Oral STAT3 Inhibitor, TTI-101, in Patients with Advanced Cancers

NCT03195699 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: SM_CP2016-0842
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 2

Brief Summary

Many patients have cancers that have increased activity of a protein called STAT3 that contributes critically to the development and growth of their cancer. Despite our knowledge of STAT3's importance to cancer, scientists and doctors have not developed a drug that targets it and that patients can take to treat their cancer more effectively than treatments that are now available. Tvardi Therapeutics, Incorporated has developed a compound, TTI-101, which can be given by mouth and acts as a direct inhibitor of STAT3. Administration of TTI-101 to mice demonstrated that it blocked growth of cancers of the breast, head and neck, lung, and liver and it was safe when administered at high doses to mice, rats, and dogs. In this application, Tvardi is proposing to further develop TTI-101 for treatment of solid tumors for which the prognosis is dismal. The investigators will determine how safe it is when administered to patients with cancer, determine whether an adequate dose can be administered to patients with cancer that will block STAT3 in their cancer, and determine whether treatment with TTI-101 leads to reduced growth of their cancer.

Conditions

Breast Cancer; Head and Neck Squamous Cell Carcinoma; Non Small Cell Lung Cancer; Hepatocellular Cancer; Colorectal Cancer; Gastric Adenocarcinoma; Melanoma; Advanced Cancer

Keywords

STAT3, cancer, inhibitor, advanced cancer

Outcome Measures

Primary Outcomes (4)

• Maximum Tolerated Dose of TTI-101

  To determine the maximum tolerated dose (MTD), dose-limiting toxicities, and tolerability of TTI-101 administered orally to patients with advanced breast cancer and other solid tumors. Dose-limiting toxicity is defined as a Grade 3 or above adverse event (using CTCAE v5.0) within the first treatment cycle (28-days).

  28 days

• Pharmacokinetics - Cmax

  Cmax(obs) will be determined by direct inspection of the plasma drug concentration versus time data point values.

  18 months

• Pharmacokinetics - Tmax

  Tmax(obs) will also be determined by direct inspection of the plasma drug concentration versus time data point values.

  18 months

• Pharmacokinetics - AUC(0-t)

  AUC(0-t) (where t = the time point for the last sample on the pharmacokinetic profile in which quantifiable drug was detected) will be estimated using linear or linear/log trapezoidal calculation.

  18 months

Secondary Outcomes (9)

• Pharmacodynamics of TTI-101 in patients

  18 months

• Complete Response (CR) - Target Lesions

  18 months

• Partial Response (PR) - Target Lesions

  18 months

• Progressive Disease (PD) - Target Lesions

  18 months

• Stable Disease (SD) - Target Lesions

  18 months

Other Outcomes (3)

• Explore association between biomarkers and antitumor efficacy and survival outcome based on RECIST 1.1 for uHCC patients.

  18 months

• Assess the effect of food on bioavailability

  18 months

• Assess the bioavailability between different formulations of TTI-101

  18 months

Study Arms (4)

Dose escalation study

EXPERIMENTAL

Participants will receive up to 4 dose levels of TTI-101 to determine RP2D

Drug: TTI-101

Dose expansion study

EXPERIMENTAL

Enrollment in the dose expansion may commence with approval from the safety review committee. Participants will be enrolled and treated at the RP2D of TTI-101

Drug: TTI-101

Food effect study

EXPERIMENTAL

Participants will be treated with TTI-101 at the RP2D under fed and fasted conditions to assess the bioavailability of TTI-101 and to determine the best conditions for taking the study drug

Drug: TTI-101

Dose expansion, cross-over study

EXPERIMENTAL

Participants will be administered different formulations of TTI-101 to compare bioavailability.

Drug: TTI-101

Interventions

TTI-101 DRUG

Oral capsule

Dose escalation study; Dose expansion study; Dose expansion, cross-over study; Food effect study

Eligibility Criteria

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

You may qualify if:

• Age ≥18 years;
• For patients with solid tumors (not unresectable HCC): Patients with histologically confirmed diagnosis of locally-advanced, inoperable, metastatic and/or treatment refractory solid tumors for whom there are no available therapies that will confer clinical benefit;
• For patients with unresectable HCC: Patients with histologically confirmed diagnosis of locally advanced, inoperable, unresectable HCC who have failed first and second lines of therapy and Child-Pugh is A or beyond second line if the performance status is preserved and Child-Pugh is A.
• Eastern Cooperative Oncology Group Performance status 0-1;
• Hemoglobin ≥9.0 g/dL, neutrophil count ≥1.0 x 109/l, platelets ≥75 x 109/L;
• Adequate renal function capability, as calculated by creatinine clearance \>40 ml/min using the Cockroft-Gault formula;
• Adequate liver function defined as total bilirubin \<1.5 x ULN, and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \<3 x ULN. For subjects with liver involvement, AST/ALT \<5 x ULN; For subjects with liver involvement, AST/ALT \<5 x ULN;
• Measurable disease using clinically appropriate criteria for the type of malignancy, RECIST v 1.1 for solid tumors;
• Negative pregnancy test at the screening visit for women of childbearing potential, defined as: female subjects after puberty unless they have been postmenopausal for at least two years, are surgically sterile, or are sexually inactive and will remain so for the course of the trial;
• Willingness to avoid pregnancy and breast feeding beginning two weeks before the first TTI-101 dose and ending three months after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must use adequate contraception in the judgment of the Investigator, such as a two-barrier method or a one-barrier method with spermicide or intrauterine device during trial treatment dosing and for 3 months after the last dose of the study; and
• Ability to read and understand the informed consent form and willingness and ability to give informed consent and demonstrate comprehension of the trial before undergoing any trial activities.

You may not qualify if:

• Previous therapy with:
• Standard therapy including chemotherapy, immunotherapy, biologic therapy, or any other anticancer therapy within 28 days (or five elimination half-lives for non-cytotoxic drugs, whichever is shorter) of Day 1 of trial drug treatment (6 weeks for nitrosureas or mitomycin);
• Any investigational agent within 28 days of Day 1 of trial drug treatment or 5 half-lives for a small molecule/targeted therapy;
• Extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years from enrollment; Ongoing toxicity (except alopecia) due to a prior therapy, unless returned to baseline or Grade 1 or less;
• Major surgical intervention or participation in a therapeutic clinical trial within 28 days from Day 1 of the first dose of TTI-101;
• Significantly impaired cardiac function such as unstable angina pectoris, congestive heart failure with New York Heart Association (NYHA) class III or IV, myocardial infarction within the last 12 months prior to trial entry; signs of pericardial effusion, 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;
• History of cerebral vascular accident or stroke within the previous 2 years;
• Uncontrolled hypertension (\>160/100mm Hg);
• History of Grade 3 or 4 allergic reactions attributed to compounds of similar chemical or biologic composition as TTI-101 (hydroxyl-naphthalene sulfonamides);
• 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);
• History of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the investigational product;
• Known human immunodeficiency virus (HIV);
• Subjects with chronic hepatitis B virus (HBV) infection, unless screening viral load \<100 IU/mL on stable doses of antiviral therapy. Note: Subjects with chronic HCV infection are allowed to enroll in the study but do not have a defined maximum viral load requirement for study entry;
• Legal incapacity or limited legal capacity;
• Pregnant or lactating women;

Sponsors & Collaborators

• Tvardi Therapeutics, Incorporated: lead
• M.D. Anderson Cancer Center: collaborator

Study Sites (2)

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Mays Cancer Center at University of Texas Health Science Center SA

San Antonio, Texas, 78229, United States

Location

Related Publications (1)

• Tsimberidou AM, Vining DJ, Arora SP, de Achaval S, Larson J, Kauh J, Cartwright C, Avritscher R, Alibhai I, Tweardy DJ, Kaseb AO. Phase I Trial of TTI-101, a First-in-Class Oral Inhibitor of STAT3, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2025 Mar 17;31(6):965-974. doi: 10.1158/1078-0432.CCR-24-2920.

  PMID: 39792482 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Non-Small-Cell Lung; Liver Neoplasms; Colorectal Neoplasms; Melanoma; Neoplasms

Interventions

C188-9 compound

Condition Hierarchy (Ancestors)

Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Head and Neck Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms

Study Officials

• Apostolia Tsimberidou, MD, PhD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: June 9, 2017
• First Posted: June 22, 2017
• Study Start: November 15, 2017
• Primary Completion: June 24, 2024
• Study Completion: June 24, 2024
• Last Updated: March 21, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)