Zanzalintinib for the Treatment of Advanced Thyroid Cancer Before Surgery

NCT ID: NCT06959511

Last Updated: 2025-11-19

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-07-22
• Study Completion Date: 2030-10-01

Brief Summary

To look at the effectiveness of zanzalintinib, followed by surgery, in treating advanced thyroid cancer. The safety of this treatment will also be studied.

Detailed Description

Primary Objectives

• To evaluate the efficacy of neoadjuvant zanzalintinib in DTC, non-RET-mutated MTC, and poorly differentiated thyroid cancer (PDTC) by overall objective response rate (overall ORR), defined as the proportion of participants who have a minor response (MR), partial response (PR), or complete response (CR) per RECIST. Participants with locally invasive extrathyroidal and/or extra nodal DTC, non- RET-mutated MTC or PDTC who have high surgical morbidity/complexity based on baseline radiographic assessment (as measured by Thyroid Neck Surgical Morbidity/Complexity Scoring, see Section 3.2.1), will be eligible for the study.

Hypothesis: Neoadjuvant administration of zanzalintinib will result in acceptable overall ORR (MR+PR+CR rate) for participants with locoregionally advanced DTC and non-RETmutated MTC, ultimately allowing patients to safely undergo complete gross surgical tumor resection with less surgical morbidity.

Secondary Objectives

• To evaluate the efficacy of neoadjuvant zanzalintinib in DTC, non-RET-mutated MTC or PDTC by objective response rate (ORR) per modified neck RECIST.
• To evaluate the safety profile of neoadjuvant zanzalintinib in thyroid cancer.
• To evaluate the efficacy of neoadjuvant zanzalintinib on progression-free survival (PFS), including overall PFS and locoregional PFS.
• To measure changes in expected and actual thyroid neck surgical morbidity/complexity scoring before and after zanzalintinib treatment.
• To evaluate the efficacy of neoadjuvant zanzalintinib by surgical margin status.

Exploratory Objectives

• To define and measure changes of patient-reported outcomes (PROs) and quality of life (QOL) as measured by MDASI-HN and EQ-5D in participants who receive zanzalintinib treatment.
• To evaluate the efficacy of neoadjuvant zanzalintinib by pathologic response.
• To evaluate the efficacy of neoadjuvant zanzalintinib by PET metabolic response.

Conditions

Neoadjuvant Treatment; Thyroid Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Neoadjuvant with Zanzalintinib Followed by Surgery

Zanzalintinib 100 mg orally once daily on Days 1 to 28 of a 28-day cycle.

Group Type: EXPERIMENTAL

Zanzalintinib

Intervention Type: DRUG

Given by po

Interventions

Zanzalintinib

Given by po

Intervention Type: DRUG

Eligibility Criteria

Exclusion Criteria

1. Medullary thyroid cancer participants with germline RET or known somatic RET mutations.

2. Prior treatment with zanzalintinib.

3. Prior treatment with a tyrosine kinase inhibitor.

4. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment.

5. Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Participants with clinically relevant ongoing complications from prior radiation therapy are not eligible.

6. 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 first dose of study treatment. Note: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of enrollment. Note: Base of skull lesions without definitive evidence of dural or brain parenchymal involvement are allowed.

7. Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin inhibitors) and platelet inhibitors (e.g., clopidogrel).

Allowed anticoagulants are the following:

1. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).

2. 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: Subjects must have discontinued oral anticoagulants within 3 days or 5 half-lives prior to first dose of study treatment, whichever is longer.

8. Any complementary medications (e.g., herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment.

9. The participant has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

a. Unstable or deteriorating cardiovascular disorders: i. Congestive heart failure New York Heart Association class 2 or higher, unstable angina pectoris, new-onset angina, serious cardiac arrhythmias (e.g., ventricular flutter, ventricular fibrillation, Torsades de pointes). ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment. iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other clinically significant arterial thrombotic and/or ischemic event within 6 months before first dose of study treatment.

iv. Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinically significant venous events within 3 months before to first dose of study treatment. Note: Subjects with a diagnosis of DVT within 6 months are allowed if asymptomatic and stable at screening and 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: Participants who don't require prior anticoagulation therapy may be eligible but must be discussed and approved by the Principal Investigator.

10. 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.

11. Symptomatic cavitating pulmonary lesion(s) or endobronchial disease (asymptomatic or radiated lesions allowed. Intratracheal disease is allowed, as long as the endotracheal disease is not associated with major bleeding episodes.

12. Lesions invading major blood vessel including, but are not limited to, inferior vena cava, pulmonary artery, or aorta. Note: Subjects with internal jugular vein involvement or tumor thrombus in the neck are eligible. Additionally, subjects with intravascular tumor extension (e.g., tumor thrombus in renal vein or inferior V. cava) may be eligiblefollowing Principal Investigator approval.

13. Other clinically significant disorders that would preclude safe study participation.

1. Active infection requiring systemic treatment. Note: Prophylactic antimicrobial treatments (antibiotics, antimycotic, antiviral) are allowed.

2. Known infection with acute or chronic hepatitis B or C, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)- related illness except for subjects meeting 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 and as required by local regulation. Note: To be eligible, participants 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.

3. Serious non-healing wound/ulcer/bone fracture. Note: non-healing wounds or ulcers are permitted if due to tumor-associated skin lesions.

4. Malabsorption syndrome.

5. Uncontrolled symptomatic hyperthyroidism or hypothyroidism.

6. Uncontrolled symptomatic hypercalcemia or hypocalcemia.

7. Moderate to severe hepatic impairment (Child-Pugh B or C).

8. Requirement for hemodialysis or peritoneal dialysis.

9. History of solid organ or allogeneic stem cell transplant.

14. Major surgery (as defined in Appendix B; e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks prior to first dose of study treatment. Minor surgery (e.g., simple excision, tooth extraction) within 5 days before first dose of study treatment. Fine needle aspiration and core biopsies are allowed on study drug without drug hold.Complete wound healing from major or minor surgery must have occurred at least prior to first dose of study treatment.

Note: Participants with clinically relevant ongoing complications from prior surgical procedures, including biopsies, are not eligible.

15. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms within 14 days per electrocardiogram (ECG) before first dose of study treatment.

Note: Triplicate ECG evaluations will be performed and the average of these 3 consecutive results for QTcF will be used to determine eligibility.

16. History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent.

17. Pregnant or lactating females.

18. Inability to swallow tablets or ingest a suspension either orally or by nasogastric (NG) or gastrostomy (PEG) tube.

19. Previously identified allergy or hypersensitivity to components of the study treatment formulations.

20. Another malignancy that requires active therapy and in the opinion of the Investigator would interfere with monitoring of radiologic assessments of response to Investigational Product, within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy.

21. Other conditions, which in the opinion of the Investigator, would compromise the safety of the participant or the participants ability to complete the study.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Exelixis

INDUSTRY

Sponsor Role: collaborator

M.D. Anderson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mark Zafereo, MD

Role: PRINCIPAL_INVESTIGATOR

M.D. Anderson Cancer Center

Locations

MD Anderson Cancer Center

Houston, Texas, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Mark Zafereo, MD

Role: CONTACT

mzafereo@mdanderson.org

713-563-9683

Facility Contacts

Mark Zafero, MD

Role: primary

mzafereo@mdanderson.org

713-563-9683

Related Links

http://www.mdanderson.org

MD Anderson Cancer Center

Other Identifiers

NCI-2025-03105

Identifier Type: OTHER

Identifier Source: secondary_id

2024-0308

Identifier Type: -

Identifier Source: org_study_id