XL092 for the Treatment of Locally Advanced or Metastatic Radioiodine Refractory Differentiated Thyroid Cancer

NCT06959641 | Recruiting Phase 2 DMC FDA Drug

• 4 other identifiers: NU 24N04NCI-2025-02747STU00223751P30CA060553
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 2

Brief Summary

This phase II trial tests how well XL092 works for the treatment of patients with differentiated thyroid cancer that has not responded to previous treatment with radioiodine (radioiodine refractory) and that has spread to nearby tissue or lymph nodes (locally advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). XL092 is in a class of medications called tyrosine kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply, which may help keep cancer cells from growing.

Conditions

Refractory Thyroid Gland Papillary Carcinoma; Locally Advanced Differentiated Thyroid Gland Carcinoma; Stage III Differentiated Thyroid Gland Carcinoma AJCC v8; Locally Advanced Poorly Differentiated Thyroid Gland Carcinoma; Locally Advanced Thyroid Gland Follicular Carcinoma; Locally Advanced Thyroid Gland Oncocytic Carcinoma; Locally Advanced Thyroid Gland Papillary Carcinoma; Metastatic Differentiated Thyroid Gland Carcinoma; Metastatic Poorly Differentiated Thyroid Gland Carcinoma; Metastatic Thyroid Gland Follicular Carcinoma; Metastatic Thyroid Gland Oncocytic Carcinoma; Metastatic Thyroid Gland Papillary Carcinoma; Refractory Differentiated Thyroid Gland Carcinoma; Refractory Poorly Differentiated Thyroid Gland Carcinoma; Refractory Thyroid Gland Follicular Carcinoma; Refractory Thyroid Gland Oncocytic Carcinoma; Stage III Thyroid Gland Follicular Carcinoma AJCC v8; Stage III Thyroid Gland Papillary Carcinoma AJCC v8; Stage IV Differentiated Thyroid Gland Carcinoma AJCC v8; Stage IV Thyroid Gland Follicular Carcinoma AJCC v8; Stage IV Thyroid Gland Papillary Carcinoma AJCC v8

Outcome Measures

Primary Outcomes (1)

• Progression free survival (PFS)

  Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria. Median PFS at 12-months will be analyzed using the Kaplan-Meier method. The 12-month PFS estimate will be reported along with the confidence interval. Cox proportional hazards models will be applied to assess the impact of covariates such as age, sex, baseline disease severity, and genetic markers on PFS, when appropriate.

  From the time of the first dose of XL092 to the first documentation of disease progression, initiation of subsequent anti-cancer therapy, completion of 12 months of participation, or death from any cause, whichever occurs first, assessed at 12 months

Secondary Outcomes (5)

• Radiographic response rate

  Up to 12 month follow-up

• Overall PFS

  From the first dose of XL092 to the date of the first progression event or death from any cause, assessed up to 12 month follow-up

• Overall survival (OS)

  From the start of treatment with XL092 to the date of death from any cause, assessed up to 12 month follow-up

• Incidence of adverse events

  Up to 30 days after the end of treatment

• Changes in quality of life

  Baseline to 12 month follow-up

Study Arms (1)

Treatment (XL092)

EXPERIMENTAL

Patients receive XL092 PO QD on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and x-ray imaging, and blood and urine sample collection throughout the study.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Other: Survey Administration; Procedure: X-Ray Imaging; Drug: Zanzalintinib

Interventions

X-Ray Imaging PROCEDURE

Undergo x-ray imaging

Also known as: Conventional X-Ray, Diagnostic Radiology, Medical Imaging, X-Ray, Plain film radiographs, Radiographic Imaging, Radiographic imaging procedure (procedure), Radiography, RG, Static X-Ray, X-Ray

Treatment (XL092)

Zanzalintinib DRUG

Given PO

Also known as: Multi-kinase Inhibitor XL092, XL 092, XL-092, XL092

Treatment (XL092)

Biospecimen Collection PROCEDURE

Undergo blood and urine sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (XL092)

Computed Tomography PROCEDURE

Undergo CT scan

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography

Treatment (XL092)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (XL092)

Survey Administration OTHER

Ancillary studies

Treatment (XL092)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have a histologically confirmed locally advanced or metastatic, radioactive iodine (RAI) refractory, differentiated thyroid cancer (including papillary, follicular, and oncocytic/Hurthle cell, and poorly differentiated thyroid cancer (PDTC)1 ), with progression within 12 months (per RECIST v1.1 response criteria) prior to study registration, and no prior therapy in the RAI-refractory setting and for which standard curative measures do not exist or are no longer effective. NOTE: availability of other standard TKI treatment options will not preclude patients from being eligible for this study. NOTE: RAI refractoriness is defined as absence of uptake of RAI on either a low-dose diagnostic test or a post-treatment RAI scan in measurable lesions or radiographic progression of disease within 12 months of the last course of RAI treatment despite the recorded uptake of RAI with that previous therapy or having a cumulative lifetime administered dose of ≥ 600mCi. Footnote 1: Poorly differentiated thyroid cancer (PDTC) is typically classified as a type of differentiated thyroid cancer (as opposed to undifferentiated thyroid cancer or anaplastic thyroid cancer)
• Patients must have measurable disease according to RECIST v1.1 (see Appendix B and Section 2).
• Patients must be age ≥ 18 years.
• Patients must exhibit an ECOG Performance Score of ≤ 2 (see Appendix C for ECOG Performance Status Scale).
• Patients must have adequate organ and bone marrow function as defined: Leukocytes (WBC) ≥ 3,000/mcL, Absolute neutrophil count (ANC) ≥ 1,500/mcL (see footnote 2 regarding use of growth factors for neutropenia), Hemoglobin (Hgb) ≥ 9 g/dL (see footnote 1 regarding transfusions for anemia and thrombocytopenia), Platelets (PLT) ≥ 100,000/mcL (see footnote 1 regarding transfusions for anemia and thrombocytopenia), Total bilirubin ≤ 1.5 x Institutional upper limit of normal (ULN) ; for subjects with Gilbert's disease ≤ 3 x ULN, AST (SGOT) ≤ 3 x Institutional ULN, ALT (SGPT) ≤ 3 x Institutional ULN, ALP (alkaline phosphatase) ≤ 3 x Institutional ULN ; For subjects with documented bone metastasis, ≤ 5 x ULN., Creatinine Clearance (CrCl) ≥ 40 mL/min (≥ 0.67 mL/sec) using the Cockcroft-Gault equation., INR ≤ 1.5 x Institutional ULN (in patients not currently on therapeutic anticoagulation), aPTT ≤ 1.2 × Institutional ULN (in patients not currently on therapeutic anticoagulation), Urine protein-to creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol).
• For patients with a known history of Human immunodeficiency virus (HIV), infected patients on effective anti-retroviral therapy must have a viral load undetectable for 6 months prior to registration. Please note this lab is not a requirement for eligibility, however, if it has been completed previously as part of the patient's health care, it should be documented for eligibility. NOTE. To be eligible, patients must not have known uncontrolled infection with Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness NOTE: patients must meet all of the following criteria: (1) on stable anti-retroviral therapy; (2) CD4+ T cell count ≥ 200/µL; and (3) an undetectable viral load. NOTE: HIV testing will be performed at screening if it is required by local regulation or per SOC. NOTE: To be eligible, patients taking CYP inhibitors (e.g., zidovudine, ritonavir, cobicistat, didanosine) or CYP3 inducers (efavirenz) must change to a different regimen not including these drugs 7 days prior to initiation of study treatment. Anti-retroviral therapies (ART) must have been received for at least 4 weeks prior to the first dose. NOTE: CD4+ T cell counts, and viral load are monitored per standard of care by the local health care provider.
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression and patients are stable for at least 4 weeks before the first dose of study treatment. NOTE: Patients with active brain metastases are not allowed. NOTE: Therapeutic doses of Low Molecular Weight Heparin (LMWH) are not permitted in patients with known brain metastases.
• Patients of child-bearing potential must have a negative pregnancy test prior to registration on study. NOTE: Patients of child-bearing potential are considered to be of child-bearing 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 consecutive months of amenorrhea in a patient of child-bearing potential \> 45 years-of-age in the absence of other biological or physiological causes). In addition, a patient of child-bearing potential \< 55 years-of-age must have a serum follicle stimulating hormone (FSH) level \> 40 mIU/mL to confirm menopause).
• The effects of XL092 on the developing human fetus are unknown. For this reason and because tyrosine kinase inhibitors (TKIs) as well as other therapeutic agents used in this trial are known to be teratogenic, sexually active fertile patients and their partners must agree 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 XL092 for patients of child-bearing potential or through 96 days after the last dose of XL092 for patients of sperm producing capacity. Because the effect of XL092 on the pharmacokinetics (PK) of contraceptive steroids has not been investigated, hormonal contraceptives may not achieve the level considered "highly effective". For this reason, an additional contraceptive method, such as a barrier method (e.g., condom), may be required. In addition, patients of sperm producing capacity must agree not to donate sperm and patients of child-bearing potential must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods. Should a patient of child-bearing potential become pregnant or suspect they are pregnant while they or their partner are participating in this study, they should inform their treating physician immediately. NOTE: See Appendix H for highly effective methods of contraception.
• Recovery to baseline or ≤ Grade 1 per NCI CTCAE v5 from AE(s) related to any prior treatments unless AE(s) are deemed clinically nonsignificant by the Treating Investigator and/or stable on supportive therapy. NOTE: Patients must have recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> Grade 1) except for alopecia, neuropathy, and other non-significant adverse events per NCI CTCAE v 5.0 (Appendix A).
• Patients must have the ability to understand and the willingness to sign a written informed consent document and comply with the protocol requirements.
• Patients must have the ability to swallow, retain and absorb oral medications. NOTE: Patients must have the ability to swallow tablets or ingest a suspension either orally or by a nasogastric (NG) or gastrostomy (PEG) tube. NOTE: See Section 4 Treatment Administration for additional information.

You may not qualify if:

• Prior treatment with XL092 (zanzalintinib).
• Patient has Hepatitis B.
• Patient has Hepatitis C. NOTE: Patients with treated Hepatitis C and positive HCV antibody test are eligible only if followed by a negative HCV RNA test and no ongoing anti-HCV therapy. The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
• Patient is pregnant or nursing (lactating) NOTE: Pregnant patients are excluded from this study because XL092 is a tyrosine kinase inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with XL092, breastfeeding should be discontinued if the mother is treated with XL092.
• Receipt of any type of small molecule kinase inhibitor treatment before the first dose of study treatment NOTE: See Section 4 for additional information on concomitant medications including restricted medications and therapies.
• Radiation therapy for bone metastases within 2 weeks, any other radiation therapy within 4 weeks before the first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. NOTE: Patients with clinically relevant ongoing complications from prior radiation therapy are not eligible
• Previously identified allergy or hypersensitivity to components of the study treatment formulations, have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to XL092 (zanzalintinib).
• Concomitant anticoagulation with oral anticoagulants (e.g., warfarin or other coumarinrelated agents, direct thrombin inhibitors, or anti-platelet agents such as clopidogrel, chronic use of aspirin above low dose levels for cardio-protection per institutional practice). NOTE: Allowed anticoagulants are the following: prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low molecular weight heparins (LMWH); Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen. NOTE: Patients must have discontinued oral anticoagulants within 3 days or 5 half-lives prior to first dose of study treatment, whichever is longer. NOTE: Therapeutic doses of LMWH are not permitted in subjects with known brain metastases.
• Any complementary medications (e.g., herbal supplements or traditional Chinese medicines) to treat cancer within 2 weeks before first dose of study treatment.
• Patient has uncontrolled, significant intercurrent or recent illness
• Other clinically significant disorders that would preclude safe study participation including having an uncontrolled intercurrent illness
• Clinically significant hematuria, hematemesis, or hemoptysis of \> 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose of study treatment.
• Symptomatic cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation. NOTE: Asymptomatic or radiated endobronchial disease lesions allowed.
• Lesions invading major blood vessel(s), including, but not limited to, inferior vena cava, pulmonary artery, or aorta. NOTE: Subjects with intravascular tumor extension (e.g., tumor thrombus in renal vein or inferior V. cava) may be eligible following Principal Investigator approval.
• Major surgery (see Appendix D) e.g., GI surgery, removal, or biopsy of brain metastasis) within 8 weeks prior to first dose of study treatment. Prior laparoscopic surgeries (i.e., nephrectomy) within 4 weeks prior to first dose of study treatment. Minor surgery (e.g., simple excision, tooth extraction) within 5 days before the first dose of study treatment. Complete wound healing from major or minor surgery must have occurred at least prior to the first dose of study treatment. NOTE: Fresh tumor biopsies should be performed at least 5 days before the first dose of study treatment for screening procedures. NOTE: Patients with clinically relevant ongoing complications from prior surgical procedures, including biopsies, are not eligible.

Sponsors & Collaborators

• National Cancer Institute (NCI): collaborator
• Jochen Lorch: lead

Study Sites (2)

Harbor-UCLA Medical Center

Torrance, California, 90502, United States

RECRUITING

Northwestern University

Chicago, Illinois, 60611, United States

RECRUITING

MeSH Terms

Conditions

Adenocarcinoma, Follicular; Thyroid Cancer, Papillary

Interventions

Specimen Handling; Magnetic Resonance Spectroscopy; X-Rays; Phantoms, Imaging

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma, Papillary; Thyroid Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Electromagnetic Radiation; Electromagnetic Phenomena; Magnetic Phenomena; Physical Phenomena; Radiation; Radiation, Ionizing; Equipment and Supplies

Study Officials

• Jochen H Lorch

  Northwestern University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: April 28, 2025
• First Posted: May 6, 2025
• Study Start: June 6, 2025
• Primary Completion (Estimated): September 11, 2028
• Study Completion (Estimated): September 11, 2030
• Last Updated: June 26, 2026

Record last verified: 2026-06

Locations

US (2)