Study of two different doses of cabozantinib in progressive, metastatic medullary thyroid cancer

Phase 1

• Conditions: Progressive Metastatic Medullary Thyroid Cancer; MedDRA version: 21.1Level: PTClassification code 10027105Term: Medullary thyroid cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Hormonal diseases [C19]

• Registration Number: EUCTR2013-003402-40-IT
• Lead Sponsor: EXELIXIS, INC.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-01-22
• Last Update Posted: 10 August 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 250

Inclusion Criteria

1. The subject has a histologically confirmed diagnosis of MTC.
2. Availability of tumor tissue for shipment to the central laboratory according to prior determination of RET mutation status:
a. For subjects lacking evidence of a RET or RAS mutation, a recent tumor tissue sample (defined as collected within 6 months prior to randomization) will be required. Tissue shall come from a progressive tumor location, preferably from the most recently progressed metastatic site if feasible. If a recent tumor sample is not available, a tumor biopsy will be obtained during screening.
b. Subjects with documentation of a RET or RAS mutation found in tumor tissue will not be required to submit a recent tumor tissue sample; however, the report demonstrating the subject’s RET or RAS mutation must be reviewed and approved by the sponsor prior to subject randomization.
c. For subjects with documentation of a hereditary RET mutation (ie, pathology report showing presence of a specific RET mutation identified in a blood sample), a tumor sample will not be required. Review and approval of the RET mutation report by the sponsor is required prior to randomization of the subject.
3. The subject has MTC that is metastatic as determined by the investigator based upon computerized tomography (CT), magnetic resonance imaging (MRI), bone scan, PET scan, or X-ray taken within 28 days before randomization.
4. The subject has disease that is measurable per RECIST 1.1 as determined by the investigator based upon CT or MRI images taken within 28 days before randomization.
5. The subject has documented progressive disease (PD) on CT, MRI, PET scan, bone scan, or X-ray as determined by the investigator per RECIST 1.1 on qualifying images taken within 4 months prior to randomization as compared to previous images taken within 14 months before the qualifying screening images.
a. PET scan can only be used to establish PD by the presence of new lesions (not to document increases in target or non-target lesions).
b. Bone scan or x-ray, can only be used to establish PD by the presence of new lesions in bone (not to document increases in target or non-target lesions).
6. The subject has recovered to baseline or CTCAE v4.0 (Common Terminology Criteria for Adverse Events, version 4.0) = Grade 1 from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy.
7. The subject is = 18 years old on the day of consent.

(For the full list of the INCL criteria please refer to the PROT)
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 139
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 72

Exclusion Criteria

1. The subject has previously received cabozantinib
2. The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (incl. investigational kinase inhibitors or hormones) within 28 days or five half-lives of the compound or active metabolites, whichever is shorter before randomization or at any time after the date of the qualifying images used to document PD for eligibility
3. The subject has received prior systemic anti-tumor therapy (eg, chemotherapy, biologic modifiers, or anti-angiogenic therapy) within 28 days of randomization (42 days for nitrosoureas or/ mitomycin C) or at any time after the date of the qualifying images used to document PD for eligibility
4. The subject has received any other type of investigational agent within 28 days before randomization or at any time after the date of the qualifying images used to document PD for eligibility
5. The subject has received radiation therapy within 28 days (14 days for radiation for bone metastases) or radionuclide treatment within 42 days of randomization. Subject is ineligible if there are any clinically relevant ongoing complications from prior radiation therapy
6. The subject has untreated and/or active (progressing or requiring anticonvulsants or corticosteroids for symptomatic control) central nervous system (CNS) metastasis. Must have completed radiation therapy = 28 days prior to randomization and stable without corticosteroids or anti-convulsant treatment for = 10 days
7. Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors
(For the full list of the EXCL criteria please refer to the PROT)

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 efficacy of oral cabozantinib at a daily dose of 60 mg compared with 140 mg in subjects with progressive metastatic medullary thyroid cancer.;Secondary Objective: Not applicable;Primary end point(s): Progression free survival (PFS) per RECIST 1.1 per independent radiology review;Timepoint(s) of evaluation of this end point: At screening and every 12 weeks (± 5 days) after randomization.<br>Assessments should continue regardless of whether study treatment is given, reduced, or discontinued through the earlier of 12 weeks after radiographic progression per RECIST 1.1 as determined by the investigator (ie, one additional assessment after investigator determined progression), or the date of initiation of subsequent systemic anti-cancer therapy.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): -Objective response rate (ORR) per RECIST 1.1 per independent radiology review<br>-Safety and tolerability of cabozantinib as assessed by AEs including hemorrhage, gastrointestinal and non-gastrointestinal fistulas,gastrointestinal perforation, hypertension, diarrhea, oral mucositis/stomatitits, and PPE, changes in laboratory parameters, and frequency of dose modifications<br>-Pharmacokinetics (PK) of Cabozantinib<br>-Biochemical response to cabozantinib as assessed by the plasma tumor markers including calcitonin (CTN) and carcinoembryonic antigen (CEA)<br>-Pharmacodynamic effects of cabozantinib on plasma biomarkers of cabozantinib target pathway inhibition and bone turnover<br>-Correlation of germline and somatic genetic alterations to tumor response or resistance, cabozantinib exposure, and/or toxicity.;Timepoint(s) of evaluation of this end point: At scheduled visits.