting investigational product (IP) or has not recovered from major side effects due to surgery.
11. 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 \>470 ms and/or pacemaker) or prior diagnosis of congenital long QT syndrome or left ventricular ejection fraction \<50% on screening echocardiogram.
12. 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.
13. History of cerebrovascular accident or stroke within the previous 2 years.
14. History of hepatic encephalopathy.
15. Uncontrolled or symptomatic hypercalcemia (ionized calcium \>1.5 mmol/L, calcium \>12 mg/dL, or corrected serum calcium \>ULN).
16. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
17. History of Grade 3 or 4 allergic reactions attributed to compounds of similar chemical or biologic composition as TTI-101 (hydroxyl-naphthalene sulfonamides).
18. Known active metastases in the central nervous system (unless stable by brain imaging studies for at least 1 month without evidence of cerebral edema and no requirements for corticosteroids or anticonvulsants).
19. History of difficulty swallowing oral medications, malabsorption, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IP.
20. Has a known history of human immunodeficiency virus (HIV) infection.
21. Participants with chronic hepatitis B virus (HBV) infection, unless screening viral load \<500 IU/mL on stable doses of antiviral therapy. Note: Participants with chronic hepatitis C virus (HCV) infection are allowed to enroll into the study but do not have a defined maximum viral load requirement for study entry. Participants with both HBV and HCV infection are excluded unless they have negative HCV ribonucleic acid (RNA).
22. History of malignancy other than HCC within 3 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (eg, 5-year overall survival \[OS\] rate \>90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
23. Has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate participation in the clinical study, or compromise compliance with the protocol such as:
* Chronic pancreatitis.
* Active untreated or uncontrolled fungal, bacterial, or viral infections (including COVID-19), sepsis, etc.
* Acute and chronic, active infectious disorders including viral and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy.
24. Is unable to understand and to comply with study instructions and requirements.

Contacts and Locations

Study Contact

Nicole Goodwin

CONTACT

Please email

info@tvardi.com

Kari Anne Rowland, MS

CONTACT

Please email

info@tvardi.com

Study Locations (Sites)

The Kirklin Clinic of University of Alabama Birmingham Hospital

Birmingham, Alabama, 35233

United States

University of California San Diego

La Jolla, California, 92093

United States

Norris Comprehensive Cancer Center

Los Angeles, California, 90033

United States

University of California Irvine Medical Center

Orange, California, 92868

United States

University of Colorado Hospital - Anschutz Medical Campus

Aurora, Colorado, 80045

United States

Georgetown Lombardi Comprehensive Cancer Center

Washington, District of Columbia, 20007

United States

Moffitt Cancer Center

Tampa, Florida, 33612

United States

The Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21231

United States

University of Michigan Rogel Cancer Center

Ann Arbor, Michigan, 48109

United States

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, 48201

United States

Washington University in St. Louis

Saint Louis, Missouri, 63129

United States

Memorial Sloan Kettering Cancer Center - New York

New York, New York, 10065

United States

Cleveland Clinic Lerner College of Medicine

Cleveland, Ohio, 44195

United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104

United States

Harold C. Simmons Comprehensive Cancer Center

Dallas, Texas, 75390

United States

DHR Health Institute for Research & Development

Edinburg, Texas, 78539

United States

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030-4000

United States

University of Texas Health Science Center - San Antonio

San Antonio, Texas, 78229

United States

Virginia Mason Medical Center

Seattle, Washington, 98101

United States

Summit Cancer Centers - North Spokane

Spokane, Washington, 99208

United States

Froedtert and Medical College of Wisconsin

Milwaukee, Wisconsin, 53226

United States

Collaborators and Investigators

Sponsor: Tvardi Therapeutics, Incorporated

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2023-03-23

Study Completion Date2025-03

Study Record Updates

Study Start Date2023-03-23

Study Completion Date2025-03

Terms related to this study

Keywords Provided by Researchers

Hepatocellular carcinoma
TTI-101
Pembrolizumab
Atezolizumab
Bevacizumab
revert

Additional Relevant MeSH Terms

Hepatocellular Carcinoma