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A Study to Investigate Sitravatinib as Monotherapy and in Combination With Tislelizumab in Patients With Unresectable Locally Advanced or Metastatic HCC or GC/GEJC

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ClinicalTrials.gov Identifier: NCT03941873
Recruitment Status : Recruiting
First Posted : May 8, 2019
Last Update Posted : August 9, 2019
Sponsor:
Information provided by (Responsible Party):
BeiGene

Brief Summary:
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 patients with unresectable locally advanced or metastatic hepatocellular carcinoma or gastric/gastroesophageal junction cancer.

Condition or disease Intervention/treatment Phase
Carcinoma, Hepatocellular Gastric/Gastroesophageal Junction Cancer Drug: Sitravatinib Drug: Sitravatinib plus Tislelizumab Drug: Sitravatinib and tislelizumab Phase 1 Phase 2

Detailed Description:

This is an open-label, multicenter Phase 1/2 clinical study for patients with histologically or cytologically confirmed unresectable locally advanced or metastatic HCC or G/GEJ cancer. All patients will receive study treatment (s) until 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 patients 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 evaluable patients 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 patients with unresectable locally advanced or metastatic HCC or G/GEJ cancer.

Phase 2 (Dose expansion for sitravatinib as monotherapy and in combination with tislelizumab): Approximately 20 patients 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 naive 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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 104 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 28, 2019
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : July 2021

Arm Intervention/treatment
Experimental: Sitravatinib monotherapy
Two dose levels of sitravatinib as monotherapy, 80 mg once daily and 120 mg once daily, will be evaluated in patients 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 RP2D.
Drug: Sitravatinib
Study subjects will receive sitravatinib capsule once daily

Experimental: Sitravatinib plus Tislelizumab
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 patients . 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 6 to 12 evaluable patients will be treated. The dose of tislelizumab during dose escalation for the combination will be kept fixed at 200 mg.
Drug: Sitravatinib plus Tislelizumab
Study subjects will receive sitravatinib capsule once daily and in combination with tislelizumab IV once every 3 weeks.

Experimental: Anti-PD-1/PD-L1 antibody naïve HCC(Monotherapy) Drug: Sitravatinib
Study subjects will receive sitravatinib capsule once daily.

Experimental: Anti-PD-1/PD-L1 antibody naive HCC(Combination) Drug: Sitravatinib and tislelizumab
Study subjects will receive sitravatinib capsule once daily and in combination with tislelizumab IV once every 3 weeks.

Experimental: Anti-PD-1/PD-L1 antibody refractory/resistant HCC Drug: Sitravatinib and tislelizumab
Study subjects will receive sitravatinib capsule once daily and in combination with tislelizumab IV once every 3 weeks.

Experimental: Anti-PD-1/PD-L1 antibody naive G/GEJ cancer Drug: Sitravatinib and tislelizumab
Study subjects will receive sitravatinib capsule once daily and in combination with tislelizumab IV once every 3 weeks.




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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:Each patient eligible to participate in this study must meet all the following criteria:

  • 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)
  • At least 1 measurable lesion as defined by RECIST v1.1. Note: Selected target lesion(s) must meet 1 of 2 criteria: 1) not previously treated with local therapy or 2) within the field of prior local therapy but with documented subsequent progression as per RECIST v1.1
  • Agreement to provide archival tumor tissue (formalin-fixed paraffin-embedded [FFPE] block with tumor tissue or approximately 15 unstained slides), if available, and blood samples for molecular analysis. Note: If archival tumor tissue is not available or of sufficient quantity, an optional fresh biopsy is highly recommended.
  • Tumor tissue needs to originate from core or punch biopsy.
  • Tumor tissue from fine-needle aspiration is not acceptable.
  • ECOG Performance Status ≤ 1 (Appendix 4)
  • Adequate organ function as indicated by the following laboratory values ≤ 7 days before the first dose of study drug(s):
  • Patients must not have required a blood or platelet transfusion or growth factor support ≤ 14days before sample collection at screening for the following
  • ANC ≥ 1.5 x 109/L
  • Platelets ≥ 75 x 109/L
  • Hemoglobin ≥ 90 g/L
  • Serum creatinine ≤ 1.5 x upper limit of normal (ULN), or estimated glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Appendix 9)
  • AST and ALT ≤ 3 x ULN or AST and ALT ≤ 5 x ULN for patients with HCC
  • Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients with Gilberts syndrome), total bilirubin < 5 x ULN for patients with HCC and cirrhosis
  • International normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 x ULN
  • Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN
  • Serum albumin ≥ 30 g/L
  • 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) Phase 1 Inclusion Criteria
  • Histologically or cytologically confirmed unresectable locally advanced or metastatic HCC or G/GEJ cancer
  • Meets eligibility criteria of any of the expansion cohorts Phase 2 Inclusion Criteria Cohorts A, B, and C: HCC
  • Histologically or cytologically confirmed unresectable locally advanced or metastatic HCC Note: Fibrolamellar, sarcomatoid, or mixed cholangiocarcinoma histology is excluded
  • Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease that is not amenable to or has progressed after loco-regional therapy and is not amenable to a curative treatment approach
  • Child-Pugh A classification for liver function (Appendix 5) assessed within 7 days of first dose of study drug(s)
  • No tumor thrombus involving main trunk of portal vein or inferior vena cava
  • No loco-regional therapy to the liver (ie, transarterial chemoembolization [TACE], transcatheter embolization, hepatic arterial infusion, radiation, radioembolization, or ablation) within 28 days before the first dose of study drug(s)
  • No prior history of ≥ Grade 2 hepatic encephalopathy before the first dose of study drug(s)
  • No clinical evidence of portal hypertension with bleeding esophageal or gastric varices within 6 months before the first dose of study drug(s) Cohort A: Anti-PD-1/PD-L1 Antibody Naive HCC
  • Failed current standard of care treatment and with no other prior immunotherapies, including but not limited to, anti-PD-1/PD-L1, anti-CTLA-4, anti-OX40, and anti-CD137 OR Cohort B: Anti-PD-1/PD-L1 Antibody Naive HCC
  • Failed current systemic treatment and with no other prior immunotherapies, including but not limited to, anti-PD-1/PD-L1, anti-CTLA-4, anti-OX40, and anti-CD137 Cohort C: Anti-PD-1/PD-L1 Antibody Refractory/Resistant (R/R) HCC
  • Received ≤ 2 lines of systemic therapy
  • Radiographic progression per RECIST v1.1 on or after anti-PD-1/PD-L1 therapy as the most recent treatment for unresectable locally advanced or metastatic HCC
  • No other prior immunotherapies, including but not limited to, anti-CTLA-4, anti-OX40, and anti CD137
  • No unacceptable toxicity from prior anti-PD-1/PD-L1 treatment, defined as:
  • ≥ Grade 3 AE related to anti-PD-1/PD-L1 treatment.
  • ≥ Grade 2 irAE associated with anti-PD-1/PD-L1 unless the AE resolved or was well controlled by withholding anti-PD-1/PD-L1 and/or treatment with steroids, with the exception of prior colitis, encephalitis, myocarditis, hepatitis, uveitis, and pneumonitis, which are exclusionary
  • Central nervous system (CNS) or ocular AE of any grade related to anti-PD-1/PD-L1 Note: Patients with a prior endocrine AE are allowed if they are stably maintained on appropriate replacement therapy and are asymptomatic Cohort D: Anti-PD-1/PD-L1 Antibody Naive G/GEJ Cancer
  • Received ≤ 2 lines of systemic therapy
  • Histologically or cytologically proven adenocarcinoma of the stomach or gastroesophageal junction, inoperable locally advanced or with metastatic disease
  • Radiographic progression per RECIST v1.1 on or after systemic treatment for unresectable locally advanced or metastatic G/GEJ cancer
  • No prior immunotherapies, including but not limited to, anti-PD-1/PD-L1, anti-CTLA-4, anti-OX40, and anti CD137
  • Known HER-2 (human epidermal growth factor receptor 2) positive disease is excluded
  • No history of gastrointestinal (GI) perforation and/or fistulae within 6 months before the first dose of study drug(s)
  • No clinically significant GI bleeding within 3 months before the first dose of study drug(s)
  • No clinically significant bowel obstruction
  • No complete gastric resection
  • No weight loss ≥ 20% within 2 months before the first dose of study drug(s)

Exclusion Criteria:Patients who meet any of the following criteria are not eligible to enroll:

  • Any known brain or leptomeningeal metastases
  • Active autoimmune diseases or history of autoimmune diseases that may relapse (Appendix 6). Note: Patients with the following diseases are not excluded and may proceed to further screening:
  • Controlled Type I diabetes
  • Hypothyroidism (provided it is managed with hormone replacement therapy only)
  • Controlled celiac disease
  • Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia)
  • Any other disease that is not expected to recur in the absence of external triggering factors
  • Any active malignancy ≤ 2 years before the first dose of study drug(s) except for specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast).
  • Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before the first dose of study drug(s). Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded:
  • Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)
  • Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption
  • Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a nonautoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen)
  • Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management, or ≥ Grade 3 hypoalbuminemia ≤ 14 days before the first dose of study drug
  • 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 drugs. Note: antiviral therapy is permitted for patients with HCC
  • Known history of human immunodeficiency virus (HIV) infection
  • Untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers with HBV DNA > 500 IU/mL or active HCV carriers. Note: Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B (HBV DNA < 500 IU/mL), and cured hepatitis C patients can be enrolled
  • 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
  • Any of the following cardiovascular criteria
  • Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤ 28 days before the first dose of study drug(s)
  • Symptomatic pulmonary embolism ≤ 28 days before the first dose of study drug(s)
  • Any history of acute myocardial infarction ≤ 6 months before the first dose of study drug(s)
  • Any history of heart failure meeting New York Heart Association Classification (NYHA) III or IV (Appendix 8) ≤ 6 months before the first dose of study drug(s)
  • Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before the first dose of study drug(s)
  • Any history of cerebrovascular accident ≤ 6 months before the first dose of study drug(s)
  • QT corrected (QTc) interval (corrected by Fridericia's method) > 450 msec Note: If QTc interval is > 450 msec on initial ECG, a follow up ECG will be performed to exclude result
  • Current left ventricular ejection fraction (LVEF) < institutional LLN as assessed by echocardiography (ECHO). The same modality used at baseline must be applied for subsequent evaluations
  • Any episode of syncope or seizure ≤ 28 days before the first dose of study drug(s)
  • Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg)
  • Hypersensitivity to tislelizumab or sitravatinib, to any ingredient in the formulation, or to any component of the container
  • Bleeding or thrombotic disorders or use of anticoagulants such as warfarin or similar agents requiring therapeutic INR monitoring within 6 months before the first dose of study drug(s)
  • Any systemic chemotherapy within 28 days of the first dose of study drugs or immunotherapy (eg, interleukin, interferon, thymoxin, etc.), hormone therapy, targeted therapy, or any investigational therapies within 14 days or 5 half-lives (whichever is shorter) of first dose of study drugs
  • Any herbal medicine used to control cancer within 14 days of the first study drug(s) administration
  • 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)
  • Administration of live vaccine ≤ 4 weeks before the first dose of study drug(s) Note: seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed
  • Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study drug(s) or affect the explanation of drug toxicity or AEs or result in insufficient or might impair compliance with study conduct
  • Concurrent participation in another therapeutic clinical study
  • Inability to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the complete stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
  • Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or medical intervention (clinically significant recurrence requiring an additional intervention within 2 weeks of intervention; cytological confirmation of any effusion permitted) within 7 days before first dose of study drug(s)
  • Pregnant or breastfeeding woman

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03941873


Contacts
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Contact: Eva Wang, COM 86-10-8567 9808 clinicaltrials@beigene.com
Contact: Tan Liang, ACOM 86-10-8567 9808 clinicaltrials@beigene.com

Locations
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China, Anhui
The Second Hospital of Anhui Medical University Not yet recruiting
Hefei, Anhui, China, 230000
Principal Investigator: Zhendong Chen         
China, Heilongjiang
Harbin Medical University Cancer Hospital Not yet recruiting
Harbin, Heilongjiang, China, 150000
Principal Investigator: Yuxian Bai         
China, Hubei
Union Hospital Tongji Medical College Huazhong University of Science and Technology Not yet recruiting
Wuhan, Hubei, China, 430000
Principal Investigator: Tao Zhang         
China, Jiangsu
The 81st Hospital of Chinese PLA Recruiting
Nanjing, Jiangsu, China, 210000
Principal Investigator: Shukui Qin         
China, Liaoning
The First Hospital of China Medical University Not yet recruiting
Shenyang, Liaoning, China, 110000
Principal Investigator: Yunpeng Liu         
China, Shanghai
Zhongshan Hospital Fudan University Not yet recruiting
Shanghai, Shanghai, China, 200000
Principal Investigator: Zhenggang Ren         
Fudan University Shanghai Cancer Center Not yet recruiting
Shanghai, Shanghai, China, 200120
Principal Investigator: Zhiqiang Meng         
Shanghai East Hospital Recruiting
Shanghai, Shanghai, China, 200120
Principal Investigator: Jing Li         
China, Zhejiang
Sir Run Run Shaw Hospital Zhejiang University School of Medicine Not yet recruiting
Hangzhou, Zhejiang, China, 310000
Principal Investigator: Hongming Pan         
The First Affiliated Hospital Zhejiang University Not yet recruiting
Hangzhou, Zhejiang, China, 310000
Principal Investigator: Weijia Fang         
Zhejiang Cancer Hospital Recruiting
Hangzhou, Zhejiang, China, 310000
Principal Investigator: Jieer Ying         
Sponsors and Collaborators
BeiGene

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Responsible Party: BeiGene
ClinicalTrials.gov Identifier: NCT03941873     History of Changes
Other Study ID Numbers: BGB-900-104
CTR20182149 ( Registry Identifier: Center for drug evaluation, CFDA )
First Posted: May 8, 2019    Key Record Dates
Last Update Posted: August 9, 2019
Last Verified: November 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by BeiGene:
Carcinoma
HCC
G/GEJ Cancer

Additional relevant MeSH terms:
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Carcinoma, Hepatocellular
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Antibodies
Immunologic Factors
Physiological Effects of Drugs