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

Prior treatment

• 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;
• History of cerebral vascular accident or stroke within the previous 2 years;
• 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;
• Previous treatment of the current malignancy with a STAT inhibitor.

Other illness

• 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 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;
• 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;

Lab values

• 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;

Other

• Subjects are ineligible to enroll in this trial if they fulfill any of the following exclusion criteria:
• Legal incapacity or limited legal capacity;
• Pregnant or lactating women;

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