A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Cabozantinib (XL184) in Subjects with Radioiodine-Refractory Differentiated Thyroid Cancer Who Have Progressed after Prior VEGFR-Targeted Therapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Exelixis Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Jun 2019 → ongoing

Decision date (initial)

2024-10-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Exelixis, Inc.

External identifiers

EU CT number

2024-516478-31-00

EudraCT number

2018-001771-21

ClinicalTrials.gov

NCT03690388

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Efficacy, Pharmacogenetic, Safety, Pharmacokinetic, Therapy

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

Conditions and MedDRA coding

progressed thyroid cancer

Regulatory references

Scientific advice from competent authorities

Swedish Medical Products Agency, Medicines And Healthcare Products Regulatory Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

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 VEGFRtargeting 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 contraception (oral, intravaginal, dermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable hormonal contraception, implantable hormonal contraception), placement of an intrauterine device, or placement of an intrauterine hormone-releasing system. Males must agree to use a barrier method (eg, condom) unless they have had a vasectomy.
13. Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman over 45 years-of-age in the absence of other biological or physiological causes. In addition, females under 55 yearsof-age must have a serum follicle stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff.

Exclusion criteria 8

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 healing of an intra-abdominal abscess must be confirmed prior to randomization c. Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon (>2.5 mL) of red blood or history of other significant bleeding within 3 months before randomization d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation e. Lesions invading major pulmonary blood vessels f. Other clinically significant disorders such a: • Active infection requiring systemic treatment, infection with human immunodeficiency virus or acquired immunodeficiency syndrome-related illness, or chronic hepatitis B or C infection• Serious non-healing wound/ulcer/bone fracture • Malabsorption syndrome • Moderate to severe hepatic impairment (Child-Pugh B or C) • Requirement for hemodialysis or peritoneal dialysis • Uncontrolled diabetes mellitus • History of solid organ transplantation
8. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before randomization. Complete wound healing from major surgery must have occurred 4 weeks before randomization and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before randomization. Subjects with clinically relevant ongoing complications from prior surgery are not eligible. For further exclusion criteria, please, see protocol section 4.3

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by blinded independent radiology committee (BIRC)
2. Objective response rate (ORR) per RECIST 1.1 by BIRC

Secondary endpoints 7

1. Overall survival (OS)
2. Duration of objective tumor response
3. Safety and tolerability
4. Pharmacokinetics (PK) of cabozantinib
5. 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
6. 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)
7. Health care resource utilization

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Exelixis Inc.

Sponsor organisation

Exelixis Inc.

Address

1851 Harbor Bay Parkway

City

Alameda

Postcode

94502-3010

Country

United States

Scientific contact point

Organisation

Exelixis Inc.

Contact name

Exelixis Medical Affairs

Public contact point

Organisation

Exelixis Inc.

Contact name

Exelixis Medical Affairs

Third parties 1

Locations

3 EU/EEA countries · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications