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

Phase 1

Conditions: Progressive Metastatic Medullary Thyroid Cancer
MedDRA version: 21.1 Level: PT Classification code 10027105 Term: Medullary thyroid cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2013-003402-40-HU

Lead Sponsor: Exelixis, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: Not specified

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 the 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 images (see Protocol Section 5.5.6.2).
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.
8. The subject has an ECOG (Eastern Cooperative Oncology Group) status = 1 at screening.
9. The subject has adequate organ and marrow function, based upon the following laboratory criteria from assessments performed within 28 days before randomization
a. Absolute neutrophil count (ANC) = 1500/mm3
b. Platelets = 100,000/mm3
c. Hemoglobin = 9 g/dL
d. Total bilirubin = 1.5 x the upper limit of normal (ULN). For subjects with known Gilbert’s disease, total bilirubin = 3.0 mg/dL.
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 x ULN
f. Serum creatinine = 1.5 x ULN or creatinine clearance = 50

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
8. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
a. Cardiovascular disorders incl.
i. Symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac arrhythmias
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment
iii. Stroke (incl. transient ischemic attack [TIA]), myocardial infarction, or other ischemic event within 6 months before randomization
iv. Thromboembolic event within 3 months before randomization.
b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before randomization,
Note: Complete healing must be confirmed prior to randomization, including radiographic evidence of complete resolution of abdominal abscess
c. Major surgery (eg, open surgery of the chest or abdominal cavity, surgery involving the viscera or removal of a large amount of tissue, removal or biopsy of brain metastasis) within 2 months before randomization. Complete healing from major surgery must have occurred 1 month before randomization. Complete healing from minor s

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<br> Main Objective: The objective of this study is to evaluate the efficacy of oral cabozantinib at a<br> daily dose of 60 mg compared with 140 mg in subjects with progressive<br> metastatic medullary thyroid cancer.<br> ;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. 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

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