Oral STAT3 Inhibitor, TTI-101, in Patients With Advanced Cancers
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|ClinicalTrials.gov Identifier: NCT03195699|
Recruitment Status : Recruiting
First Posted : June 22, 2017
Last Update Posted : February 24, 2020
|Condition or disease||Intervention/treatment||Phase|
|Breast Cancer Head and Neck Squamous Cell Carcinoma Non Small Cell Lung Cancer Hepatocellular Cancer Colorectal Cancer Gastric Adenocarcinoma Melanoma Advanced Cancer||Drug: TTI-101||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Study of TTI-101, an Oral Inhibitor of Signal Transducer and Activator of Transcription (STAT) 3, in Patients With Advanced Cancers|
|Actual Study Start Date :||November 15, 2017|
|Estimated Primary Completion Date :||July 2020|
|Estimated Study Completion Date :||July 2020|
Experimental: Dose escalation study
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.
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.
- Maximum Tolerated Dose of TTI-101 [ Time Frame: 6 months ]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).
- Pharmacokinetics - Cmax [ Time Frame: 6 months ]Cmax(obs) will be determined by direct inspection of the plasma drug concentration versus time data point values.
- Pharmacokinetics - Tmax [ Time Frame: 6 months ]Tmax(obs) will also be determined by direct inspection of the plasma drug concentration versus time data point values.
- Pharmacokinetics - AUC(0-t) [ Time Frame: 6 months ]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.
- Pharmacodynamics of TTI-101 in peripheral blood mononuclear cells (PBMC) of patients [ Time Frame: 6 months ]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.
- Pharmacodynamics of TTI-101 in tumors of patients [ Time Frame: 6 months ]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) - Target Lesions [ Time Frame: 6 months ]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) - Target Lesions [ Time Frame: 6 months ]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) - Target Lesions [ Time Frame: 6 months ]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) - Target Lesions [ Time Frame: 6 months ]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) - Non-target Lesions [ Time Frame: 6 months ]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 - Non-target Lesions [ Time Frame: 6 months ]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) - Non-target Lesions [ Time Frame: 6 months ]Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression).
- Best Overall Response [ Time Frame: 6 months ]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.
- Explore association between biomarkers and antitumor efficacy and survival outcome based on RECIST 1.1 for uHCC patients. [ Time Frame: 6 months ]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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03195699
|Contact: Sherri Thomas, RN, CCRPfirstname.lastname@example.org|
|Contact: Katie Lyon, MS, CCRPemail@example.com|
|United States, Texas|
|The University of Texas MD Anderson Cancer Center||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Apostolia M. Tsimberidou, MD, PhD 713-792-4259 firstname.lastname@example.org|
|Principal Investigator:||Apostolia Tsimberidou, MD, PhD||The University of Texas MD Anderson Cancer Center|