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
- Trial ID
- 2025-521043-20-00
- Protocol
- XL092-311
- Sponsor
- Exelixis Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to evaluate progression-free survival by blinded independent central review of zanzalintinib versus everolimus in patients with previously treated, unresectable, locally advanced or metastatic neuroendocrine tumors. This endpoint is clinically relevant as it assesses the ability of zanzalintinib to delay disease progression compared to the standard comparator in this patient population.
The secondary objectives include:
• To evaluate objective response rate by blinded independent central review of zanzalintinib versus everolimus
• To evaluate overall survival of zanzalintinib versus everolimus
Participants
This clinical trial enrolled a total of **268 participants** diagnosed with **neuroendocrine tumors** (NETs). The study population included both **male and female participants** aged **18 years or older**. Participants were required to have histologically confirmed, locally advanced, unresectable, or **metastatic**, well-differentiated **Grade 1, 2, or 3 NETs** of **pancreatic** or **extra-pancreatic origin**, including primary tumor sites of non-pancreatic gastrointestinal, lung, thymus, other, or unknown primary site. Both functional and nonfunctional tumors were permitted, as were **SSTR positive** and **SSTR negative** tumors. Eligible participants demonstrated documented **radiographic disease progression** per **RECIST 1.1** within 12 months before randomization and had **measurable disease** at baseline. The trial required an **ECOG performance status** of 0 or 1, indicating that participants were ambulatory and capable of self-care. Participants with **pancreatic NETs** and nonfunctional **extra-pancreatic NETs** could have received up to one line of prior systemic anticancer treatment, while those with functional extra-pancreatic NETs were required to have received exactly one line of prior systemic anticancer therapy such as **PRRT** or **chemotherapy**. Prior treatment with **somatostatin analogs** was allowed and did not count toward the limit of prior systemic therapy. Participants were required to have adequate organ and marrow function, including specific thresholds for **absolute neutrophil count**, **platelets**, **hemoglobin**, liver enzymes, **renal function**, and cardiac parameters including **left ventricular ejection fraction** of at least 50%. Female participants of childbearing potential and male participants with female partners were required to use highly effective contraception during the study and for specified periods after the last dose of study treatment.
Plans and Procedures
This is a Phase 2/3, multicenter, randomized, open-label clinical trial evaluating zanzalintinib versus everolimus in participants with previously treated, unresectable, locally advanced or metastatic neuroendocrine tumors. The trial is designed to assess the efficacy and safety of zanzalintinib compared to everolimus as a treatment option for this patient population. The study employs a randomized design where participants will be allocated to receive either the test product zanzalintinib or the comparator product everolimus. Both investigational medicinal products are administered orally in tablet form. The primary objective of the trial is to evaluate progression-free survival by blinded independent central review of zanzalintinib versus everolimus. Secondary objectives include assessment of objective response rate per RECIST 1.1 as determined by blinded independent central review and evaluation of overall survival.
Eligible participants must have histologically confirmed, locally advanced/unresectable or metastatic, well-differentiated Grade 1, 2, or 3 neuroendocrine tumors of pancreatic origin or extra-pancreatic origin, including primary tumor sites of non-pancreatic gastrointestinal, lung, thymus, other, or unknown primary site. Both functional and nonfunctional tumors are permitted, and somatostatin receptor positive and negative tumors are allowed. Participants must have measurable disease according to RECIST 1.1 criteria and documented radiographic disease progression within 12 months before randomization. Participants with pancreatic neuroendocrine tumors and nonfunctional extra-pancreatic neuroendocrine tumors may have received up to one line of prior systemic anticancer treatment, while participants with functional extra-pancreatic neuroendocrine tumors must have received exactly one line of prior systemic anticancer therapy. Additional key inclusion criteria include age 18 years or older, ECOG performance status of 0 or 1, and adequate organ and marrow function as defined by specific laboratory parameters including absolute neutrophil count, platelet count, hemoglobin, liver function tests, renal function, and cardiac function with left ventricular ejection fraction of at least 50 percent.
The maximum daily dose for everolimus is 10.00 mg, while zanzalintinib dosing parameters allow for doses up to 99999.99 mg daily. The maximum treatment period for both products is 14 months. Participants must have recovered to baseline or Grade 1 or less from adverse events related to any prior treatments unless the adverse events are clinically nonsignificant and stable on supportive therapy. Archival tumor tissue is required if available, and if not available, a fresh biopsy may be submitted if it can be safely and feasibly obtained. Female participants of childbearing potential must not be pregnant or breastfeeding at screening, and both male and female participants must agree to use highly effective methods of contraception during the study and for specified periods after the last dose of study treatment.
The estimated recruitment start date for the trial is December 29, 2025, with an estimated end date of June 4, 2029, indicating an overall trial duration of approximately 3.5 years. Participant involvement will extend throughout the treatment period, which may continue for up to 14 months, followed by survival follow-up as required by the protocol. Early termination from the study may occur due to disease progression, unacceptable toxicity, withdrawal of consent, protocol deviation, or at the discretion of the investigator if continued participation is not in the best interest of the participant. The trial will assess safety and efficacy endpoints through regular monitoring visits that include clinical assessments, laboratory evaluations, imaging studies, and adverse event reporting throughout the treatment and follow-up periods.
Treatment
The experimental medication **XL092** (zanzalintinib) is administered as an oral **tablet** formulation containing the active substance **N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide**. The product is supplied in multiple tablet strengths to accommodate dosing requirements. XL092 is administered via **oral use** with a maximum treatment period of 14 days per cycle. The maximum daily dose has been specified as 99999.99 milligrams, with a maximum total dose of 99999.99 milligrams. The medication is classified as a chemical entity and is not a paediatric formulation.
The **comparator** treatment in this clinical trial is **everolimus**, administered as an oral tablet formulation. Everolimus is provided in tablet form for oral administration with a **maximum daily dose** of **10.00 milligrams**. The maximum total dose is specified as 99999.99 milligrams, with a maximum treatment period of 14 days per cycle. The active substance everolimus is of chemical origin. The product requires study-specific labeling and is not designated as an orphan drug or paediatric formulation. The route of administration is oral use.
Efficacy
Efficacy will be assessed through the evaluation of progression-free survival per RECIST 1.1 as determined by blinded independent central review. This represents the primary endpoint of the trial. Radiographic disease progression will be documented based on imaging assessments using computed tomography or magnetic resonance imaging. Participants must have measurable disease according to RECIST 1.1 criteria as determined by the Investigator at baseline. Previously irradiated or embolized tumor lesions may be considered as target lesions only if progression has been unequivocally documented at that site since radiation. Documented radiographic disease progression per RECIST 1.1 within 12 months before randomization is required for trial entry, with radiologic imaging reports or clinic notes indicating growth of existing lesions or development of new lesions.
Secondary efficacy endpoints include objective response rate per RECIST 1.1 as assessed by blinded independent central review and overall survival. The trial will evaluate the efficacy of zanzalintinib versus everolimus in participants with previously treated, unresectable, locally advanced or metastatic neuroendocrine tumors. Tumor tissue samples will be collected, with archival tumor tissue required if available, or a fresh biopsy if archival tissue is not available and can be safely obtained.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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.
- ECOG performance status of 0 or 1.
- Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.
- 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).
Exclusion Criteria
- Histologically confirmed neuroendocrine carcinomas (including small cell lung cancer), medullary thyroid cancer, pheochromocytoma, paraganglioma, Merkel cell carcinoma, and mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN).
- 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.
- Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before randomization. Note: Eligible participants must be neurologically asymptomatic and without corticosteroid treatment at the time of randomization. Note: Approval from the Sponsor is required for cases including base of skull lesions without definitive evidence of dural or brain parenchymal involvement.
- Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before randomization. Complete wound healing from major or minor surgery must have occurred at least before randomization. Note: Fresh tumor biopsies are to be performed ≥ 7 days before randomization. Participants with clinically relevant ongoing complications from prior surgical procedures, including biopsies, are not eligible.
- Lesions invading major blood vessels including, but not limited to, inferior vena cava, pulmonary artery, or aorta. Note: Participants with intravascular tumor extension may be eligible following Sponsor approval.
- Concomitant anticoagulation with anticoagulants except for those specified below. Allowed anticoagulants are: • Prophylactic use of low-dose aspirin for cardioprotection (per local applicable guidelines) • Low molecular weight heparins (LMWH) or specified direct factor Xa inhibitors (rivaroxaban, fondaparinux, edoxaban, apixaban) in participants without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before randomization and without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
- 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 ≤ 6.
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 29 Dec 2025 | 7 |
 Belgium | Recruiting | 29 Dec 2025 | 8 |
 France | Recruiting | 29 Dec 2025 | 29 |
 Germany | Recruiting | 29 Dec 2025 | 22 |
 Italy | Recruiting | 29 Dec 2025 | 36 |
 The Netherlands | Recruiting | 29 Dec 2025 | — |
 Poland | Recruiting | 29 Dec 2025 | 21 |
 Spain | Recruiting | 29 Dec 2025 | 39 |
| Netherlands | — | — | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
XL092 | Test | TABLET | ORAL USE | 99999.99 | 14 | PRD10205699 |
XL092 | Test | TABLET | ORAL USE | 99999.99 | 14 | PRD10205698 |
EVEROLIMUS | Comparator | — | ORAL USE | 10.00 | 14 | SUB02065MIG |
EVEROLIMUS | Comparator | — | ORAL USE | 10.00 | 14 | SUB02065MIG |
XL092 | Test | TABLET | ORAL USE | 99999.99 | 14 | PRD10205697 |