Efficacy and safety of Cabozantinib (XL184) in subjects who have progressed after VEGFR-targeted treatment

Phase 1

• Conditions: Radioiodine-Refractory Differentiated Thyroid Cancer which has progressed after priorVEGFR-targeted therapy; MedDRA version: 20.0Level: PTClassification code 10066474Term: Thyroid cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2018-001771-21-CZ
• Lead Sponsor: Exelixis, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2019-06-04
• Last Update Posted: 2 September 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

1. Histologically or cytologically confirmed diagnosis of DTC, including the following subtypes (Note: results of a previous biopsy will be accepted):
a. PTC including histological variants of PTC such as follicular variant, tall cell, columnar cell, cribriform-morular, solid, oxyphil, arthin-like, trabecular, tumor with nodular fasciitis-like stroma, Hürthle cell variant of papillary carcinoma, poorly differentiated
b. FTC including histological variants of FTC such as Hürthle cell, clear cell, insular, and poorly differentiated
2. Measurable disease according to RECIST 1.1 on CT/MRI performed within 28 days prior to randomization
3. Must have been previously treated with or deemed ineligible for treatment with Iodine-131 for DTC
4. Must have been previously treated with at least one of the following VEGFR-targeting TKI agents for DTC: lenvatinib or sorafenib.
(Note: Up to two prior VEGFR-targeting TKI agents are allowed including (but not limited to) lenvatinib and sorafenib.)
5. Must have experienced documented radiographic progression per RECIST 1.1 per Investigator during or following treatment with a VEGFR-targeting TKI prior to starting the next anticancer therapy (which may be treatment in this study)
6. Recovery to baseline or = Grade 1 (Common Terminology Criteria for Adverse Events Version 5 [CTCAE v5]) from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy
7. Age = 16 years old on the day of consent
8. Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1
9. Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 10 days before randomization:
a. Absolute neutrophil count = 1500/mm3 (= 1.5 GI/L) without receipt of granulocyte colony-stimulating factor support within 2 weeks before screening laboratory sample collection
b. Platelets = 100,000/mm3 (= 100 GI/L) without receipt of transfusion within 2 weeks before screening laboratory sample collection
c. Hemoglobin = 9 g/dL (= 90 g/L) without receipt of transfusion within 2 weeks before screening laboratory sample collection
d. Alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) = 3 × upper limit of normal (ULN). ALP = 5 × ULN if the subject has documented bone metastases e. Bilirubin = 1.5 × the ULN. For subjects with known Gilbert’s disease = 3 × ULN
f. Serum creatinine = 2.0 × ULN or calculated creatinine clearance = 30 mL/min (= 0.5 mL/sec) using the Cockcroft-Gault (see Table 5-2 for Cockcroft-Gault formula).
g. Urine protein/creatinine ratio (UPCR) = 1 mg/mg (= 113.2 mg/mmol)
10. Must be receiving thyroxine suppression therapy, and TSH must be below the lower cutoff of the reference range or less than 0.50 mIU/L (< 0.50 µIU/mL), whichever is lower, within 28 days before randomization.
(Note: If hormone replacement therapy is tolerated a TSH level of = 0.1 mIU/L should be targeted.)
11. Capable of understanding and complying with the protocol requirements and signed informed consent (or informed assent and parental/guardian consent for subjects < 18 years of age)
12. Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception that alone or in combination result in a failure rate of less than 1% per year when used consistently and correctly during the course of the study and for 4 months after the last dose of study treatment. For females, such methods include combined hormonal contrace

Exclusion Criteria

1. Prior treatment with any of the following:
a. Cabozantinib
b. Selective small-molecule BRAF kinase inhibitor (eg, vemurafenib, dabrafenib)
c. More than 2 VEGFR-targeting TKI agents (eg, lenvatinib, sorafenib, sunitinib, pazopanib, axitinib, vandetanib)
d. More than 1 immune checkpoint inhibitor therapy (eg, PD-1 or PD-L1 targeting agent)
e. More than 1 systemic chemotherapy regimen (given as single agent or in combination with another chemotherapy agent)
2. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer, before randomization
3. Receipt of any type of anticancer antibody (including investigational antibody) or systemic chemotherapy within 4 weeks before randomization
4. Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before randomization. Subjects with clinically relevant ongoing complications from prior radiation therapy that have not completely resolved are not eligible (eg, radiation esophagitis or other inflammation of the viscera).
5. 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. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of randomization.
6. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel), except for the following allowed anticoagulants:
• Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH)
• Anticoagulation with therapeutic doses of LMWH in subjects without known brain metastases who are on a stable dose of LMWH for at least 6 weeks before randomization and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
7. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
a. Cardiovascular disorders:
i. Congestive heart failure class 3 or 4 as defined by the New York Heart Association, unstable angina pectoris, serious cardiac arrhythmias
ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venous thrombosis [DVT], pulmonary embolism) within 6 months before randomization. Subjects with a more recent diagnosis of DVT are allowed if stable, asymptomatic, and treated with LMWH for at least 6 weeks before randomization.
b. Gastrointestinal disorders (GI; eg, malabsorption syndrome or gastric outlet obstruction) including those associated with a high risk of perforation or fistula formulation:
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction
ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before randomization
Note: Complete h

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The objective of this study is to evaluate the effect of cabozantinib compared with placebo on Progression Free Survival (PFS) and Objective Response Rate (ORR) in subjects with Radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy.;Secondary Objective: No;Primary end point(s): • Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by blinded independent radiology committee (BIRC)<br>• Objective response rate (ORR) per RECIST 1.1 by BIRC;Timepoint(s) of evaluation of this end point: throughout the study and based on study assessments and procedures as stated in the protocol section 5

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): • Overall survival (OS)<br>• Duration of objective tumor response<br>• Safety and tolerability<br>• Pharmacokinetics (PK) of cabozantinib<br>• Relationship of baseline and postbaseline changes in biomarkers, serum thyroglobulin (Tg), and circulating tumor cells (CTCs) and/or circulating DNA (ctDNA) with treatment and/or clinical outcome assessments may be performed <br>• Change in mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and global health as assessed by the EuroQol Health questionnaire instrument (EQ-5D-5L)<br>• Health care resource utilization;Timepoint(s) of evaluation of this end point: throughout the study and based on study assessments and procedures as stated in the protocol section 5