E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable, Locally Advanced, or Metastatic Medullary Thyroid Cancer |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055107 |
E.1.2 | Term | Thyroid cancer metastatic |
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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 |
To evaluate progression-free survival (PFS) with XL184 treatment as compared with placebo in subjects with unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC) |
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E.2.2 | Secondary objectives of the trial |
To evaluate overall survival (OS) with XL184 treatment as compared with placebo To evaluate the objective response rate (ORR) and duration of response in subjects with measurable disease with XL184 treatment as compared with placebo, as per modified Response Evaluation Criteria In Solid Tumors (mRECIST) To evaluate changes in serum levels of calcitonin and carcinoembryonic antigen (CEA) as prognostic biomarkers for XL184 treatment benefit as compared with placebo To assess the potential relationship between RET germline and/or tumor DNA sequence alteration and the efficacy of XL184 To assess the pharmacodynamic effects of XL184 To evaluate the safety and tolerability of XL184 treatment To assess the pharmacokinetics (PK) of XL184 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. The subject has a histologically confirmed diagnosis of MTC that is unresectable, locally advanced, or metastatic, and disease that is measurable or non-measurable per mRECIST. 2. The subject is at least 18 years old. 3. The subject has an ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2. 4. The subject has documented progressive disease (PD) on computerized tomography (CT), magnetic resonance imaging (MRI) bone scan, or X-ray (confirmed by the blinded central independent review committee [IRC]) per mRECIST at screening compared with a previous image done within 14 months of screening. 5. The subject has at least 10 unstained, consecutive slides of one archival tumor block or paraffin block, or a fresh tumor biopsy will be identified by the investigator for shipment to the central lab. The subject may be enrolled without providing slides if the site can provide the Sponsor with documentation of a germline mutation in RET in the subjects blood, or a sporadic mutation in RET in the subjects tumor tissue. 6. The subject has recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Grade ≤ 1 from clinically significant adverse events (AEs) due to anti-neoplastic agents, investigational drugs, or other medications that were administered prior to randomization. 7. The subject has a life expectancy of > 3 months. 8. The subject has organ and marrow function as follows: absolute neutrophil count ≥ 1500/mm3, platelets ≥ 100,000/mm3, hemoglobin ≥ 9 g/dL, bilirubin ≤ 1.5 times the upper limit of normal (does not apply to subjects with Gilberts syndrome), serum creatinine ≤ 1.5 mg/dL, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal. 9. Subjects who are sexually active (male and female) must agree to use medically accepted methods of contraception during the course of the study and for 3 months following discontinuation of study treatments. 10. The subject has no other diagnosis of malignancy (unless non-melanoma skin cancer, carcinoma in situ of the cervix, or a malignancy diagnosed ≥ 2 years previously) and currently has no evidence of malignancy (unless non-melanoma skin cancer or carcinoma in situ of the cervix). 11. Female subjects of childbearing potential must have a negative pregnancy test at screening. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. 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, anti-estrogens, or ovarian suppression. |
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E.4 | Principal exclusion criteria |
1. The subject has received prior systemic anti-tumor therapy (eg, chemotherapy, biologic modifiers, or anti-angiogenic therapy) within 4 weeks of randomization (6 weeks for nitrosoureas or mitomycin C). 2. The subject has received radiation to ≥ 25 % of bone marrow. 3. The subject has received treatment with other investigational agents within 4 weeks of randomization. 4. The subject has received treatment with XL184. 5. The subject has brain metastases or spinal cord compression, unless completed radiation therapy ≥ 4 weeks prior to randomization and stable without steroid and without anti-convulsant treatment for ≥ 10 days. 6. The subject has a history of clinically significant hematemesis or a recent history of hemoptysis of > 2.5 mL of red blood or other signs indicative of pulmonary hemorrhage or evidence of endobronchial lesion(s). 7. The subject has a urine protein/creatinine ratio of ≥ 1 (reported in grams of protein over grams of creatinine). 8. The subject has serious intercurrent illness, such as hypertension (two or more blood pressure readings performed at screening of > 140 mmHg systolic or > 90 mmHg diastolic) despite optimal treatment, unhealed wounds from recent surgery, or cardiac arrhythmias; or a recent history of serious disease such as either symptomatic congestive heart failure or unstable angina pectoris within the past 3 months, or myocardial infarction, stroke, or transient ischemic attack within the past 6 months. 9. The subject is pregnant or breastfeeding. 10. The subject has an active infection requiring systemic treatment. 11. The subject has a known allergy or hypersensitivity to any of the components of the XL184 or placebo formulations (Sections 6.2 and 6.3). 12. The subject is incapable of understanding and complying with the protocol or unable to provide informed consent. |
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E.5 End points |
E.5.1 | Primary end point(s) |
the comparison of progression-free survival (PFS) in subjects treated with XL184 versus placebo. |
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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 | No |
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 | Yes |
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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | Yes |
E.8.2.3 | Other | No |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 53 |
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 | Information not present in EudraCT |
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 |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 10 |