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

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.

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.