In a 3 + 3 cohort design, three patients are initially enrolled into a given dose cohort. If there is no DLT observed in any of the first three subjects, the trial proceeds with enrolling additional subjects into the next higher dose cohort. If one subject develops a DLT at a specific dose, an additional three subjects are enrolled into that same dose cohort. Development of DLTs in >1 of 6 subjects in a specific dose cohort will determine the MTD and no further dose escalation is done.
Dose Level/TTI-101 (mg/kg/day) administered in divided doses every 12 hours 1/3.2 2/6.4 3/12.8 4/25.6 5/To be determined and approved through the amended protocol
At the end of the dose escalation phase of the study, the investigators will determine the characteristics of the patients who will be enrolled at the expansion phase of the study.

Breast Cancer

Head and Neck Squamous Cell Carcinoma

Non Small Cell Lung Cancer

Hepatocellular Cancer

Colorectal Cancer

Gastric Adenocarcinoma

Melanoma

Advanced Cancer

Patients in the first cohort are treated at dose level 1. Each cohort of a dose level will include at least 3 patients, who will be evaluated for at least one cycle (28-days). The next dose level will be determined after careful review of the tolerability and pharmacokinetics of the previous cohort. If the current dose is the lowest dose and the rule indicates dose de-escalation, we will treat the new patients at the lowest dose unless the number of DLTs reaches the elimination boundary, at which point we will terminate the trial for safety. If the current dose is the highest dose and the rule indicates dose escalation, we will treat the new patients at the highest dose.

TTI-101

The University of Texas MD Anderson Cancer Center

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

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 using Luminex bead-based assays, without and with cytokine stimulation both before and after receiving TTI-101 will be measured. Changes in pY-STAT1 and pY-STAT3 over time will be assessed.

Levels of pY-STAT3 will be scored by percentage of positive cells and intensity of staining. Analyses will be at only two time points: before and after 28-day cycle.

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.

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.

Tvardi Therapeutics, Incorporated

M.D. Anderson Cancer Center

This is an observational study, there is no intervention.

NSCLC Non Small Cells Lung Cancer

Centre Hospitalier D Argenteuil

Site 12

Centre Hospitalier Universitaire

Centre Hospitalier du Morvan

Centre François Baclesse

Centre Hospitalier René Dubos

Site 33

Site 07

Site 32

Site 04

Centre Hospitalier Les Oudairies

Hospital du Cluzeau

Site 00

Centre Hospitalier Régional

Site 25

Site 06

Site 01

Site 19

Site 20

Site 18

Site 17

Hôpital Yves Le Foll

Site 14

Site 11

Retrospective Study in Non Small Cell Lung Cancer (NSCLC) With Epidermal Growth Factor Receptor (EGFR)

Retrospective Multicenter Observational Study in NSCLC Patients With Epidermal Growth Factor Receptor (EGFR) Activating Mutation Treated First Line by Tyrosine Kinase Inhibitor (TKI)

• Primary outcome: the therapeutic management of secondary resistance to EGFR TKI (erlotinib or gefitinib) in patients with advanced NSCLC with EGFR activating mutation. Comparison of demographic, clinical, biological features and outcome of patients continuing EGFR TKI at progression versus interrupting TKI at progression. Composite measures will be performed : demographic and clinical data, Progression Free Survival (PFS), Overall Survival (OS), mutational status, mode of progression, therapeutic approach at progressive disease in patients with EGFR mutation treated in first line by EGFR TKI (all population and subgroups : patients receiving EGFR-TKI at progressive disease - Group 1 -, patients discontinuing EGFR TKI at progressive disease - Group 2- ).

A comparison of clinical data and outcome of patients receiving EGFR-TKI beyond progressive disease (group 1) versus discontinuing EGFR-TKI at progressive disease (group 2) will be made.

• Median Progression Free Survival (PFS) (months) in group 1 and 2 - from start of EGFR TKI to first progression : PFS 1- and - from first progression to second progression : PFS2 -.

• Univariate an multivariate analysis of OS between the 2 groups will be adjusted using the Cox model. Variables as : age, gender, PS, histology, brain metastasis, EGFR mutations (deletions in exon 19, L858R mutations), TKI continued or TKI stopped at progression, metastasis number and site, will be considered for adjustment.

• Univariate and multivariate analysis of OS between the 2 groups will be adjusted using the Cox model. Following variables will be considered for adjustment: age, gender, PS, histology, brain metastases, EGFR mutations (deletions in exon 19, L858R mutations), TKI continued to progression or TKI stopped at progression, metastasis number and site

oncogene addiction/tyrosine

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

Retrospective Study in Non Small Cell Lung Cancer (NSCLC) With Epidermal Growth Factor Receptor (EGFR)

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