Clinical Trials /

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

NCT03195699

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Oral STAT3 Inhibitor, TTI-101, in Patients With Advanced Cancers
  • 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

Clinical Trial IDs

  • ORG STUDY ID: SM_CP2016-0842
  • NCT ID: NCT03195699

Conditions

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

Interventions

DrugSynonymsArms
TTI-101Dose escalation study

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Dose escalation studyExperimentalOral administration of TTI-101 for up to 6 28-day cycles
  • TTI-101

Eligibility Criteria

        Inclusion Criteria

        All of the following inclusion criteria must be fulfilled for eligibility:

          1. Age ≥18 years;

          2. 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;

          3. Eastern Cooperative Oncology Group Performance status 0-1;

          4. Hemoglobin ≥9.0 g/dL, neutrophil count ≥1.0 x 109/l, platelets ≥100 x 109/L;

          5. Adequate renal function capability, as calculated by creatinine clearance >60 ml/min
             using the Cockroft-Gault formula;

          6. 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;

          7. Measurable disease using clinically appropriate criteria for the type of malignancy,
             RECIST v 1.1 for solid tumors;

          8. Negative blood 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;

          9. 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

         10. 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.

        Exclusion Criteria

        Subjects are ineligible to enroll in this trial if they fulfill any of the following
        exclusion criteria:

          1. Previous therapy with:

               1. Standard therapy including chemotherapy, immunotherapy, biologic therapy, or any
                  other anticancer therapy within 28 days (or five elimination half-lives for
                  non-cytotoxics, whichever is shorter) of Day 1 of trial drug treatment (6 weeks
                  for nitrosureas or mitomycin);

               2. Any investigational agent within 28 days of Day 1 of trial drug treatment or 5
                  half-lives for a small molecule/targeted therapy;

          2. 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;

          3. Major surgical intervention or participation in a therapeutic clinical trial within 28
             days from Day 1 of the first dose of TTI-101;

          4. 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;

          5. History of cerebral vascular accident or stroke within the previous 2 years;

          6. Uncontrolled hypertension (>160/100mm Hg);

          7. History of Grade 3 or 4 allergic reactions attributed to compounds of similar chemical
             or biologic composition as TTI-101 (hydroxyl-naphthalene sulfonamides);

          8. 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);

          9. History of difficulty swallowing, malabsorption, or other chronic gastrointestinal
             disease or conditions that may hamper compliance and/or absorption of the
             investigational product;

         10. Known human immunodeficiency virus or viral hepatitis;

         11. Legal incapacity or limited legal capacity;

         12. Pregnant or lactating women;

         13. Any other condition, which in the opinion of the investigator, might impair the
             subject's tolerance of trial treatment, the safety of the individual subject, or the
             outcome of the trial;

         14. Previous treatment of the current malignancy with a STAT inhibitor.
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose of TTI-101
Time Frame:6 months
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Pharmacodynamics of TTI-101 in peripheral blood mononuclear cells (PBMC) of patients
Time Frame:6 months
Safety Issue:
Description: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.
Measure:Pharmacodynamics of TTI-101 in tumors of patients
Time Frame:6 months
Safety Issue:
Description: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.
Measure:Complete Response (CR) - Target Lesions
Time Frame:6 months
Safety Issue:
Description: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.
Measure:Partial Response (PR) - Target Lesions
Time Frame:6 months
Safety Issue:
Description:Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Measure:Progressive Disease (PD) - Target Lesions
Time Frame:6 months
Safety Issue:
Description: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).
Measure:Stable Disease (SD) - Target Lesions
Time Frame:6 months
Safety Issue:
Description: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.
Measure:Complete Response (CR) - Non-target Lesions
Time Frame:6 months
Safety Issue:
Description: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).
Measure:Non-CR/Non-PD - Non-target Lesions
Time Frame:6 months
Safety Issue:
Description:Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.
Measure:Progressive Disease (PD) - Non-target Lesions
Time Frame:6 months
Safety Issue:
Description:Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression).
Measure:Best Overall Response
Time Frame:6 months
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Tvardi Therapeutics, Incorporated

Trial Keywords

  • STAT3, cancer, inhibitor, advanced cancer

Last Updated

September 17, 2018