TT-4 As a Single Agent in Subjects with Advanced Selected Solid Tumors

Phase I/II First-in-Human Study of TT-4 As a Single Agent in Participants with Advanced Selected Solid Tumors

The purpose of this study is to evaluate the safety and tolerability of orally administered TT-4 in subjects with advanced selected solid tumors. The dose escalation portion of the study will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of TT-4.

Multicenter, open-label dose-escalation Phase I/II clinical study, designed to evaluate the safety, tolerability, PK, PD, anti-tumor activity, and efficacy of TT-4 in subjects diagnosed with Colorectal Cancer (CRC), Gastric cancer (GC), Hepatocellular Carcinoma (HCC) and locally advanced, unresectable, or metastatic Pancreatic Cancer (PANC); who have failed or are not eligible for standard of care treatment.

The study will be conducted in two phases. Dose escalation (Phase 1) will be to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), safety and tolerability of TT-4 in subjects with advanced subjects diagnosed with Colorectal Cancer (CRC), Gastric cancer (GC), Hepatocellular Carcinoma (HCC) and locally advanced, unresectable, or metastatic Pancreatic Cancer (PANC); who have failed or are not eligible for standard of care treatment. Dose expansion (Phase 2) will be to further explore the safety and tolerability of the MTD and/or RP2D, PK, PD, antitumor activity, and efficacy of TT-4.

Inclusion Criteria

To eligible for inclusion in the dose escalation cohort or expansion cohort 1 in this study, subjects must meet all of the following criteria:

1. Subjects must be ≥18 years of age.

2. Subjects or their legal representative must be able to provide written informed consent to participate in the trial prior to the performance of any study-specific procedures.

3. Diagnosis of histologically or cytologically confirmed advanced selected solid tumors

   • Cohort A dose escalation: Colorectal Cancer, Gastric cancer, Hepatocellular Carcinoma and locally advanced, unresectable, or metastatic Pancreatic Cancer, who have failed or are not eligible for standard of care treatment.
   • Cohort B: Advanced colorectal cancer (CRC), who have failed or not eligible for standard of care
   • Cohort C: Advanced Gastric cancer (GC), who have failed or not eligible for standard of care
   • Cohort D: Advanced Hepatocellular Carcinoma (HCC), who have failed or not eligible for standard of care
   • Cohort E: Locally advanced, unresectable, or metastatic Pancreatic Cancer (PANC), who have failed or not eligible for standard of care

4. ECOG performance status (PS) score 0-1

5. Have measurable disease per RECIST 1.1 or (for subjects in the expansion cohorts) iRECIST as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

6. Subjects must have locally advanced, recurrent or metastatic neoplastic disease that is not curable by currently available therapies.

7. Failure to respond to standard therapy, or for whom no appropriate therapies are available (based on the judgment of the Investigator)

8. Life expectancy of ≥ 3 months

9. Subjects must have adequate hematologic function based on the following:

   • Absolute neutrophil count ≥ 1.5 x 109/L
   • Platelet count ≥ 100 x 109/L
   • Hemoglobin ≥ 9.0 g/dL

10. Subjects must have adequate hepatic function based on the following:

    • Total bilirubin <1.5 × upper limit of normal (ULN) Patients with a known history of Gilbert's syndrome (≤ 3.0 × ULN) and/or isolated elevations of indirect bilirubin are eligible for study participation
    • Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x ULN (≤5 × ULN for subjects with known hepatic metastases)

11. Subjects must have adequate renal function based on the following:

    - Serum creatinine ≤1.5 × ULN

12. For women of childbearing potential (WCBP): negative serum β human chorionic gonadotropin (βhCG) pregnancy test within 1 week before first treatment (WCBP defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally post-menopausal for at least 12 consecutive months for women > 55 years of age)

13. Human immunodeficiency virus (HIV) infected subjects must be on antiretroviral therapy (ART) and have a well-controlled HIV infection/disease defined as:

    1. Subjects on ART must have a CD4+ T cell count >350 cells/mm3 at time of screening
    2. Subjects on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening
    3. Subjects on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1).

14. For women of childbearing potential (WCBP): negative urine pregnancy test (UPT) within 1 week before first treatment (WCBP defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally post-menopausal for at least 12 consecutive months for women > 55 years of age). WCBP should be placed on effective birth control directly after testing negative for pregnancy; if not, then WCBP should have a UPT on Day 1 of every cycle, prior to drug administration. Any positive or indeterminant UPT result must be confirmed by Serum.

15. Female subjects of childbearing potential must use a highly effective mode of contraception or abstain from heterosexual activity for the duration of the trial and for 120 days following the last dose of study medication. A female is NOT of childbearing potential if she has undergone bilateral salpingoophorectomy or is menopausal, defined as an absence of menses for 12 consecutive months. Male subjects must agree to use highly effective contraception.

16. Ability to adhere to the study visit schedule and all protocol requirements

Exclusion Criteria

Subjects are to be excluded from the study if they meet any of the following criteria:

1. Major surgery within 4 weeks prior to Screening

2. Anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal therapy, targeted therapy, or investigational agents within five half-lives or four weeks, whichever is shorter, prior to administration of the first dose of study treatment.

3. Subjects with active central nervous system (CNS) metastases; however, subjects who have undergone radiation and/or surgery for the treatment of CNS metastases, who are neurologically stable, and who are no longer taking pharmacologic doses of corticosteroids are eligible; subjects with leptomeningeal metastases are not eligible.

4. Has received prior radiotherapy within 2 weeks of start of study treatment. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

5. Primary CNS malignancy

6. HIV-infected subjects with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.

7. Subjects who are hepatitis B surface antigen positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to enrollment.

   Note: Subjects should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention.

   Hepatitis B screening tests are not required unless:

   • Known history of HBV infection
   • As mandated by local health authority.

8. Subjects with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening. Note: Subjects must have completed curative antiviral therapy at least 4 weeks prior to enrollment.

   Hepatitis C screening tests are not required unless:

   • Known history of HCV infection
   • As mandated by local health authority.

9. Subjects who require immunosuppressive therapy including, but not limited to, treatment with corticosteroids in pharmacologic doses (equivalent to ≥10 mg prednisone daily), cyclosporine, mycophenolate, azathioprine, methotrexate, adalimumab, infliximab, vedolizumab, tofacitinib, dupilumab, rituximab, etc. or systemic steroids (except for steroid use as cortisol replacement therapy in documented adrenal insufficiency)

10. Ongoing systemic bacterial, fungal, or viral infections at Screening

    a. NOTE: Subjects on antimicrobial, antifungal, or antiviral prophylaxis are not specifically excluded if all other inclusion/exclusion criteria are met

11. Administration of a live vaccine within 30 days of first dose of study drug

12. Baseline QT interval corrected with Fridericia's method (QTcF) > 480 ms (average of triplicate readings)

    a. NOTE: Criterion does not apply to subjects with a right or left bundle branch block.

13. Subjects with a history of Torsade de Pointes or taking QT-prolonging drugs

14. Prior surgery or gastrointestinal dysfunction that may affect drug absorption (eg, gastric bypass surgery, gastrectomy)

15. Female subjects who are pregnant or breastfeeding

16. Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix, or prostate intraepithelial neoplasia

17. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease

18. History of peptic ulcer and/or gastrointestinal bleed within the past 6 months prior to Screening

19. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months prior to Screening

20. Unstable or severe uncontrolled medical condition (eg, unstable cardiac function, unstable pulmonary condition including pneumonitis and/or interstitial lung disease, uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the Investigator's judgment, increase the risk to the subject associated with his or her participation in the study