A Study to Investigate Sitravatinib as Monotherapy and in Combination With Tislelizumab in Participants With Unresectable Locally Advanced or Metastatic Hepatocellular Carcinoma (HCC) or Gastric/Gastroesophageal Junction Cancer (GC/GEJC)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety,tolerability, pharmacokinetics and preliminary antitumor activity of sitravatinib as monotherapy and in combination with tislelizumab in participants with unresectable locally advanced or metastatic hepatocellular carcinoma or gastric/gastroesophageal junction cancer.

Detailed Description
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This is an open-label, multicenter Phase 1/2 clinical study for participants with histologically or cytologically confirmed unresectable locally advanced or metastatic HCC or G/GEJ cancer. All participants will receive study treatment (s) until progressive disease (PD), unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor. This study consists of the following phases. Phase 1 (Dose escalation for sitravatinib as monotherapy and in combination with tislelizumab): Two dose levels of sitravatinib as monotherapy, 80 mg once daily and 120 mg once daily, will be evaluated in participants with unresectable locally advanced or metastatic HCC or G/GEJ cancer. A modified 3+3 design will be used in the dose escalation. Approximately 6 to 12 DLT evaluable participants will be treated with sitravatinib as monotherapy. The combination dose escalation of sitravatinib (80 mg once daily and 120 mg once daily; modified 3+3 design) with tislelizumab (200 mg every 3 weeks, in both cohorts) will be evaluated in participants with unresectable locally advanced or metastatic HCC or G/GEJ cancer. Approximately 12 to 24 DLT evaluable participants will be treated with sitravatinib in combination with tislelizumab. Phase 2 (Dose expansion for sitravatinib as monotherapy and in combination with tislelizumab): Approximately 20 participants will be enrolled in each cohort. There will be a total of 4 cohorts in the study. Cohort A: Anti-PD-1/PD-L1 Antibody Naïve or Refractory/Resistant HCC Cohort B: Anti-PD-1/PD-L1 antibody naive HCC Cohort C: Anti-PD-1/PD-L1 antibody refractory/resistant HCC Cohort D: Anti-PD-1/PD-L1 antibody naive G/GEJ cancer

Official Title
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A Phase 1/2 Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of Sitravatinib as Monotherapy and in Combination With Tislelizumab in Patients With Unresectable Locally Advanced or Metastatic HCC or GC/GEJC

Conditions
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Carcinoma, Hepatocellular, Gastric/Gastroesophageal Junction Cancer

Intervention / Treatment
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* Drug: Sitravatinib
* Drug: Sitravatinib plus Tislelizumab
* Drug: Sitravatinib
* Drug: Sitravatinib and tislelizumab
* Drug: Sitravatinib and tislelizumab
* Drug: Sitravatinib and tislelizumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically or cytologically confirmed, unresectable, locally advanced, or metastatic HCC/GC/GEJC Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments Age ≥ 18 years on the day of signing the ICF (or the legal age of consent in the jurisdiction in which the study is taking place) Adequate organ function Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and ≥ 120 days after the last dose of study drug(s), and have a negative serum pregnancy test ≤ 7 days of first dose of study drug(s) Nonsterile males must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 120 days after the last dose of study drug(s) Failed current standard-of-care treatment, or standard-of-care treatment is considered not appropriate at present Key Exclusion Criteria: Active leptomeningeal disease or uncontrolled brain metastasis. Active autoimmune diseases or history of autoimmune diseases that may relapse Any active malignancy ≤ 2 years History of interstitial lung disease, noninfectious pneumonitis or uncontrolled diseases including pulmonary fibrosis, acute lung diseases, etc Severe chronic or active infections (including tuberculosis infection, etc) requiring systemic antibacterial, antifungal, or antiviral therapy within 14 days prior to first dose of study drug(s). Known history of human immunodeficiency virus (HIV) infection Untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers. Any major surgical procedure requiring general anesthesia ≤ 28 days before the first dose of study drug(s) Prior allogeneic stem cell transplantation or organ transplantation Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg) Bleeding or thrombotic disorders or use of anticoagulants such as warfarin or similar agents requiring therapeutic international normalized ratio (INR) monitoring Any systemic chemotherapy within 28 days of the first dose of study drug(s) or hormone therapy, targeted therapy, or any investigational therapies Toxicities (as a result of prior anticancer therapy) that have not recovered to baseline or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, neuropathy, and specific laboratory abnormalities) Inability to swallow capsules or disease significantly affecting gastrointestinal function Pregnant or breastfeeding woman NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitravatinib monotherapy<br>Two dose levels of sitravatinib as monotherapy, 80 mg once daily and 120 mg once daily, will be evaluated in participants with unresectable locally advanced or metastatic HCC or G/GEJ cancer. A modified 3+3 design will be used in the dose escalation to confirm recommended Phase 2 dose (RP2D) | Drug: Sitravatinib<br>* Study participants will receive sitravatinib capsule once daily<br>|
| Experimental: Sitravatinib plus Tislelizumab<br>The combination dose escalation of sitravatinib (80 mg once daily and 120 mg once daily; modified 3+3 design) with tislelizumab (200 mg every 3 weeks, in both cohorts) will be evaluated in unresectable locally advanced or metastatic HCC or G/GEJ cancer participants . If the combination dose of 80 mg sitravatinib and 200 mg tislelizumab has been declared tolerable, the dose of sitravatinib will be escalated to 120 mg and tislelizumab will remain fixed at 200 mg. Approximately 12 to 24 evaluable participants will be treated. The dose of tislelizumab during dose escalation for the combination will be kept fixed at 200 mg | Drug: Sitravatinib plus Tislelizumab<br>* Study participants will receive sitravatinib capsule once daily and in combination with tislelizumab IV once every 3 weeks.<br>|
| Experimental: Anti-PD-1/PD-L1 Antibody Naïve or R/R HCC (Monotherapy)<br> | Drug: Sitravatinib<br>* Study participants will receive sitravatinib capsule once daily.<br>|
| Experimental: Anti-PD-1/PD-L1 antibody naive HCC(Combination)<br> | Drug: Sitravatinib and tislelizumab<br>* Study participants will receive sitravatinib capsule once daily and in combination with tislelizumab IV once every 3 weeks.<br>|
| Experimental: Anti-PD-1/PD-L1 antibody refractory/resistant HCC<br> | Drug: Sitravatinib and tislelizumab<br>* Study participants will receive sitravatinib capsule once daily and in combination with tislelizumab IV once every 3 weeks.<br>|
| Experimental: Anti-PD-1/PD-L1 antibody naive G/GEJ cancer<br> | Drug: Sitravatinib and tislelizumab<br>* Study participants will receive sitravatinib capsule once daily and in combination with tislelizumab IV once every 3 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of participants with adverse events (AEs) and serious adverse events (SAEs) per NCI-CTCAE version 5.0 |  | Up to approximately 3 years | 
| Phase 2: Objective response rate (ORR) | ORR based on RECIST v1.1 by investigator | Up to approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carcinoma, HCC, G/GEJ Cancer