I. Assess efficacy of the treatment zanzalintinib (XL092) in radioiodine refractory/radioactive iodine refractory (RAIR) differentiated thyroid cancer (DTC) patients by evaluating the proportion of patients alive and without progression at 12 months.
SECONDARY OBJECTIVES:
I. Assess efficacy of XL092 treatment in RAIR DTC patients by imaging. II. Assess efficacy of the treatment XL092 in RAIR DTC patients by evaluating progression free survival.
III. Assess efficacy for RAIR DTC patients treated with XL092 evaluating the overall survival time.
IV. Assess the safety and tolerability of XL092 monotherapy in patients with RAIR DTC.
V. Characterize the quality of life in RAIR DTC patients treated with XL092 monotherapy.
EXPLORATORY OBJECTIVES:
I. Assess immune cell landscape in XL092 treated patients. II. Assess by next generation sequencing (NGS) and biomarker analysis, mechanisms that lead to response or failure to XL092.
OUTLINE:
Patients receive XL092 orally (PO) daily (QD) on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan or magnetic resonance imaging (MRI) and x-ray imaging, and blood and urine sample collection throughout the study.
After completion of study treatment, patients are followed up at 30 days then every 3 months for 12 months.
A Phase 2 Open Label Study of XL092 as First Line Therapy in Radioiodine Refractory Differentiated Thyroid Cancer
Study Start Date
June 5, 2025
Actual Primary Completion Date
2yrs 1mo from now
Actual Study Completion Date
4yrs 1mo from now
Groups and Cohorts
Group/Cohort
Intervention/Treatment
Treatment (XL092)
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
Undergo blood and urine sample collection
Outcome Measures
Primary Outcome Measures
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.
Secondary Outcome Measures
Radiographic response rate
Defined as the proportion of patients who achieve a complete response or partial response as per RECIST v1.1. The point estimate of the objective response rate will be reported with its 2-sided 95% Clopper-Pearson exact confidence interval.
Overall PFS
Will use the Kaplan-Meier method to estimate the overall PFS distribution. Subgroup comparisons will be made using log-rank tests, and a Cox proportional hazards model will be employed to assess covariate effects.
Overall survival (OS)
OS will also be analyzed using the Kaplan-Meier estimator. Differences in survival distributions across patient subgroups will be evaluated using log-rank tests, and Cox models will be used to explore the effects of demographic and clinical variables on OS.
Incidence of adverse events
Assessed by clinical review of all relevant parameters, including adverse events (AEs), concomitant medication queries, Eastern Cooperative Oncology Group performance status, weight and vital signs measurements, electrocardiogram measurements, and clinical laboratory testing values. The severity of AEs will be graded as mild, moderate, severe, or life-threatening according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All reported toxicities, regardless of attribution, by toxicity type and maximum grade will be summarized, and sorted by number of patients experiencing the toxicity. The maximum grade consolidates the reports of a given toxicity for a patient over time by taking the maximum across time. Categorical data analyses and summary statistics will be used to report AEs.
Changes in quality of life
Eligibility Criteria
Ages Eligible for Study
(Adult, Older Adult)
Sexes Eligible for Study
All
Accepts Healthy Volunteers
No
Inclusion Criteria
Inclusion:
3.1.1 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)
3.1.2 Patients must have measurable disease according to RECIST v1.1 (see Appendix B and Section 2).
3.1.3 Patients must be age ≥ 18 years.
3.1.4 Patients must exhibit an ECOG Performance Score of ≤ 2 (see Appendix C for ECOG Performance Status Scale).
3.1.5 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).
3.1.6 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.
3.1.7 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.
3.1.8 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).
3.1.9 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.
3.1.10 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).
3.1.11 Patients must have the ability to understand and the willingness to sign a written informed consent document and comply with the protocol requirements.
3.1.12 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.
Exclusion Criteria
Inclusion:
3.1.1 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)
3.1.2 Patients must have measurable disease according to RECIST v1.1 (see Appendix B and Section 2).
3.1.3 Patients must be age ≥ 18 years.
3.1.4 Patients must exhibit an ECOG Performance Score of ≤ 2 (see Appendix C for ECOG Performance Status Scale).
3.1.5 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).
3.1.6 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.
3.1.7 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.
3.1.8 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).
3.1.9 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.
3.1.10 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).
3.1.11 Patients must have the ability to understand and the willingness to sign a written informed consent document and comply with the protocol requirements.
3.1.12 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. Exclusion:
3.2.1 Prior treatment with XL092 (zanzalintinib).
3.2.2 Patient has Hepatitis B.
3.2.3 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.
3.2.4 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.
3.2.5 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.
3.2.6 Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy (including investigational therapy or investigational device) before the first dose of study treatment. NOTE: See Section 4 for additional information on concomitant medications including restricted medications and therapies. NOTE: RAI, a radionuclide therapy given systemically, is allowed prior therapy, see inclusion criterion 3.1.1 and criterion 3.2.7.
3.2.7 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
3.2.8 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).
3.2.9 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.
3.2.10 Any complementary medications (e.g., herbal supplements or traditional Chinese medicines) to treat cancer within 2 weeks before first dose of study treatment.
3.2.11 Patient has uncontrolled, significant intercurrent or recent illness
3.2.12 Other clinically significant disorders that would preclude safe study participation including having an uncontrolled intercurrent illness
3.2.13 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.
3.2.14 Symptomatic cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation. NOTE: Asymptomatic or radiated endobronchial disease lesions allowed.
3.2.15 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.
3.2.16 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.
3.2.17 Corrected QT interval calculated by the Fridericia formula (QTcF) \> 480 ms within 14 days per electrocardiogram (ECG) before first dose of study treatment. NOTE: ECG evaluation is required at screening; QT prolongation is a potential side effect of VEGFR associated TKIs, such as XL092; NOTE: see Section 4 regarding prohibited concomitant medications that are known to prolong the QT interval (see http://www.qtdrugs.org for a list of drugs which have the potential to prolong the QT interval); see Section 5 Study Procedures for full details on the ECG evaluation eligibility requirement.
3.2.18 History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent
3.2.19 Patients with: • any other active malignancy within 2 years prior to start of study treatment • a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen NOTE: Allowed: Superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy. Incidentally diagnosed prostate cancer is allowed if assessed as stage ≤ T2N0M0 and Gleason score ≤ 6.
3.2.20 Administration of a live, attenuated vaccine (e.g., Intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guérin, yellow fever, varicella, and TY21a typhoid vaccines) is prohibited: • Within 30 days before the first dose of study treatment and • Prohibited for all patients while on study treatment NOTE: Experimental vaccines are not allowed while on study
Contacts and Locations
Sponsors and Collaborators
Jochen Lorch
Locations
Harbor-UCLA Medical Center | Torrance California, United States, 90502Northwestern University | Chicago Illinois, United States, 60611
Investigators
Principal Investigator: Jochen H Lorch, Northwestern University
More Information
Additional Relevant MeSH Terms
Adenocarcinoma, FollicularThyroid Cancer, PapillaryAdenocarcinomaCarcinomaNeoplasms, Glandular and EpithelialNeoplasms by Histologic TypeNeoplasmsAdenocarcinoma, PapillaryThyroid NeoplasmsEndocrine Gland NeoplasmsNeoplasms by SiteHead and Neck NeoplasmsEndocrine System DiseasesThyroid Diseases
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