| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration-resistant Prostate Cancer (CRPC) |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The objective of this study is to evaluate the effect of cabozantinib compared to prednisone on overall survival in men with previously treated metastatic castration-resistant prostate cancer with bone-dominant disease who have experienced disease progression on docetaxel-containing chemotherapy and abiraterone or MDV3100.
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Documented histological or cytological diagnosis of prostate cancer.
2. Serum testosterone levels less than 50 ng/dL (< 1.75 nmol/L) within 28 days before randomization.
3. Evidence of bone metastasis related to prostate cancer on bone scans from a protocol-credentialed scanner within 28 days before randomization.
4. The subject must have received prior docetaxel (minimum cumulative dose of 225 mg/m2) and either abiraterone or MDV3100 treatment and have evidence of investigator-assessed prostate cancer progression on each agent independently.
For docetaxel: subjects must have progressed during or after docetaxel-containing therapy.
For abiraterone or MDV3100: subjects must have experienced disease progression during abiraterone or MDV3100 therapy.
Prostate cancer progression is defined as:
a. PSA progression according to modified PCWG2 (Prostate Cancer Working Group 2) criteria: PSA level of at least 2 ng/mL (2 µg/L) which has subsequently risen on at least 2 successive occasions, at least 2 weeks apart. If the second risen value is lower than the first risen value, then an additional test for rising PSA will be required to document progression. The value of the additional test must be higher than the first risen value (Scher et al. 2008).
or
b. Radiographic progression in soft tissue or bone lesions.
Note: There is no limit on other prior anti-cancer treatments, including prior cabazitaxel (except Exclusion Criterion #1).
5. Subjects without prior orchiectomy must be currently taking and willing to continue LHRH analogue (agonist or antagonist) therapy until permanent discontinuation of study treatment.
6. The subject must have recovered to baseline or CTCAE v.4.0 (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. ≥ 18 years old on the day of consent.
8. ECOG performance status 0-2
9. Adequate organ and marrow function, defined as follows, based upon laboratory tests performed within 7 days before randomization:
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L)
b. Platelets ≥ 100,000/mm3 (≥ 100 GI/L)
c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L)
d. Total bilirubin ≤ 1.5 x the upper limit of normal (for subjects with Gilbert’s disease, ≤ 3 mg/dL or ≤ 51.3 µmol/L)
e. Serum albumin ≥ 2.8 g/dL (≥ 28 g/L)
f. Serum creatinine ≤ 1.5 x the upper limit of normal or calculated creatinine clearance ≥ 50 mL/min (≥ 0.84 mL/sec; by the Cockcroft –Gault method) or GFR > 30 mL/min (> 0.50 mL/sec).
Note: For GFR estimation, the Cockcroft and Gault equation should be used [GFR = CrCl (mL/min) = (140 - age) x wt (kg)/(serum creatinine x 72)]
g. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 x the upper limit of normal
h. Lipase < 1.5 times the upper limit of normal
i. Serum phosphorus ≥ lower limit of normal
j. Urine protein/creatinine ratio (UPCR) ≤ 1 (≤ 113.17 mg/mmol creatinine)
10. The subject must be capable of understanding and complying with the protocol requirements and must have signed the informed consent document.
11. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment.
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| E.4 | Principal exclusion criteria |
1. The subject received prior cabozantinib.
2. The subject has received docetaxel, abiraterone or MDV3100 within 2 weeks before randomization.
3. The subject has received any other type of anti-cancer agent (except agents to maintain castrate status) within 2 weeks before randomization.
4. The subject has received radiation therapy within 4 weeks (includes radiation targeting bone metastases) or radionuclide treatment within 6 weeks of randomization. Subject is excluded if there is any prior history of radiation therapy to the mediastinum (unless radiation targeted bone metastases).
5. The subject has known brain metastases or cranial epidural disease
6. The subject requires at the time of randomization therapeutic doses of anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or FXa inhibitors, antiplatelet agents (eg, clopidogrel), aspirin above low dose levels for cardioprotection per local applicable guidelines, or aspirin in combination with dipyridamole. Use of agents other than warfarin or warfarin-related agents is allowed if doses are in accordance with prescribing information for prophylaxis for thromboembolic events.
Note: Therapeutic doses of heparin are allowed as clinically indicated for supportive treatment after randomization (see Section 7.2).
7. The subject requires chronic concomitant treatment of strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s Wort).
8. Uncontrolled and/or significant intercurrent illness including, but not limited to, the following conditions:
a. Cardiovascular disorders such as symptomatic congestive heart failure (CHF), uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment (BP must be controlled at screening), unstable angina pectoris, clinically-significant cardiac arrhythmias, history of stroke (including TIA, or other ischemic event) within 6 months before randomization, myocardial infarction within 6 months before randomization, history of thromboembolic event within 6 months before randomization
b. Gastrointestinal disorders such as malabsorption syndrome or gastric outlet obstruction.
c. Risks for GI perforation or fistula formation which include intra-abdominal tumor/metastases invading GI tract; active peptic ulcer disease, active inflammatory bowel disease, active ulcerative colitis, active diverticulitis, active cholecystitis or active symptomatic cholangitis or active appendicitis; history of abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess, or prior GI surgery (particularly when associated with delayed or incomplete healing) within 6 months before first dose of study treatment. Complete healing following abdominal surgery or resolution of intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib.
d. Risk for non-GI fistula formation which includes previous surgical intervention (such as PEG tube placement) and evidence of intraluminal disease involving the trachea or esophagus.
e. Other disorders such as active infection requiring systemic treatment; serious non-healing wound/ulcer/bone fracture; organ transplant; uncompensated hypothyroidism, uncontrolled diabetes mellitus
f. History of surgery within 6 months before randomization:
• With wound healing complications – major surgery within 6 months, minor surgery within 3 months;
• Without wound healing complications – major surgery within 3 months, minor surgery within 1 month
• Note: Complete wound healing from prior surgery is required at least 30 days before randomization.
9. Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon of red blood, or other signs indicative of pulmonary hemorrhage within 3 months, or history of other significant bleeding within 6 months before randomization.
10. The subject has cavitating pulmonary lesion(s) or a lesion invading or encasing a major blood vessel.
11. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 msec within 7 days before randomization (see Section 5.5.4 for Fridericia formula).
Three ECGs separated by approximately 3 minutes or longer must be performed. If the average of these three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in this regard
12. The subject is unable to swallow tablets or capsules.
13. Previously-identified allergy or hypersensitivity to components of the study treatment formulations.
14. The subject has had another diagnosis of malignancy (except non-melanoma skin cancer, adequately treated stage I colon cancer, superficial transitional carcinoma of the bladder) within 2 years before randomization.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Overall survival is defined as the time from the date of randomization to the date of death (due to any cause). Subjects not known to have expired at the time of analysis will generally be censored at the date last known alive. Detailed censoring rules for overall survival will be described in the SAP. |
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| E.5.2 | Secondary end point(s) |
| Bone scan response at the end of Week 12 by IRF. The stratified CMH test will be used as the primary analysis of this endpoint. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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) | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 148 |
| 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 |
| Belgium |
| Canada |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Puerto Rico |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
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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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| Subjects will be followed until death or the Sponsor decides to no longer collect these data. |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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