Patient case: 58-year-old female with endometrial cancer; genetic feature: PIK3R1

Clinical trial: Fruquintinib in Combination With Sintilimab in Patients With Advanced Solid Tumor

Summary: This study is composed of dose escalation stage and dose expansion stage. In dose escalation stage, patients with advanced solid tumor will be enrolled and administrated with Fruquintinib in combination with Sintilimab. The MTD ( maximum tolerated dose) or RP2D ( Recommended Phase 2 Dose) will be determined in this stage. In dose expansion stage, additional patients will be enrolled and be treated at RP2D to evaluate the safety, tolerability and efficacy.

Detailed description: This study is composed of dose escalation stage and dose expansion stage. In dose escalation stage, 9-12 patients with advance solid tumor will be sequentially enrolled in Cohort A (Fruquintinib 3 mg QD (once a day), oral dosing, 3 weeks on/1 weeks off+Sintilimab 200mg Q4W(4 times a week), intravenous dosing) and Cohort B (Fruquintinib 4 mg QD, oral dosing, 3 weeks on/1 week off+Sintilimab 200mg Q4W, intravenous dosing). The MTD or RP2D will be determined in this stage. In dose expansion stage, 75 patients with advanced solid tumor will be enrolled and treated with RP2D. Efficacy, safety and tolerability will be assessed and PK (Pharmacokinetics) analysis will be performed in this study.

Eligibility: Inclusion Criteria:
  -  Signed informed consent;
  -  18-75 years old; BMI≥18.5;
  -  Histological or cytological diagnosed unresectable or metastatic advanced solid tumor ( including hepatic cell cancer, ovarian cancer, endometrial cancer, thymic cancer , NSCLC and renal cancer) ;
  -  Standard of care failed (disease progressed after standard of care or not tolerated for standard of care or no standard of care available or not eligible for standard of care;
  -  ECOG (Eastern Cooperative Oncology Group) performance status of 0-1;
  -  Child-Pugh score of A (e.g. ＜7);
  -  Measurable lesions per the response evaluation criteria (RECIST 1.1)(Patients with only evaluable lesions are eligible for dose escalation stage);If the patient had regional therapy on the only lesion she/he has, it must have imaging evidence confirming disease progression after the regional therapy;
  -  The test value for bone marrow, liver and renal function evaluation within 7 days prior to first dosing should meet the requirements below:
  -  ANC(Absolute Neutrophil Count) ≥1.5×109/L and Plt ≥100×109/L and hemoglobin ≥90g/L;
  -  TBIL≤1.5 ×ULN;(Upper Limit of Normal)
  -  ALT(Alanine Transaminase) and AST (Aspartate Transaminase) ≤1.5×ULN for patients without metastasis at liver; ALT and AST ≤3×ULN for patients without metastasis at liver;
  -  Albumin≥28g/L;
  -  Cr≤1.5×ULN or Clearance of Creatinine Rate ≥60ml/min (calculated by Cockcroft-Gault formula);
  -  Proteinuria ＜2+ by urinalysis; if Proteinuria ≥2+, proteinuria ＜1g by 24-hours urinary protein test is required;
  -  Life expectancy of more than 12 weeks;
  -  Negative of blood pregnancy test within 7 days prior to first dosing for fertile female patients. Fertile female and male patients agree to use effective contraceptive methods during the study and within 6 months post to the last dose, such as double barrier contraception, condoms, oral or injection contraceptives, intrauterine devices, abstinence, etc. All female patients will be considered fertile unless the female patient has natural menopause or has undergone artificial menopause or sterilization (hysterectomy, bilateral appendage resection);
  Exclusion Criteria:
  -  The adverse events due to previous anti-tumor therapy has not recovered to ≤ CTCAE Grade 1, except alopecia and peripheral neurotoxicity with ≤ CTCAE grade 2 caused by platinum chemotherapy;
  -  Suffering with other malignant tumors within 5 years prior to screening (expect cured basal cell carcinoma or squamous carcinoma at skin, cervical carcinoma in situ) only for patients at dose expansion stage;
  -  Fibrolamellar hepatocellular carcinoma or sarcomatoid hepatocellular carcinoma confirmed by histology diagnosis;
  -  Central nervous system (CNS) metastasis in previous or screening;
  -  Systematic anti-tumor therapy with approved or investigational drugs within 4 weeks prior to first dosing, including but not limited to : chemotherapy (A 2-week wash-out period required for oral fluorouracil), endocrine therapy, and bio-immunotherapy, targeted therapy (A 2-week or 5-half-lives wash-out period for small molecule target therapy) and traditional Chinese medicine (limited to the traditional Chinese medicine with clear indication for anti-tumor; a 1-week wash-out period required prior to first dosing);
  -  Radical radiotherapy (more than 25% bone marrow involved) within 4 weeks prior to first dosing;
  -  Brachytherapy (such as radioactive beads implantation) within 60 days prior to first dosing;
  -  Any therapy with anti-PD-1,or anti-PD-L1/l2 antibodies or anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) antibody (or any other antibody acting on T cell costimulatory or checkpoint pathway) or VEGFR inhibitor treatment in previous;
  -  Steroids (more than 10 mg/ tiprednisone or other equivalent hormones) or other immunosuppressive agents for systemic therapy within 4 weeks prior to first dosing, except nasal spray, inhaled or other topical use of steroid (i.e. no more than 10mg/ tiprednisone or equivalent doses of other corticosteroids);
  -  History of any active autoimmune disease or autoimmune disease, including but not limited to interstitial pneumonia, uveitis, inflammatory bowel disease, hepatitis, pituitary inflammation, vasculitis, systemic lupus erythematosus, etc. (except patients with hypothyroidism that can be controlled only by hormone replacement therapy and patients with type I diabetes who only need insulin replacement therapy);
  -  Any live or attenuated live vaccine within 4 weeks prior to first dosing or planned for the duration of the study;
  -  Major surgeries within 60 days prior to first dosing;
  -  Any surgery or invasive treatment (except puncture biopsy, intravenous catheterization), or unhealed wounds, ulcers, fractures within 4 weeks prior to first dosing;
  -  Uncontrollable malignant pleural effusion, ascites or pericardial effusion (defined as ineffectively controlled by diuresis or puncture drainage judged by investigators) ;
  -  Drug uncontrollable hypertension, defined as systolic blood pressure ≥ 140 mmHg and / or diastolic blood pressure ≥ 90 mmHg;
  -  Any disease or condition affecting drug absorption, or inability to take the investigational drug orally;
  -  CYP3A4 inducers or inhibitors, P-gp or BCRP (Breast Cancer Resistant Protein) substrates were taken within 2 weeks or less than 5 half-lives (whichever was longer) prior to first dosing
  -  The patients have active ulcer of stomach and duodenum, ulcerative colitis and other digestive tract diseases or unresectable tumors with active bleeding, or other conditions that may cause gastrointestinal bleeding and perforation, as judged by investigators; or the existence of gastrointestinal perforation or gastrointestinal fistula uncured post to previous surgical treatment;
  -  Patients with evidence or history of propensity to thrombus or hemorrhage within 2 months prior to first dosing, regardless of severity;
  -  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;
  -  Arterial thrombosis or deep venous thrombosis within 6 months prior to first dosing, or thromboembolic events (including stroke and/or transient ischemic attack) within 12 months prior to first dosing;
  -  Cardiovascular diseases of significant clinical significance, including, but not limited to acute myocardial infarction, severe/unstable angina pectoris or coronary artery bypass grafting within 6 months prior to first dosing, congestive heart failure with New York Heart Association (NYHA) grade ≥ 2；Left ventricular ejection fraction (LVEF) ＜50%;
  -  Clinically significant abnormal electrolyte abnormality as judged by investigators;
  -  Active infection or fever of unknown origin prior to first dosing (body temperature > 38.5℃) at screening;
  -  Patients with active pulmonary tuberculosis receiving anti-tuberculosis treatment or with anti-tuberculosis treatment within 1 year prior to first dosing;
  -  History of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, severe impairment of the lung function, etc., which may interfere with the detection and treatment of suspected drug-related lung toxicity, except radiation pneumonitis in the radiation treatment area;
  -  Confirmed human immunodeficiency virus (HIV) infection;
  -  Clinically significant liver disease, including active viral hepatitis [HBsAg and/or HbcAb is positive and HBV (hepatitis B virus) DNA > 1000 copies/ mL or > 200 IU/mL; HCV(hepatitis C virus) antibody positive and HCV RNA positive], or other active hepatitis, clinically significant moderate to severe cirrhosis;
  -  Any unapproved drug taken within 4 weeks prior to first dosing.
  -  Female patients with pregnancy or breastfeeding;
  -  History of allergies to any ingredient of Sintilimab or Fruquintinib or significant allergy history to any mono-antibody;
  -  Any condition by which investigators judge patients not suitable to participate in this study

Relevance to patient case: not relevant