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 | 17.0 |
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
docetaxelcontaining
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
intraabdominal
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
nonmelanoma
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 | Yes |
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 | 29 |
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 |