TT-10 (PORT-6) and TT-4 (PORT-7) as Single Agents and in Combination in Subjects With Advanced Selected Solid Tumors

Inclusion Criteria

• •To be eligible for inclusion in the dose escalation cohorts or expansion cohorts in this study, participants must meet all of the following criteria:
• •1. Participants must be ≥18 years of age.
• •2. Participants or their legal representative must be able to provide written informed consent to participate in the study prior to the performance of any study-specific procedures.
• •3. Diagnosis of histologically or cytologically confirmed advanced selected solid tumors:
• •Cohort A - TT-10 dose escalation:
• •1. RCC: Participants with locally advanced or metastatic RCC that have previously received at least two prior systemic regimens, including vascular endothelial growth factor (VEGF)-targeted therapy and checkpoint inhibitor therapy
• •2. CRPC: Participants with metastatic CRPC who have previously received a second-generation hormonal agent (unless contraindicated) and a taxane-based chemotherapy.
• •3. SCCHN: Participants with advanced or metastatic SCCHN that is incurable by surgery or radiotherapy and that has progressed during or after a platinum-based chemotherapy and/or checkpoint inhibitor therapy (separately or in combination)
• •4. NSCLC: Participants with metastatic NSCLC that is intolerant or resistant to standard therapy or for which no standard therapy is available
• •Cohort B - TT-4 dose escalation:
• •1. CRC: Participants with metastatic CRC that is intolerant or resistant to standard therapy or for which no standard therapy is available
• •2. CRPC: Participants with metastatic CRPC who have previously received a second-generation hormonal agent (unless contraindicated) and a taxane-based chemotherapy
• •3. NSCLC: Participants with metastatic NSCLC that is intolerant or resistant to standard therapy or for which no standard therapy is available
• •4. Endometrial cancer: Participants with metastatic endometrial cancer that is intolerant or resistant to standard therapy or for which no standard therapy is available
• •5. Ovarian cancer: Participants with metastatic ovarian cancer that is intolerant or resistant to standard therapy or for which no standard therapy is available
• •Cohort C- TT-10 + TT- 4 dose escalation and expansion:
• •a. The tumor types will include 1 or more of those enrolled in the respective Escalation Cohorts (A and B), and will be determined following review of the dose escalation data by the SMC.
• •4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0 - 1
• •5. Have measurable disease per RECIST 1.1 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. Failure to respond to standard therapy, or for whom no appropriate therapies are available (based on the judgment of the investigator)
• •7. Consent to baseline biopsy, with the following exceptions:
• •1. Participants whose only site(s) of disease are in areas considered moderate or high risk may be enrolled without a fresh biopsy with Sponsor approval;
• •2. Archival tissue may be submitted in lieu of a fresh biopsy if collected within 6 months of screening and without intervening systemic therapy.
• •8. Participants must have adequate hematologic function based on the following:
• •* ANC ≥ 1.5 x 109/L
• •* Platelet count ≥ 100 x 109/L
• •* Hemoglobin ≥ 9.0 g/dL
• •9. Participants must have adequate hepatic function based on the following:
• •* Total bilirubin \< 1.5 x upper limit of normal (ULN) (unless elevated due to Gilbert's syndrome)
• •* ALT/AST ≤ 2.5 x ULN (≤ 5 x ULN for participants with known hepatic metastases)
• •10. Participants must have adequate renal function based on the following:
• •* Serum creatinine ≤ 1.5 x ULN; or
• •* Serum creatinine clearance ≥ 60 mL/min, as determined by Cockcroft-Gault equation
• •11. 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 study intervention administration. Any positive or indeterminant UPT result must be confirmed by serum.
• •a. Female participants of childbearing potential must use a highly effective mode of contraception or abstain from heterosexual activity for the duration of the study and for 120 days following the last dose of study intervention. 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 participants must agree to use highly effective contraception.
• •12. Ability to adhere to the study visit schedule and all protocol requirements
• •13. Must be able to swallow capsules
• •Participants will be excluded from the study if they satisfy any of the following criteria at the Screening visit unless otherwise stated:
• •Participants are to be excluded from the study if they meet any of the following criteria:
• •1. Major surgery within 4 weeks prior to Screening
• •Note: Participants 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
• •Hepatitis C screening tests are not required unless:
• •* Known history of HCV infection
• •* As mandated by local health authority
• •8. Participants 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)
• •9. Participants requiring administration of drugs known to be strong inhibitors or inducers of CYP3A4, 2C9 or 2C19
• •10. Participants requiring drugs that modify gastric pH, such as proton-pump inhibitors (PPIs) or H2 blockers. Antacids, such as calcium carbonate or aluminum hydroxide-based products, will be allowed during the study, but are recommended to be taken either 4 hours before or 2 hours after dosing of TT 10 (PORT 6) or PORT-7.
• •11. Ongoing systemic bacterial, fungal or viral infections at Screening