Clinical Trials /

A Phase 1b Study to Assess Sitravatinib in Combination With Tislelizumab in Patients With Advanced Solid Tumors.

NCT03666143

Description:

This is an open-label, multicenter, non-randomized Phase 1b clinical trial for patients with histologically or cytologically confirmed locally advanced or metastatic tumors including non- squamous NSCLC, RCC, or OC.

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
  • Malignant Ovarian Epithelial Tumor
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1b Study to Assess Sitravatinib in Combination With Tislelizumab in Patients With Advanced Solid Tumors.
  • Official Title: A Phase 1b Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of Sitravatinib in Combination With Tislelizumab in Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: BGB-900-103
  • NCT ID: NCT03666143

Conditions

  • Non-squamous, Non-small Cell Lung Cancer (NSCLC), Renal Cell Carcinoma (RCC), and Ovarian Cancer (OC)

Interventions

DrugSynonymsArms
Sitravatinib TislelizumabAnti-PD-1/PD-L1 antibody refractory/resistant NSCLC

Purpose

This is an open-label, multicenter, non-randomized Phase 1b clinical trial for patients with histologically or cytologically confirmed locally advanced or metastatic tumors including non- squamous NSCLC, RCC, or OC. All patients will receive sitravatinib 120 mg orally once daily in combination with tislelizumab 200 mg IV once every 3 weeks until occurrence of PD, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor. There will be 5 cohorts in the study. Approximately 20 patients will be enrolled into each cohort. The patients will be enrolled according to their tumor type and prior anti-programmed cell death protein-1 (PD-1)/PD-L1 antibody treatment. - Cohort A: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic, non-squamous NSCLC - Cohort B: Anti-PD-1/PD-L1 antibody naïve metastatic, non-squamous NSCLC - Cohort C: Anti-PD-1/PD-L1 antibody refractory/resistant metastatic or advanced RCC - Cohort D (China-only): Metastatic or advanced RCC without prior systemic therapy - Cohort E: Anti-PD-1/PD-L1 antibody naïve recurrent and platinum resistant Epithelial OC A Safety Monitoring Committee (SMC) will review the safety, tolerability, and pharmacology data from the initial 6 patients (regardless of assigned cohort) that complete the first treatment cycle in Australia. Recruitment will be on hold in Australia until these data have been reviewed. For participating China sites only, the initial 6 patients enrolled in China regardless of assigned cohort will have their safety, tolerability, and pharmacology data reviewed by the SMC. Recruitment in China only will be on hold until the data have been reviewed. The SMC may assess the combination regimen as safe, but may also decide to evaluate a dosing regimen that was not predefined or not previously studied, if evaluation of toxicity at such a dose is desired.

Trial Arms

NameTypeDescriptionInterventions
Anti-PD-1/PD-L1 antibody refractory/resistant NSCLCExperimental
  • Sitravatinib Tislelizumab
Anti-PD-1/PD-L1 antibody naïve NSCLCExperimental
  • Sitravatinib Tislelizumab
Anti-PD-1/PD-L1 antibody refractory/resistant RCCExperimental
  • Sitravatinib Tislelizumab
Metastatic or advanced RCC without prior systemic therapyExperimental
  • Sitravatinib Tislelizumab
Anti-PD-1/PD-L1 naïve recurrent / platinum resistant OCExperimental
  • Sitravatinib Tislelizumab

Eligibility Criteria

        Inclusion Criteria:

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

          1. Able to provide written informed consent and can understand and agree to comply with
             the requirements of the study and the schedule of assessments

          2. Age ≥ 18 years on the day of signing the informed consent form (or the legal age of
             consent in the jurisdiction in which the study is taking place)

          3. At least 1 measurable lesion as defined by RECIST v1.1 Note: Selected target lesion(s)
             must meet one of these criteria: 1) not previously treated with local therapy or 2)
             within the field of prior local therapy but with subsequent progression as per RECIST
             v1.1.

          4. Agreement to provide archival tumor tissue (formalin-fixed paraffin-embedded block
             [FFPE] 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.

          5. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 (Appendix 4)

          6. Adequate hematologic and end-organ function, as defined by the following laboratory
             values (obtained ≤ 7 days before first dose): a. Patients must not have required a
             blood or platelet transfusion or growth factor support ≤ 14 days before sample
             collection i. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L ii. Platelets ≥ 75 x 109/L
             iii. Hemoglobin ≥ 90 g/L b. 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 equation (Appendix 8) c. Aspartate transaminase
             (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN, or AST and ALT ≤ 5.0 x ULN for
             patients with documented liver metastases d. Serum total bilirubin ≤ 1.5 x ULN (total
             bilirubin must be < 3 x ULN for patients with Gilberts syndrome) e. International
             normalized ratio (INR) ≤ 1.5 or prothrombin time ≤ 1.5 x ULN f. Activated partial
             thromboplastin time (aPTT) ≤ 1.5 x ULN

          7. 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 drugs and have a negative serum pregnancy test ≤ 7 days of first dose of study
             drugs

          8. Non-sterile 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 drugs
             Cohort-Specific Inclusion Criteria Cohort A, Cohort B: Metastatic, non-squamous NSCLC

          9. Histologically or cytologically confirmed, Stage IV non-squamous NSCLC 10. Mixed
             histology (ie, squamous and non-squamous) is allowed if the major histological
             component is non-squamous. • Patients with disease known to be positive for epidermal
             growth factor receptor (EGFR), c-ros oncogene 1 receptor tyrosine kinase 1 (ROS1),
             anaplastic lymphoma kinase (ALK) mutations or ALK fusions are excluded. • For
             undocumented cases, fresh or archival tumor tissue is required for central
             confirmation of wild type EGFR status.

        11. ≤ 2 lines of systemic therapy Cohort A: Anti-PD-1/PD-L1 antibody refractory or
        resistant metastatic, non-squamous NSCLC 12. Radiographic progression per RECIST v1.1 on or
        after anti-PD-1/PD-L1 therapy as the most recent treatment for metastatic NSCLC 13. No
        other prior immunotherapies, including, but not limited to, anti-CTLA-4, anti-OX40 and
        anti-CD137 Cohort B: Anti-PD-1/PD-L1 antibody naïve metastatic, non-squamous NSCLC 14.
        Radiographic progression per RECIST v1.1 on or after systemic treatment for metastatic
        NSCLC without prior exposure to anti-PD-1/PD-L1 agent Cohort C, Cohort D: Metastatic or
        advanced Renal Cell Carcinoma (RCC) 15. Histologically or cytologically confirmed
        metastatic or advanced clear cell RCC, or RCC with a primary clear cell component Cohort C:
        Anti-PD-1/PD-L1 antibody refractory or resistant metastatic or advanced RCC 16.
        Radiographic progression per RECIST v1.1 on or after anti-PD-1/PD-L1 therapy as the most
        recent treatment for mRCC 17. ≤ 2 lines of systemic therapy including anti-PD-1/PD-L1
        antibody treatment 18. No other prior immunotherapies, including, but not limited to,
        anti-CTLA-4, anti-OX40 and anti-CD137 Cohort D: Metastatic or advanced RCC without prior
        systemic therapy Note: Cohort D will only enroll in China. 19. Systemic therapy is not
        available, is considered not suitable, or has been refused by the patient 20. Prior
        neoadjuvant/adjuvant therapy for RCC is acceptable if completed > 12 months prior to
        enrollment.

        Cohort E: Anti-PD-1/PD-L1 antibody naïve recurrent and platinum-resistant Epithelial
        Ovarian Cancer (OC) Note: Resistant to platinum-based therapy is defined as relapse 1-6
        months after last dose of platinum-based treatment.

        21. Histologically confirmed advanced ovarian cancer 22. No platinum-refractory disease (PD
        < 1 month of last dose of platinum-based chemotherapy) 23. No prior exposure to
        anti-PD-1/PD-L1 agent

        Exclusion Criteria:

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

               1. Unacceptable toxicity on prior anti-PD-1/PD-L1 treatment, defined as follows: a.
                  ≥ Grade 3 AE related to anti-PD-1/PD-L1 b. ≥ Grade 2 immune-related AE associated
                  with anti-PD-1/PD-L1 unless the AE resolved or was well controlled by withholding
                  the 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. c. CNS or ocular AE of any grade related to anti-PD-1/PD-L1 Note:
                  Patients with a prior endocrine AE are permitted to enroll if they are stably
                  maintained on appropriate replacement therapy and are asymptomatic.

               2. Active leptomeningeal disease or uncontrolled brain metastasis. Patients with
                  equivocal findings or with confirmed brain metastases are eligible for enrollment
                  provided that they are asymptomatic and radiologically stable without the need
                  for corticosteroid treatment for ≥ 4 weeks before first dose of study drugs. •
                  Patients with new asymptomatic CNS metastases detected at the screening scan must
                  receive radiation therapy and/or surgery for CNS metastases. o Following
                  treatment, these patients may then be eligible, provided all other criteria,
                  including those for patients with a history of brain metastases, are met.

               3. Active autoimmune diseases or history of autoimmune diseases that may relapse
                  (Appendix 5) Note: Patients with the following diseases are not excluded and may
                  proceed to further screening: a. Controlled Type I diabetes b. Hypothyroidism
                  (provided it is managed with hormone replacement therapy only) c. Controlled
                  celiac disease d. Skin diseases not requiring systemic treatment (eg, vitiligo,
                  psoriasis, alopecia) e. Any other disease that is not expected to recur in the
                  absence of external triggering factors

               4. Any active malignancy ≤ 2 years before first dose of study drugs except for the
                  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)

               5. Any condition that required systemic treatment with either corticosteroids (> 10
                  mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14
                  days before first dose of study drugs Note: Patients who are currently or have
                  previously been on any of the following steroid regimens are not excluded: a.
                  Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) b.
                  Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with
                  minimal systemic absorption c. Short course (≤ 7 days) of corticosteroid
                  prescribed prophylactically (eg, for contrast dye allergy) or for the treatment
                  of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused
                  by contact allergen)

               6. 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 first dose of study drugs

               7. History of interstitial lung disease, noninfectious pneumonitis or uncontrolled
                  diseases, including pulmonary fibrosis, acute lung diseases, etc.

               8. 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

               9. Known history of HIV infection

              10. Untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers with
                  HBV DNA > 500 IU/mL or active hepatitis C (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.

              11. Any major surgical procedure requiring general anesthesia ≤ 28 days before first
                  dose of study drugs

              12. Prior allogeneic stem cell transplantation or organ transplantation

              13. Any of the following cardiovascular risk criteria: a. Cardiac chest pain, defined
                  as moderate pain that limits instrumental activities of daily living, ≤ 28 days
                  before first dose of study drugs b. Symptomatic pulmonary embolism ≤ 28 days
                  before first dose of study drugs c. Any history of acute myocardial infarction ≤
                  6 months before first dose of study drugs d. Any history of heart failure meeting
                  New York Heart Association Classification (NYHA) III or IV (Appendix 7) ≤ 6
                  months before first dose of study drugs e. Any event of ventricular arrhythmia ≥
                  Grade 2 in severity ≤ 6 months before first dose of study drugs f. Any history of
                  cerebrovascular accident ≤ 6 months before first dose of study drugs g. 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 confirm result h.
                  Cardiac left ventricular ejection fraction (LVEF) ≤ lower limit of normal (LLN)
                  as assessed by echocardiography (ECHO). The same modality used at baseline must
                  be applied for subsequent evaluations. i. Any episode of syncope or seizure ≤ 28
                  days before first dose of study drugs

              14. Inadequately controlled hypertension (defined as systolic blood pressure > 150
                  mmHg and/or diastolic blood pressure > 100 mmHg)

              15. Hypersensitivity to tislelizumab or sitravatinib, to any ingredient in the
                  formulation, or to any component of the container

              16. Bleeding or thrombotic disorders or use of anticoagulants such as warfarin or
                  similar agents requiring therapeutic INR monitoring within 6 months before first
                  dose of study drugs

              17. 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

              18. Any herbal medicine used to control cancer within 14 days of first dose of study
                  drugs

              19. Toxicities (as a result of prior anticancer therapy) that have not improved to
                  baseline or stabilized, except for AEs not considered a likely safety risk (eg,
                  alopecia, neuropathy, and specific laboratory abnormalities)

              20. Administration of live vaccine ≤ 4 weeks prior to first dose of study drugs Note:
                  seasonal vaccines for influenza are generally inactivated vaccines and are
                  allowed. Intranasal vaccines are live vaccines and are not allowed.

              21. Underlying medical conditions or alcohol or drug abuse or dependence that will be
                  unfavorable for the administration of study drugs or affect the explanation of
                  drug toxicity or AEs; or expected insufficient compliance during the study
                  according to investigator's judgement

              22. Concurrent participation in another therapeutic clinical trial

              23. Inability to swallow capsules or disease significantly affecting gastrointestinal
                  function such as malabsorption syndrome, resection of the stomach or small bowel,
                  bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial
                  or complete bowel obstruction

              24. Spinal cord compression in one or more of the following criteria a. Not
                  definitively treated with surgery and/or radiation b. Treated but without
                  evidence that disease has been clinically stable for > 2 weeks prior to first
                  dose of study drugs

              25. Pregnant or breastfeeding woman
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with adverse events (AEs) and serious adverse events (SAEs) per NCI-CTCAE version 5.0
Time Frame:All AEs and SAEs will be reported until either 30 days after last dose of study drug(s) or initiation of new anticancer therapy, whichever occurs first. Immune-related should be reported until 90 days after the last dose of tislelizumab
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:BeiGene

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