TT-10 as a Single Agent in Subjects With Advanced Selected Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of orally administered TT-10 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-10.

Detailed Description
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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-10 in subjects diagnosed with advanced Renal cell cancer (RCC), castrate resistant prostate cancer (CRPC) and Non-small cell lung cancer (NSCLC); 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-10 in subjects with advanced subjects diagnosed with advanced Renal cell cancer (RCC), castrate resistant prostate cancer (CRPC) and Non-small cell lung cancer (NSCLC); 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, anti-tumor activity, and efficacy of TT-10.

Official Title
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Phase I/II First-in-Human Study of TT-10 as a Single Agent in Subjects With Advanced Selected Solid Tumors

Conditions
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Renal Cell Cancer, Castrate Resistant Prostate Cancer, Non Small Cell Lung Cancer, Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: TT-10


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Participants must be ≥ 18 years of age. 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. Diagnosis of histologically or cytologically confirmed advanced selected solid tumors Cohort A dose escalation: RCC, CRPC and NSCLC who have failed or are not eligible for standard of care treatment. Cohort B: Metastatic RCC who have failed or are not eligible for standard of care treatment. Cohort C: Metastatic CRPC who have failed or are not eligible for standard of care treatment. Cohort D: Metastatic NSCLC who have failed or are not eligible for standard of care treatment. Cohort E: Exploratory Biopsy - Inclusive of participants with RCC, CRPC and/or NSCLC who have failed or are not eligible for standard of care treatment and have an accessible tumor for pre- and post dose biopsies. Eastern Cooperative Oncology Group performance status score 0 - 1 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. Failure to respond to standard therapy, or for whom no appropriate therapies are available (based on the judgment of the investigator) Cohort E Only: Fresh tissue sample obtained prior to treatment initiation and agree to on-treatment biopsy from same lesion. Life expectancy of ≥ 3 months Participants 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 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) Alanine aminotransferase/aspartate aminotransferase ≤ 2.5 x ULN (≤ 5 x ULN for participants with known hepatic metastases) 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 Exclusion Criteria: Major surgery within 4 weeks prior to Screening Participants with active central nervous system (CNS) metastases; however, participants 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; participants with leptomeningeal metastases are not eligible. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants 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. Prior anti-cancer therapy within 4 weeks prior to the start of study intervention. A 2 week washout is acceptable for short-acting drugs (eg, tyrosine kinase inhibitors). Any treatment-related toxicities must be resolved to Grade 0 - 1. Human immunodeficiency virus-infected participants Participants 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: 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 Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at Screening. Note: Participants 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 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) Participants requiring administration of drugs known to be strong inhibitors or inducers of CYP3A4, 2C9 or 2C19 Participants requiring drugs that modify gastric pH, such as proton-pump inhibitors, H2 blockers or antacids (eg, calcium, magnesium or aluminum containing over-the-counter medications) Ongoing systemic bacterial, fungal or viral infections at Screening - NOTE: Participants on antimicrobial, antifungal or antiviral prophylaxis are not specifically excluded if all other inclusion/exclusion criteria are met Administration of a live vaccine within 6 weeks of first dose of study intervention. Messenger ribonucleic acid vaccines for the prevention of Coronavirus Disease 2019 (COVID-19) infection are permitted. Baseline QT interval corrected with Fridericia's method (QTcF) > 470 ms (average of triplicate readings) - NOTE: Criterion does not apply to participants with a right or left bundle branch block. Prior surgery or gastrointestinal dysfunction that may affect drug absorption (eg, gastric bypass surgery, gastrectomy) Female participants who are pregnant or breastfeeding Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix or prostate intraepithelial neoplasia 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 History of peptic ulcer and/or gastrointestinal bleed within the past 6 months prior to Screening History of stroke, unstable angina, myocardial infarction or ventricular arrhythmia requiring medication or mechanical control within the last 6 months prior to Screening 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 participant associated with his or her participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multiple Ascending Dose<br>3+3 Dose escalation until MTD and/or R2PD of TT-10 is determined | Drug: TT-10<br>* TT-10 orally administered BID starting at 10 mg and will be increased to 200 mg (additional dose levels maybe explored, if appropriate based on emerging safety, PK or PD data).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with Dose Limiting Toxicities (DLTs) of TT-10 during the dose escalation phase | All toxicities will be graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | 28 Days | 
| Define the maximum tolerated dose (MTD) or phase 2 recommended dose of TT-10 during the dose escalation phase | To confirm the maximum tolerated dose (MTD) of TT-10, defined as the highest dose level at which <2 out of 6 participants experience a dose-limiting toxicity | Through study completion, an average of 1 year | 
| Expansion cohort primary objective - safety | Incidence and severity of treatment-related adverse events (TRAEs) in participants treated at the recommended phase 2 dose in the expansion phase | Through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is to be reported as the proportion of patients who have a Complete Response or Partial Response per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 | From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years) | 
| Duration of Response (DoR) | Defined as the time from first documented objective response per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 to the date of first documented radiographic progression of disease (PD) or death. | From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years) | 
| Progression Free Survival (PFS) | Time from first dose to the date of the first confirmed documented progression per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 | From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 2 years) | 
| Peak serum concentration (Cmax) of TT-10 | PK Parameter | Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose | 
| Area under the serum concentration versus time curve (AUC) of TT-10 | PK Parameter | Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose | 
| Half-life of TT-10 | PK Parameter | Predose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Failed or not eligible for standard of care, Advanced Selected Solid Tumors, TT-10, Adenosine, Adenosine Antagonist, A2A, A2AR Inhibitor, PORT-6, ADPORT-601