MC# 21-02 - An Open-Label Phase Ib/II Study of Surufatinib in Combination with Tislelizumab in Subjects With Advanced Solid Tumors

  • Agent(s): Surufatinib
  • Disease Type(s): Colorectal, Gastric, Sarcoma, Lung-SCLC, Gastroesophageal Junction, Neuroendocrine, Thyroid
  • Phase(s): I, II
  • Drug Classification(s): Immunotherapy, Monoclonal Antibody, Targeted Therapy
  • Molecular Target(s): PD-1, VEGFR1, VEGFR2, VEGFR3, FGFR1

Mechanism of Action

Tislelizumab is a monoclonal antibody directed against the negative immunoregulatory human cell surface receptor PD-1 that binds to PD-1 and inhibits the binding of PD-1 to the PD-1 ligands PD-L1 and PD-L2.  This prevents the activation of PD-1 and its downstream signaling pathways.  This may restore immune function through the activation of both T cells and T-cell-mediated immune responses against tumor cells.

Surufatinib is a small molecule inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, and the fibroblast growth factor receptor type 1 (FGFR1) that binds to and inhibits VEGFRs and FGFR1 thereby inhibiting VEGFR- and FGFR1-mediated signal transduction pathways.  This leads to a reduction of angiogenesis and tumor cell proliferation in VEGFR/FGFR1-overexpressing tumor cells.

Purpose

In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of the combination of Surufutanib when given with Tislelizumab
  • How much of the study drugs, Surufatinib and Tislezimuab, are absorbed into the blood and how fast they are removed
  • If research tests can be used in the future to predict who will benefit from the combination of Surufatinib and Tislelizumab
Inclusion Criteria
  1. Willing and able to provide informed consent signed by study patient or legally acceptable representative, as specified by health authorities and institutional guidelines
  2. ≥18 years of age
  3. Part 1: have evaluable lesions (according to Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1]);
  4. Part 2: have measurable lesions (according to RECIST v1.1)
  5. Absolute neutrophil count (ANC) of ≥1.5×109/L, platelet count of ≥100×109/L, and hemoglobin ≥9 g/dL
  6. Serum total bilirubin (TBIL) <1.5 times the upper limit of normal (ULN)
  7. Proteinuria <2+ by urinalysis; if proteinuria ≥2+, proteinuria <1 g by 24-hour urinary protein test is required
  8. Patients without liver metastases: must have alanine aminotransferase (ALT) and/or AST levels ≤2.5 times the ULN.  Patients with liver metastases: must have ALT and AST levels ≤5 times the ULN
  9. Creatinine clearance ≥60 mL/min, as calculated by the Cockcroft-Gault formula
  10. International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) ≤1.5 × ULN
  11. Have a performance status of 0 or 1 on the ECOG scale
  12. Female patients of childbearing potential and male patients with partners of childbearing potential: agree to use a highly effective form(s) of contraception that results in a low failure rate when used consistently and correctly.

Dose Escalation:

  1. Histologically or cytologically documented, locally advanced or metastatic solid malignancy of any type that has progressed on or are intolerant of standard therapies and for which no curative therapy exists

Dose Expansion:

  1. Histologically or cytologically documented, locally advanced or metastatic
  • Cohort A: adenocarcinoma of the colon or rectum that is microsatellite stable. Patients must have progressed on, or had discontinued due to intolerable toxicity to the following agents: fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF targeted therapy, and if RAS wild-type and anti-epidermal growth factor receptor antibody therapy. Treatment progression is defined as disease progression during or within 3 months after the last dose of standard therapy. Prior therapy could have included adjuvant chemotherapy if a tumor had recurred within 6 months after the last administration of treatment.  Note: Eligibility also requires knowledge of tumor RAS status (wild type or mutant) as reported by investigators.
  • Cohort B: progressive, low, or intermediate grade (Grade 1 or Grade 2) NETs of thoracic (B1) or GEP (B2) origins. Patients must have radiological documentation of progression of disease in the last 6 months prior to the initiation of study treatment and must have progressed on at least 1 line of standard therapy for metastatic disease
  1. For NETs originating from the thorax,
    1. Grade 1 is defined as <2 mitoses/10 high-power field (HPF) and no necrosis
    2. Grade 2 is defined as 2-10/10 HPF and/or foci of necrosis
  2. For NETs originating from GEP,
    1. Grade 1 is defined as <2 mitoses/10 HPF and/or <3% Ki-67 index
    2. Grade 2 is defined as 2-20/10 HPF and/or 3-20% Ki-67 index
  3. If the mitotic ratio and Ki-67 index correspond to different grade, the higher grade is used to assign classification.
  • Patients who have functioning NETs and have been on a stable dose of an SSA for a minimum of 2 months prior to the first dose of study treatment for control of their secretory symptoms will be eligible.  NOTE: Prior therapy with a somatostatin analog is considered 1 line of therapy.
  • Cohort C: SCLC that has progressed on standard first line chemotherapy treatment
  • Cohort D: Adenocarcinoma of the stomach or gastroesophageal junction and have progressed on at least 2 prior lines of therapy.  Must be microsatellite stable and have tumor stain for PD-L1 by combined positive score ≥5%.
  • Cohort E: ASPS (E1) or UPS (E2).  Patients must have radiological documentation of disease progression in the last 3 months prior to the initiation of study treatment and have progressed on or had discontinued due to intolerable toxicity to at least 1 line of standard therapy or be unsuitable for standard frontline cytotoxic chemotherapy.
  • Cohort F: Anaplastic thyroid cancer (a diagnosis that is noted to be consistent with anaplastic thyroid cancer is acceptable) that is considered not curable by resection. Patients with a BRAFV600E mutation must have previously been treated with 1 line of systemic therapy with a BRAF-targeted therapy. Prior cytotoxic chemotherapy and radiation for local disease control is not considered a prior line of therapy.
  1. Patients in dose expansion: must be able to provide a minimum of 10 unstained slides for central confirmation of PD-L1 expression and microsatellite stability testing. In the event archived tumor samples are not available for testing, patients may opt for a core needle biopsy prior to beginning protocol therapy if medically feasible. Patients in Cohort F must also undergo core needle biopsy.
Exclusion Criteria
  1. AEs due to previous antitumor therapy has not recovered to CTCAE ≤Grade 1, except alopecia and peripheral neurotoxicity with CTCAE ≤Grade 2
  2. Part 2 patients with CRC (Cohort A), NETs (Cohort B), and ASPS (Cohort E1): previous treatment with anti-PD-1, anti-PD-L1/L2 antibodies, anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) antibody, or any other antibody acting on T cell costimulatory or checkpoint pathway.  Note: Patients in the Part 1 and patients in Part 2 Cohorts C (SCLC), D (gastroesophageal junction or Gastric cancer), or E2 (UPS) may have received previous treatment with anti-PD-1, anti-PD-L1/L2 antibodies, CTLA-4 antibody, or any other antibody acting on T cell costimulatory or checkpoint pathway.
  3. Previous treatment with surufatinib
  4. Uncontrollable hypertension, defined as systolic blood pressure (BP) ≥140 mmHg and/or diastolic BP ≥90 mmHg
  5. Gastrointestinal disease or condition that investigators suspect may affect drug absorption, including, but not limited to, active gastric and duodenal ulcers, ulcerative colitis and other digestive disease, gastrointestinal tumor with active bleeding, or other gastrointestinal conditions that may cause bleeding or perforation by investigator's discretion
  6. History or presence of a serious hemorrhage (>30 mL within 3 months), hemoptysis (>5 mL blood within 4 weeks), or life-threatening thromboembolic event within 6 months
  7. Clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction within 6 months prior to enrollment, severe/unstable angina pectoris or coronary artery bypass grafting, congestive heart failure according to the New York Heart Association classification ≥2, ventricular arrhythmias which need drug treatment, or left ventricular ejection fraction (LVEF) <50%
  8. QT interval corrected by the method of Fredericia (QTcF) ≥480 milliseconds
  9. Other malignant tumors within 5 years prior to screening (except cured basal-cell carcinoma or squamous carcinoma at skin and cervical carcinoma in situ)
  10. Antitumor therapy received within 2 weeks or 5 half-lives, whichever is shorter, prior to the initiation of the investigational treatment
  11. Palliative radiotherapy for a bone metastasis lesion within 2 weeks prior to the initiation of the study treatment
  12. Strong inducers or inhibitors of Cytochrome P450, family 3, subfamily A (CYP3A) taken within two weeks prior to the first study treatment
  13. Any clinically significant active infection, including, but not limited to, known human immunodeficiency virus (HIV) infection
  14. Known history of active viral hepatitis
    • Patients with detectable HBsAg or detectable HBV DNA should be managed per treatment guidelines
    • Patients with a negative HCV antibody test at Screening or positive HCV antibody test followed by a negative HCV RNA test at Screening are eligible
  15. Brain metastases and/or leptomeningeal disease and/or spinal cord compression untreated with surgery and/or radiotherapy and without clinical imaging evidence of stable disease (SD) for 14 days or longer.  Patients requiring steroids within 4 weeks prior to start of study treatment will be excluded.
  16. Used corticosteroids (prednisone or other steroids with equivalent efficacy at a dose of >10 mg/day) or other immunosuppressants for systemic therapy within 2 weeks before the first drug administration. Nasal  spray,  inhaled,  or  other  topical  steroids  are allowed (ie, ≤10 mg/day of prednisone or other glucocorticoids at an equivalent dose)
  17. For patients with NETs: administration of SSAs in the absence of secretory symptoms discontinued at least 4 weeks before the first dose of study treatment;
  18. Active autoimmune diseases or history of autoimmune diseases that may relapse with the following exceptions:
    • Controlled Type 1 diabetes
    • Hypothyroidism (provided it is managed with hormone-replacement therapy only)
    • Controlled celiac disease
    • Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, or alopecia)
    • Any other disease that is not expected to recur in the absence of external triggering factors
  19. Any live or attenuated live vaccine within 4 weeks prior to first dosing or planned for the duration of the study
  20. Major surgeries within 60 days prior to first dosing
  21. Uncontrollable malignant pleural effusion, ascites, or pericardial effusion (defined as ineffectively controlled by diuresis or puncture drainage judged by investigators)
  22. High risk of bleeding at screening due to tumor invasion into major vessels, such as pulmonary artery, the superior vena cava, or the inferior vena cava, as determined by investigators
  23. Arterial thrombosis or thromboembolic events (including stroke and/or transient ischemic attack) within 12 months prior to first dosing
  24. Patients with a history of deep venous thrombosis within 6 months prior to first dose, unless they have been on a stable dose of anti-coagulation for at least 4 weeks prior to first dosing or have completed a planned course of anticoagulation
  25. Clinically significant abnormal electrolyte abnormality as judged by investigators
  26. Active severe infection or with an unexplained fever >38.3°C during screening or the first day of study treatment administration; refer to protocol for information for coronavirus disease 2019 (COVID-19) risk assessment
  27. Active pulmonary tuberculosis and receiving anti-tuberculosis treatment or with anti- tuberculosis treatment within 1 year prior to first dosing
  28. History of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, severe impairment of the lung function, etc. that may interfere with the detection and treatment of suspected drug-related lung toxicity, except radiation pneumonitis in the radiation treatment area
  29. Female patients who are pregnant or breastfeeding
  30. History of allergies to any ingredient of surufatinib or its capsule shell, including tartrazine (E102), tislelizumab, or to any mono-antibody
  31. Any condition by which investigators judge patients not suitable to participate in this study

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://www.clinicaltrials.gov/ct2/show/NCT04579757

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Re: MC# 21-02