2025-521043-20-00
尚未招募
2/3 期
A Phase 2/3, multicenter, randomized open-label study of zanzalintinib vs everolimus in participants with previously treated, unresectable, locally advanced or metastatic neuroendocrine tumors
概览
- 阶段
- 2/3 期
- 状态
- 尚未招募
- 入组人数
- 8
- 试验地点
- 4
- 主要终点
- Progression-free survival per RECIST 1.1 as assessed by blinded independent central review
概览
简要总结
To evaluate progression-free survival by blinded independent central review of zanzalintinib versus everolimus
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 是
入选标准
- •Histologically confirmed, locally advanced/unresectable or metastatic, well-differentiated Grade 1, 2, or 3 NETs of pancreatic origin or extra-pancreatic origin (extra-pancreatic includes primary tumor sites of non-pancreatic gastrointestinal, lung, thymus, other, and unknown primary site). • Documentation of histology from a primary or metastatic tumor site is allowed. • Functional (ie, associated with symptoms or a clinical syndrome related to hormone secretion by the tumor) or nonfunctional tumors are allowed. • SSTR positive and negative tumors are allowed. Note: SSTR expression status will be collected. For participants without known SSTR status, a SSTR-scan (preferred PET-based) will be required during screening to determine SSTR status. Refer to Section 5.6.6.4 for recommended SSTR-imaging methods.
- •Adequate organ and marrow function, based upon all of the following assessments: a. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 x 109/L) without granulocyte colony stimulating factor support within 2 weeks before screening laboratory sample collection. b. Platelets ≥ 100,000/mm3 (≥ 100 x 109/L) without transfusion within 2 weeks before screening laboratory sample collection. c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion within 2 weeks before screening laboratory sample collection. d. International Normalized Ratio (INR) ≤ 1.3 and activated partial thromboplastin time (aPTT) ≤ 1.2 × upper limit of normal (ULN). e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN. For all participants with documented liver metastases: ALT and AST ≤ 5 × ULN. f. Alkaline phosphatase (ALP) ≤ 3 × ULN. For participants with documented liver or bone metastases ≤ 5 × ULN. g. Total bilirubin ≤ 1.5 × ULN. For participants with Gilbert’s disease ≤ 3 × ULN. h. Calculated creatinine clearance ≥ 30 mL/min (≥ 0.50 mL/sec) using the Cockcroft-Gault equation. i. Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol), or 24-hour urine protein < 1 g. j. Negative hepatitis B surface antigen (HBsAg) test. k. Negative hepatitis C virus (HCV) antibody test, or positive HCV antibody test followed by a negative HCV RNA test and no ongoing anti-HCV therapy. Note: The HCV RNA test only needs to be performed for participants who have a positive HCV antibody test. l. Fasting serum cholesterol ≤ 300 mg/dL (≤ 7.75 mmol/L) AND fasting triglycerides ≤ 2.5 x ULN. If either threshold is exceeded treatment can only start after initiation of lipid lowering treatment. m. Hemoglobin A1c (HbA1c) ≤ 8%. For participants with a condition (eg, hemoglobin variant) that affects the interpretation of HbA1c results, a fasting glucose ≤ 160 mg/dL (≤ 8.9 mmol/L). n. Left ventricular ejection fraction (LVEF) assessment with documented LVEF ≥ 50% by transthoracic echocardiogram (TTE) within 6 months before randomization. o. Corrected QT interval calculated by the Fridericia formula (QTcF) ≤ 480 ms per electrocardiogram (ECG) within 28 days before randomization. Note: Triplicate ECG evaluations may be performed and the average of these consecutive results for QTcF can be used to determine eligibility.
- •Female participants and male participants with female partner(s) are eligible if the participant agrees to follow guidance to use highly effective methods of contraception during the course of the study and for the following durations after the last dose of study treatment (whichever is later): • Through 186 days after the last dose of zanzalintinib for female participants of childbearing potential or through 96 days after the last dose of zanzalintinib for male participants. • Through 8 weeks after the last dose of everolimus for female participants of childbearing potential or through 4 weeks after the last dose of everolimus for male participants. In addition, participants must agree not to donate sperm or eggs (ova, oocyte) for the purpose of reproduction during these same periods.
- •Female participants of childbearing potential must not be pregnant or breastfeeding at screening. Female participants are considered to be of childbearing potential unless one of the following criteria are met: documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a female participant > 45 years-of-age in the absence of other biological or physiological causes. In addition, females < 55 years-of-age must have a serum follicle stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause).
- •Allowed prior lines of therapy, based on the site of NET and functional status: a. Participants with a diagnosis of pNET and nonfunctional epNET can have received up to one line of prior systemic anticancer treatment for NET. b. Participants with functional epNET must have received one, and no more than one, line of prior systemic anticancer therapy (PRRT or chemotherapy) for NET. Notes: - Prior treatment with SSA is allowed and does not count towards the requirement of prior line of systemic anticancer therapy. - Continuation of treatment with SSA while on study treatment is only allowed for participants with functional NETs who have been on a stable dose of SSA for at least 8 weeks before randomization. - Re-treatment with the same agent does not count towards the number of allowed prior systemic therapies.
- •Documented radiographic disease progression per RECIST 1.1, as assessed by the Investigator based on imaging assessments (computed tomography [CT] or magnetic resonance imaging [MRI]) within 12 months before randomization. Note: The radiologic imaging reports and/or clinic notes indicating growth of existing lesions or development of new lesions must be provided during screening.
- •Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1; Eisenhauer et al, 2009) as determined by the Investigator. Note: Previously irradiated or embolized tumor lesions can be considered as target lesions only if progression has been unequivocally documented at that site since radiation.
- •Archival tumor tissue is required, if available. If archival tumor tissue is not available, a fresh biopsy may be submitted if it can be safely and feasibly obtained. Every attempt should be made to provide tumor tissue. Specific requirements for tumor tissue samples will be described in the Laboratory Manual.
- •Recovery to baseline or ≤ Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v5 from AE(s) related to any prior treatments unless AE(s) are clinically nonsignificant and/or stable on supportive therapy in the opinion of the Investigator.
- •Age 18 years or older on the day of consent.
排除标准
- •Histologically confirmed neuroendocrine carcinomas (including small cell lung cancer), medullary thyroid cancer, pheochromocytoma, paraganglioma, Merkel cell carcinoma, and mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN).
- •The participant has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: a. Cardiovascular disorders: i. Congestive heart failure (CHF) New York Heart Association class 2 or higher, unstable angina pectoris, new-onset angina, serious cardiac arrhythmias (eg, ventricular flutter, ventricular fibrillation, Torsades de pointes). ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment. iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction, pulmonary embolism (PE), and other ischemic events within 6 months before randomization. iv. Deep vein thrombosis (DVT) within 3 months before randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before randomization. b. GI disorders including those associated with a high risk of perforation or fistula formation: i. Tumors invading the GI tract from external viscera (eg, adjacent organs). ii. Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis. iii. Acute obstruction of the bowel, gastric outlet, or pancreatic or biliary duct within 6 months before randomization unless cause of obstruction is definitively managed and participant is asymptomatic. iv. Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra abdominal abscess within 6 months before randomization. Note: Complete healing of an intra-abdominal abscess must be confirmed before randomization. v. Ascites, pleural effusion, or pericardial fluid requiring drainage ≤ 28 days before randomization. c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding (eg, gastrointestinal or pulmonary hemorrhage) within 3 months before randomization. d. Other clinically significant disorders such as: i. Serious non-healing wound/ulcer/bone fracture per Investigator judgment. ii. Active infection requiring systemic antimicrobial treatment (antibiotics, antimycotic, antiviral). Note: Prophylactic antibiotic treatment is allowed. iii. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. Note: HIV testing will be performed at screening if and as required by local regulation. iv. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. v. Pharmacologically uncompensated/symptomatic hypothyroidism. Note: Asymptomatic hypothyroidism only requiring hormone replacement is allowed. vi. Moderate to severe hepatic impairment (NCI-Organ Dysfunction Working Group [ODWG] criteria) or known cirrhosis. vii. Requirement for hemodialysis or peritoneal dialysis. viii. History of solid organ or allogeneic stem cell transplant.
- •Inability or unwillingness to swallow study medications or presence of gastrointestinal condition that might affect the absorption of study drug (eg, clinically significant malabsorption syndrome).
- •Previously identified allergy or hypersensitivity to active pharmaceutical ingredient or any component of either study treatment formulations.
- •Any other active malignancy within 2 years prior to randomization, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy (eg, basal or squamous cell skin cancer, or carcinoma in situ of the breast). Incidentally diagnosed prostate cancer is allowed if assessed as stage ≤ T2N0M0 and Gleason score ≤
- •Administration of a live, attenuated vaccine within 30 days of randomization and during treatment. Note: If feasible, approved non-live vaccines for SARS-CoV-2 should be administered at least 2 weeks before randomization
- •Prior treatment with a VEGFR-targeting tyrosine kinase inhibitor (eg, sunitinib) or an mTOR inhibitor (eg, everolimus).
- •Systemic chemotherapy and any liver-directed or other ablative therapy within 4 weeks before randomization. Note: Prior treatment with hepatic artery embolization (including bland embolization, chemoembolization, and selective internal radiation therapy) or ablative therapies is allowed if measurable disease remains outside of the treated area or if there is documented disease progression in a treated site.
- •Systemic radionuclide therapy within 6 weeks before randomization.
- •Radiation therapy for bone metastases within 2 weeks, any other radiation therapy, except as indicated above, within 4 weeks before randomization. Note: Participants with clinically relevant ongoing complications from prior radiation therapy are not eligible.
结局指标
主要结局
Progression-free survival per RECIST 1.1 as assessed by blinded independent central review
Progression-free survival per RECIST 1.1 as assessed by blinded independent central review
次要结局
- 1. Objective response rate per RECIST 1.1 as assessed by blinded independent central review
- 2. Overall survival
研究者
Exelixis Inc.
Scientific
Exelixis Inc.
研究点 (4)
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