| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Progressive Metastatic Medullary Thyroid Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Medullary thyroid cancer, a rare type of thyroid cancer, that has spread to other parts of the body |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10027105 |
| E.1.2 | Term | Medullary thyroid cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 mL/min (using the Cockcroft-Gault equation: CrCl (mL/min) = (140 – age) x wt (kg) / (serum creatinine [mg/dL] x 72); for females multiply by 0.85
g. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein < 1 g
h. Prothrombin time (PT)/INR or partial thromboplastin time (PTT) test results at screening ≤ 1.3 x the laboratory ULN
10. The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.
11. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (defined in Appendix E) during the course of the study and for 4 months after the last dose of study treatment.
12. Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing
potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or other reasons. |
|
| E.4 | Principal 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 surgery must have occurred at least 7 days before randomization. Subjects with clinically relevant complications from prior surgery are not eligible
d. Cavitating pulmonary lesion(s) or endobronchial disease
e. Lesion invading a major blood vessel (eg, pulmonary artery, aorta, carotid artery, or vena cava)
f. Clinically significant bleeding risk including the following within 3 months of randomization: hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) of red blood, or other signs indicative of pulmonary hemorrhage, or history of other significant bleeding if not due to reversible external factors
g. Other clinically significant disorders such as:
i. Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)-related illness
ii. Serious non-healing wound/ulcer/bone fracture
iii. Malabsorption syndrome
iv. Uncompensated/symptomatic hypothyroidism
v. History of solid organ transplantation
9. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before randomization. Note: If the QTcF is >500 ms in the first ECG, a total of three ECGs should be performed. If the average of these three consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard.
10. The subject is unable to swallow multiple tablets or capsules
11. The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation
12. The subject is pregnant or breastfeeding
13. The subject has had a diagnosis of another malignancy within 2 years before randomization, except for superficial scan cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS) per RECIST 1.1 per independent radiology review |
|
| E.5.1.1 | 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. |
|
| E.5.2 | Secondary end point(s) |
•Objective response rate (ORR) per RECIST 1.1 per independent radiology review
•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
•Pharmacokinetics (PK) of Cabozantinib
•Biochemical response to cabozantinib as assessed by the plasma tumor markers including calcitonin (CTN) and carcinoembryonic antigen (CEA)
•Pharmacodynamic effects of cabozantinib on plasma biomarkers of cabozantinib target pathway inhibition and bone turnover
•Correlation of germline and somatic genetic alterations to tumor response or resistance, cabozantinib exposure, and/or toxicity. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Cabozantinib (XL184) 140 mg/Day |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Canada |
| Croatia |
| France |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Sweden |
| Turkey |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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