Ensayos clínicos

Inclusion Criteria:

• Willing and able to provide informed consent signed by the study patient or legally acceptable representative, as specified by health authorities and institutional guidelines.
• Age of ≥ 18 years.
• Safety Lead-in: Must have histologically or cytologically documented advanced or metastatic solid tumors of any type who have progressed on standard systemic therapy and for which no effective therapy or standard of care exists. Patients with TNBC in the Safety Lead-in must meet eligibility criteria defined in cohorts A or B, and those with EC in the Safety Lead-in must meet eligibility criteria defined in cohort C.
• Cohorts A and B: Must have histologically or cytologically documented, advanced or metastatic TNBC as defined by ASCO-CAP guidelines (Allison 2020). Up to 15 patients in each cohort can have ER or PGR low positive disease as defined by ASCO-CAP guidelines, if the treating physician considers the patient not eligible for adjuvant endocrine therapy. TNBC is defined as ER/PGR positivity of < 1%, and ER/PGR low positive disease is defined by ER/PGR positivity of 1% to 10% (Allison 2020). (Note that the guidelines use PR as the abbreviation for progesterone receptor.) Cohort C: Must have histologically or cytologically documented, advanced or metastatic endometrial carcinoma.
• Cohort D: Must have histologically or cytologically confirmed advanced or metastatic, unresectable adenocarcinoma of the colon or rectum. All other histological types are excluded.
• Cohorts A and B: Must have progressed on at least 1 line, but no more than 3 lines, of cytotoxic therapy in the locally advanced or metastatic setting. For patients who have disease recurrence within 12 months of completion of adjuvant therapy, adjuvant chemotherapy will be considered first-line chemotherapy in the metastatic setting:
  • Patients in cohort A must have received prior immunotherapy in the metastatic setting;
  • Patients in cohort B must not have received prior therapy with an ICI or other immunotherapy in the metastatic setting.
• Cohort C: Patients must have progressed on 1 prior platinum-based chemotherapy regimen for EC. Participants may have received up to 1 additional line of platinum-based chemotherapy if given in the neoadjuvant or adjuvant setting and must not have received prior therapy with an ICI or other immunotherapy.
• Cohort D: Patients must have failed 2 lines of standard chemotherapies, including fluorouracil, oxaliplatin, and irinotecan. Failed chemotherapies are defined as the occurence of PD or intolerable toxicities during the treatment or after the last dose. Additional requirements:
  • All patients must have received treatment with an anti-VEGF antibody (e.g., bevacizumab, aflibercept, or ramucirumab);
  • Patients with RAS wild-type tumors must have received an anti-EGFR antibody treatment (e.g., cetuximab or panitumumab);
  • Each line of treatment for advanced disease until PD includes 1 or more cytotoxic chemotherapy drugs used for ≥ 1 cycle;
  • Previous adjuvant/neoadjuvant therapy is allowed. If relapse or metastasis occurred during the adjuvant/neoadjuvant treatment period or within 6 months after the completion of adjuvant treatment, that adjuvant/neoadjuvant therapy is considered as the failure of first line systemic chemotherapy for PD.
• Must have tumor tissue (fresh or archival tumor tissues as formalin-fixed paraffinembedded blocks or approximately 15 unstained slides) collected for retrospective analysis of PD-L1 expression level, and/or MSS/MSI status, and other exploratory biomarkers related to response and resistance. Submission of < 15 unstained slides is permitted, and patients may be enrolled after confirmation with the sponsor.
• ECOG performance status of 0 or 1.
• Expected survival of ≥ 12 weeks.
• Have measurable disease as defined by RECIST v1.1. Tumors that were treated with radiotherapy are not considered measurable per RECIST v1.1 unless there has been documented progression of those lesions.'
• Adequate organ function indicated by the following laboratory values:
  • Absolute neutrophil count of ≥ 1.5×10^9 /L;
  • Platelet count of ≥ 100×10^9 /L;
  • Hemoglobin ≥ 9 g/dL;
  • Serum total bilirubin ≤ 1.5× upper limit of normal (ULN) (total bilirubin must be < 3 × ULN for patients with documented Gilbert’s syndrome);
  • Patients without liver metastases must have ALT and AST ≤ 2.5 × ULN; patients with liver metastases must have ALT and AST ≤ 5 × ULN;
  • Urine protein ≤ 1+ by dipstick or 24-hour urine protein < 1 g/24 hours. Patients with 1+ proteinuria by dipstick must undergo 24-hour urine collection to assess urine protein level;
  • Serum creatinine < 1.5× ULN and creatinine clearance (CrCl) ≥60 mL/min per Cockcroft-Gault;
  • International normalized ratio (INR) and activated prothrombin time (aPTT) ≤ 1.5 ULN unless the patient is receiving anticoagulation therapy and INR and aPTT values are within the intended therapeutic range.
• For female patients of childbearing potential and male patients with partners of childbearing potential, agreement to use a highly effective form(s) of contraception that results in a low failure rate (< 1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 120 days after taking the last dose of study drug. Such methods include oral hormonal contraception (combined estrogen/progestogen or progestogen-only) associated with inhibition of ovulation together with a barrier method (e.g., diaphragm, always containing a spermicide), intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner, or sexual abstinence. Oral contraception should always be combined with an additional contraceptive method (i.e., barrier method) because of a potential interaction with the study drug. The same criteria are applicable to male patients involved in this clinical trial if they have a partner of childbirth potential, and male patients must always use a condom. All female patients will be considered to have childbearing potential unless the said female patient has had natural menopause, induced artificial menopause, or undergone sterilization (hysterectomy and bilateral salpingo-oophorectomy).
• PD-L1 status, as determined locally, must be documented for each patient in Cohorts A, B, and C, and MSS/MSI status must be documented for each patient in Cohorts C and D. The results should be available in the source documentation and be those used to make treatment decisions for the patient. A redacted copy of the local results should accompany the archival tumor samples submitted as part of the protocol.

Exclusion Criteria:

• Adverse events due to previous anti-tumor therapy have not recovered to ≤ CTCAE Grade 1, except alopecia and peripheral neurotoxicity with ≤ CTCAE Grade 2.
• Other malignancies except for non-melanoma skin cancer, in situ cervical cancer, or bladder cancer (Tis and T1) that have been adequately treated during the 5 years prior to screening.
• Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of SD for 14 days or longer; patients requiring steroids within 4 weeks prior to start of study treatment are excluded.
• Systemic anti-neoplastic therapies or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy, and immunotherapy.
• Systemic small molecule-targeted therapies (e.g., tyrosine kinase inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug.
• Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of study drug.
• Brachytherapy (i.e., implantation of radioactive seeds) within 60 days prior to the first dose of study drug.
• Mean QT interval corrected by the method of Fridericia (QTcF) ≥ 480 ms.
  • EXCEPT for Safety Lead-in and Cohort A, patients who have previously received any anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, and anti-cytotoxic T lymphocyte-associated antigen-4 antibody (or any other antibody acting on T-cell co-stimulation or checkpoint pathways) in the metastatic setting are excluded.
• Any condition that requires 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), with the following exceptions:
  • Adrenal replacement (dose of ≤10 mg daily of prednisone or equivalent);
  • Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with minimal systemic absorption;
  • Short course (≤ 7 days) of corticosteroid prescribed prophylactically (e.g., for contrast dye allergy) or for the treatment of a non-autoimmune condition (e.g., delayed-type hypersensitivity reaction caused by contact allergen).
• 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 (e.g., vitiligo, psoriasis, or alopecia).
• Any other disease that is not expected to recur in the absence of external triggering factors.
• Live vaccine ≤ 28 days before the first dose of study drug(s):
  • Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.
• Active infection requiring systemic antibacterial, antifungal, or antiviral therapy (not including antiviral therapy for hepatitis) for ≤ 14 days prior to the first dose of study drug(s) or a positive test for severe acute respiratory syndrome coronavirus 2 in the absence or presence of symptoms.
• Active tuberculosis that is being treated with anti-tuberculosis therapy or that have received treatment with anti-tuberculosis therapy within 1 year before the first drug administration.
• History or presence of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases including but not limited to pulmonary fibrosis, acute lung diseases, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, severely impaired lung function, and other patients with conditions that may interfere with the detection and treatment of suspected drug-related pulmonary toxicity; radiation pneumonitis in the radiation therapy area is allowed.
• Untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers with HBV DNA > 500 IU/mL (or > 2500 copies/mL) or active hepatitis C at screening:
  • Patients with inactive hepatitis B surface antigen (HBsAg carriers who are treated and have stable HBV [HBV DNA 2 weeks before the first dose of study drug(s);
  • Patients with a negative hepatitis C virus (HCV) antibody test at screening or a positive HCV antibody test followed by a negative HCV ribonucleic acid (RNA) test at screening are eligible. The HCV RNA test should be performed only for patients who tested positive for the HCV antibody.
• Known history of human immunodeficiency virus (HIV) infection.
• Major surgery within 60 days before the first drug administration. Patients must have recovered adequately from the toxicity and/or complications from the intervention prior to the first dose of study drug(s).
• Patients who had any surgical or invasive therapy (except for puncture biopsy and venous catheterization) within 4 weeks before the first drug administration, or have unhealed wounds, ulcers, or fractures.
• Prior allogeneic stem cell transplantation or organ transplantation.
• Any of the following cardiovascular risk factors:
  • Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living (ADL), ≤ 28 days before the first dose of study drug(s);
  • Pulmonary embolism or venous thromboembolism ≤ 6 months before the first dose of study drug(s);
  • Acute myocardial infarction ≤ 6 months before the first dose of study drug(s);
  • Heart failure meeting New York Heart Association Function Classification III or IV ≤ 6 months before the first dose of study drug(s); left ventricular ejection fraction (LVEF) of < 50%;
  • Ventricular arrhythmia Grade ≥ 2 in severity ≤ 6 months before the first dose of study drug(s);
  • Cerebrovascular accident ≤ 12 months before the first dose of study drug(s);
  • Uncontrolled hypertension that cannot be managed by standard antihypertension medications, which is specified as systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mmHg. The patient must have blood pressures below both limits. Repeated assessments are permitted;
  • Syncope or seizure ≤ 28 days before the first dose of study drug(s).
• Inability to swallow capsules, or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the complete small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
• Received strong inducers of cytochrome P450, family 3, subfamily A (CYP3A) taken within 2 weeks (or 5 times the t1/2 of the drug, whichever is longer) prior to the first study treatment.
• Active gastrointestinal and duodenal ulcers, ulcerative colitis, and other gastrointestinal disease or unresectable tumors with active bleeding; other conditions that the investigator determines to possibly cause gastrointestinal bleeding, perforation, and other conditions; or prior gastrointestinal perforation or gastrointestinal fistula that has not recovered after surgical treatment.
• History or presence of hemorrhage from any site (such as melena, hematemesis, hemoptysis, fresh in stool) within 2 months before the screening.
• Tumor invasion of a large vascular structure (e.g., pulmonary artery, the superior or inferior vena cava).
• History of arterial thrombus or deep vein thrombosis within 6 months prior to the first drug administration; patients with implanted intravenous infusion pump or catheter-related thrombosis or superficial vein thrombosis, except for patients with stable thrombus after routine anticoagulant therapy.
• Stroke event and/or transient ischemic attack within 12 months.
• Women who are pregnant or lactating.
• Patients with known allergy to any of the components of tislelizumab or fruquintinib preparations including tartrazine (E102) and sunset yellow (E110) or who have any previous history of severe allergy to monoclonal antibodies.
• Patients must not have received prior treatment with a VEGFR tyrosine kinase inhibitor.
  • Except for Cohort D (MSS mCRC), patients must not have received prior treatment with a VEGFR antibody.

Eligibility last updated 6/1/22.  Questions regarding updates should be directed to the study team contact.