Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Digestive System Diseases

Carcinoma

Breast Neoplasms

Adenocarcinoma

Melanoma

Carcinoma, Non-Small-Cell Lung

Carcinoma, Squamous Cell

Lung Neoplasms

Carcinoma, Hepatocellular

Liver Neoplasms

Squamous Cell Carcinoma of Head and Neck

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Head and Neck Neoplasms

Liver Diseases

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

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

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

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

TTI-101

Apostolia Tsimberidou, MD, PhD

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.

Signal transducer and activator of transcription 3 (STAT3) is a member of a family of seven closely related proteins responsible for transmission of peptide hormone signals from the extracellular surface of cells to the nucleus. STAT3 is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation, resistance to apoptosis, metastasis, immune evasion, tumor angiogenesis, epithelial mesenchymal transition (EMT), response to DNA damage, and the Warburg effect. STAT3 also is a key mediator of oncogene addiction and supports the self-renewal of tumor-initiating cancer stem cells that contribute to cancer initiation, cancer maintenance, and relapse in several types of tumors. STAT3 activity is increased in \~50% of all cancers, due either to naturally occurring STAT3 mutations, as have been demonstrated in human inflammatory hepatocellular adenomas and large granular lymphocytic leukemia, or, more commonly as a result of activation of signaling molecules upstream of STAT3, including receptor tyrosine kinases (RTK; e.g. epidermal growth factor receptor, EGFR), tyrosine kinase-associated receptors (e.g. the family of IL-6 cytokine receptors or G-protein coupled receptors, GPCR), and Src kinases (e.g. Src, Lck, Hck, Lyn, Fyn, or Fgr). Thus, STAT3 is an attractive target for drug development to treat many types of cancer including breast cancer, head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), gastric adenocarcinoma and melanoma.

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

Phase I Study of TTI-101, an Oral Inhibitor of Signal Transducer and Activator of Transcription (STAT) 3, in Patients With Advanced Cancers

Assess the association between STAT3 inhibition, fibrosis (if applicable), antitumor activity and survival outcomes after receiving TTI-101. Tissue and blood immune monitoring will be based on 2 biopsies. Association between biomarkers including pY-STAT3, PD1, and PD-L1 proteins expression by IHC, gene expression profiling, and antitumor efficacy and survival outcome of TTI-101 based on RECIST 1.1.

Assess the effect of food on bioavailability of TTI-101 in the dose expansion phase

Assess the bioavailability between different formulations of TTI-101 in the dose expansion phase

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).

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

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

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.

Levels of pY-STAT3 measured before and before and after receiving TTI-101 will be measured.

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis).

Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.

Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression).

The best overall response is the best response recorded from the start of the study treatment until the end of treatment, taking into account any requirement for confirmation. The patient's best overall response assignment will depend on the findings of both target and non-target disease and will also take into consideration the appearance of new lesions.

Spots Global Cancer Trial Database for stat3, cancer, inhibitor, advanced cancer