| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| castration-resistant prostate cancer (CRPC) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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) |
|
| 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 safety and efficacy of cabozantinib compared with mitoxantrone plus prednisone. |
|
| 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 must have an histological or cytological diagnosis of CRPC (including serum testosterone levels less than 50 ng/dL within 28 days before randomization).
2. The subject must have evidence of bone metastasis related to prostate cancer on bone scans from a protocol credentialed scanner within 28 days before randomization.
3. The subject must have documented pain from bone metastases that requires opioid narcotic intervention. The average daily worst pain intensity reported by the subject during the 7 day Run In Stage, with a minimum of 4 days of reporting, must be at least 4 but no more than 8 on an 11-point NRS.
4. The subject must have adopted a narcotic regimen that consists of one SR opioid agent taken daily for chronic pain (taken on a minimum of 5 days out of the 7 day Run-In Stage) and one IR opioid agent for breakthrough pain, documented during the Run In Stage. The narcotic analgesic regimen must be optimized to provide maximal pain relief without intolerable narcotic-related side effects, according to subject’s goals for comfort and function (see Appendix E).
Note: Subjects requiring narcotic infusions (other than IV push) at screening are not eligible for the study.
5. The subject must have received prior docetaxel and either abiraterone or MDV3100 treatment. For docetaxel: subjects must have received a minimum of three cycles or progressed during or after any amount of a docetaxel containing therapy.
For abiraterone or MDV3100: subjects must have discontinued abiraterone or MDV3100 due to disease progression.
Prostate cancer progression is defined as:
a. PSA progression according to PCWG2 (Prostate Cancer Working Group 2) criteria: PSA level of at least 2 ng/mL 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 anticancer treatments, including prior cabazitaxel (except Exclusion Criterion #1).
6. Subjects without prior orchiectomy must be currently taking and willing to continue LHRH analogue (agonist or antagonist) therapy until permanent discontinuation of study treatment.
7. The subject must have recovered to baseline or CTCAE v.4.0 ≤ Grade 1 from toxicities related to any prior treatments, unless AE(s) are clinically non significant or easily manageable (eg, hypertension, hypoalbuminemia, hypophosphatemia).
8. The subject must be ≥ 18 years old on the day of consent.
9. The subject must have adequate organ and marrow function assessed within 7 days before randomization, based on the following:
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 (for subjects with Gilbert’s disease, ≤ 3 mg/dL)
e. Serum albumin ≥ 2.8 g/dL
f. Serum creatinine ≤ 1.5 x the upper limit of normal or estimated calculated creatinine clearance ≥ 60 mL/min (using the Cockcroft Gault equation) or glomerular filtration rate (GFR) > 40 mL/min (using a 24 hour urine creatinine clearance test)
Note: Cockcroft Gault creatinine clearance (mL/min) = (140 - age) x weight (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
10. The subject must have a left-ventricular ejection fraction of ≥ 50% assessed within 28 days before randomization by echocardiogram or multigated acquisition scan (MUGA)
11. The subject must be capable of understanding and complying with the protocol requirements (including having the ability to access an IVRS and self-report pain and narcotic use) and must have signed the ICF.
12. 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 6 months after the last dose of study treatment. |
|
| E.4 | Principal exclusion criteria |
1. The subject has received any prior cabozantinib or mitoxantrone.
2. The subject has received docetaxel, abiraterone, or MDV3100 within 2 weeks before randomization.
3. The subject has received any other type of cytotoxic or investigational anticancer agent within 2 weeks before randomization.
4. The subject has received radiation therapy within 4 weeks (includes radiation targeting bone metastases), radionuclide treatment within 6 weeks, or radiation therapy to the thoracic cavity unless radiation targets bone metastases) within 3 months before randomization.
5. The subject has received serotonergic psychiatric medication(s) (Appendix J) within 2 weeks (5 weeks for fluoxetine) before randomization.
6. The subject has known brain metastases or uncontrolled epidural disease.
7. The subject requires at the time of randomization any of the following:
a. Therapeutic doses of anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or FXa (coagulation factor X) inhibitors, antiplatelet agents (eg, clopidogrel), aspirin above low dose levels for cardioprotection per local applicable guidelines, or aspirin in combination with dipyridamole.
Note: Therapeutic doses of heparin are allowed as clinically indicated for supportive treatment after randomization (see Section 7.2).
b. Any additional drugs or herbal products used for the treatment of prostate cancer (including but not limited to chemotherapies other than mitoxantrone, bicalutamide, nilutamide, ketoconazole, diethylstilbestrol [DES], 5 α reductase inhibitors [finasteride, dutasteride], Saw Palmetto, and PC-SPES)
8. The subject has uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
a. Cardiovascular disorders such as symptomatic congestive heart failure, uncontrolled hypertension defined as sustained blood pressure (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 (transient ischemic attack 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, symptomatic cholangitis or gastric outlet obstruction, history of gastric/intestinal perforation, abdominal fistula, or intra-abdominal abscess within 6 months before randomization
c. Other disorders such as active infection requiring systemic treatment; serious non-healing wound/ulcer/bone fracture; organ transplant; uncompensated hypothyroidism
d. History of surgery within 1-6 months before randomization:
i. With wound healing complications – major surgery within 6 months, minor surgery within 3 months;
ii. 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 28 days before randomization.
9. The subject has experienced 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. The subject has a corrected QT interval (QTc) > 500 ms within 28 days before randomization.
12. The subject is unable to swallow capsules or tablets or tolerate infusions.
13. The subject has a previously-identified allergy or hypersensitivity to components of the study treatment formulations.
14. The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.
15. 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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the proportion of subjects with pain response at Week 6 confirmed at Week 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Bone scan response at Week 12 per IRF (primary analysis designates subjects with soft tissue progression as non-responders): The stratified CMH test will be used as the primary analysis of this endpoint.
• Overall survival: The stratified log-rank test will be used as the primary analysis for this endpoint. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Bone scan response: Week 12
Overall survival: 28 months after the first subject is randomized (expected July 2014). |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Canada |
| Ireland |
| United Kingdom |
| United States |
|
| 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
|
| When the required number of events have been observed for the final overall survival (OS) analysis. |
|
| 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 | 8 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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