A Study of TTI-101 as Monotherapy and in Combination in Participants With Locally Advanced or Metastatic, and Unresectable Hepatocellular Carcinoma

1. Pregnant or breastfeeding.

2. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.

3. History of leptomeningeal disease.

4. Previous treatment of the current malignancy with a signal transducer and activator of transcription (STAT) inhibitor.

5. Previous therapy with:

1. Standard therapy including chemotherapy, immunotherapy, biologic therapy, or any other anticancer therapy within 28 days (or 5 elimination half-lives for non-cytotoxics, whichever is shorter) of Cycle 1 Day 1 (6 weeks for nitrosoureas or mitomycin).

2. Any investigational agent within 28 days (or 5 elimination half-lives for a non-cytotoxic investigational therapy, whichever is shorter) of Cycle 1 Day 1 or 5 half-lives for a small molecule/targeted therapy.

6. Extensive prior radiotherapy to more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years from enrollment.

7. Herbal preparations are not allowed throughout the study. These herbal medications include but are not limited to St. John's wort, kava, ephedra (mahung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Participants should stop using herbal medications 7 days prior to the first dose of study treatment.

8. Is not fully recovered from all coronavirus disease 2019 (COVID-19)-related symptoms for 2 weeks prior to Cycle 1 Day 1, if previously tested positive for COVID-19.

9. Ongoing toxicity (except alopecia) due to a prior therapy, unless returned to baseline or Grade 1 or less.

10. Has had major surgery within 3 weeks prior to starting investigational product (IP) or has not recovered from major side effects due to surgery.

11. Significantly impaired cardiac function such as unstable angina pectoris, congestive heart failure with New York Heart Association Class III or IV, myocardial infarction within the last 12 months prior to study entry; serious arrhythmia (including QTc prolongation of \>450 ms for males and \>470 ms for females and/or pacemaker) or prior diagnosis of congenital long QT syndrome or left ventricular ejection fraction \<50% on screening echocardiogram.

12. Pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Participants with indwelling catheters for control of effusions or ascites are allowed.

13. History of cerebrovascular accident or stroke within the previous 2 years.

14. History of hepatic encephalopathy.

15. Uncontrolled or symptomatic hypercalcemia (ionized calcium \>1.5 mmol/L, calcium \>12 mg/dL, or corrected serum calcium \>ULN).

16. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).

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

18. 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).

19. History of difficulty swallowing oral medications, malabsorption, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IP.

20. Has a known history of human immunodeficiency virus (HIV) infection.

21. Participants with chronic hepatitis B virus (HBV) infection, unless screening viral load \<500 IU/mL on stable doses of antiviral therapy. Note: Participants with chronic hepatitis C virus (HCV) infection are allowed to enroll into the study but do not have a defined maximum viral load requirement for study entry. Participants with both HBV and HCV infection are excluded unless they have negative HCV ribonucleic acid (RNA).

22. History of malignancy other than HCC within 3 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (eg, 5-year overall survival \[OS\] rate \>90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.

23. Has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate participation in the clinical study, or compromise compliance with the protocol such as:

* Chronic pancreatitis.

* Active untreated or uncontrolled fungal, bacterial, or viral infections (including COVID-19), sepsis, etc.

* Acute and chronic, active infectious disorders including viral and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy.

24. Is unable to understand and to comply with study instructions and requirements.

Cohort B:

25. Discontinued prior treatment with anti-PD-1 or anti-PD-L1 for any reason other than disease progression.

Cohort C:

26. Inadequately controlled arterial hypertension (defined as systolic blood pressure \[BP\] ≥150 mmHg and/or diastolic BP ≥100 mmHg), based on an average of ≥3 BP readings on ≥2 sessions.

27. Participant has received prior systemic chemotherapy for locally advanced or metastatic and/or unresectable HCC. However, participant may have received either neo-adjuvant or adjuvant chemotherapy as long as it was completed at least 6 months prior to the first dose of study treatment.

28. Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high risk for bleeding and a prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment.

29. Urine dipstick for proteinuria ≥2+ at screening. If a 24-hour urine collection shows \<1 g of protein in 24 hours, the participant is eligible.

30. Current or recent (within 10 days of first dose of study treatment) use of aspirin (\>325 mg/day) or treatment with dipyridamole, ticlopidine, clopidogrel, and cilostazol.

31. Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants. Prophylactic anticoagulants (eg, low-dose warfarin with target INR \<1.5 × ULN or low-dose low molecular weight heparin) are allowed.

32. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to the first dose of bevacizumab.

33. History of gastrointestinal perforation or evidence of abdominal free air not explained by paracentesis or recent surgical procedure.

34. Metastatic disease that involves major airways or blood vessels. Participants with portal or hepatic vein involvement are not excluded.

35. Participant has experienced any of the following within 6 months prior to enrollment: arterial thromboembolic event (including myocardial infarction, coronary arterial disease, transient ischemic attack, stroke, etc), congestive heart failure, hemoptysis, or pulmonary embolism.

36. Participant has experienced a fistula.

Cohorts B and C:

37. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during pembrolizumab treatment or within 5 months after the last dose of pembrolizumab treatment.

38. Active or history of immune-mediated disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:

* Participants with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.

* Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.

* Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (eg, participants with psoriatic arthritis are excluded) are eligible for the study provided all of the following conditions are met:

* Rash must cover \<10% of body surface area.

* Disease is well controlled at baseline and requires only low-potency topical corticosteroids.

* No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.

39. History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

40. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor α \[TNF-α\] agents) within 2 weeks prior to initiation of study treatment. Participants receiving low-dose corticosteroids (equivalent of prednisone 10 mg/day or lower) or who receive pulse corticosteroids due to intravenous (IV) contrast allergy are not excluded.

41. Active tuberculosis.

42. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.

43. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Participants receiving prophylactic antibiotics (eg, to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.

44. Prior allogeneic stem cell or solid organ transplantation.

45. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.

What this study is about