Study of Cabozantinib (XL184) Versus Mitoxantrone Plus Prednisone in Men With Previously Treated Symptomatic Castration-resistant Prostate Cancer

Study Overview
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Brief Summary
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Bone metastases and associated pain are a major cause of morbidity and mortality in castration-resistant prostate cancer (CRPC). Most approved therapies have shown some ability to reduce soft tissue lesions but none meaningfully impacts bone metastases (as demonstrated by lack of resolution of lesions on bone scan with these agents) or the pain associated with these metastases. This study will evaluate the effect of cabozantinib versus mitoxantrone plus prednisone on pain response and bone scan response in men with CRPC.

Official Title
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A Phase 3, Randomized, Double-blind, Controlled Trial of Cabozantinib (XL184) Versus Mitoxantrone Plus Prednisone in Men With Previously Treated Symptomatic Castration-resistant Prostate Cancer

Conditions
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Prostate Cancer, Castration Resistant Prostate Cancer, Pain, Prostatic Neoplasms

Intervention / Treatment
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* Drug: cabozantinib
* Drug: mitoxantrone
* Drug: prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological diagnosis of castration resistant prostate cancer (serum testosterone less than 50 ng/dL). Evidence of bone metastasis related to prostate cancer on bone scans. Documented pain from bone metastases that requires opioid narcotic intervention. Adopted a narcotic regimen that consists of one sustained release opioid agent taken daily for chronic pain and one immediate release opioid agent for breakthrough pain. Received prior docetaxel and either abiraterone or MDV3100 treatment and has evidence of investigator assessed prostate cancer progression on each agent independently. Maintenance of LHRH agonist or antagonist unless treated with orchiectomy. Recovered from toxicities related to any prior treatments, unless the toxicities are clinically non significant or easily manageable. Adequate organ and marrow function. A left-ventricular ejection fraction (LVEF) of >/= 50% assessed by echocardiogram or MUGA (multigated acquisition scan). Capable of understanding and complying with the protocol requirements (including having the ability to access an interactive voice recognition system and self-report pain and narcotic use) and signed the informed consent form. Sexually active fertile patients 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 3 months after the last dose of study treatment. Exclusion Criteria: Prior treatment with cabozantinib or mitoxantrone. Treatment with docetaxel, abiraterone, or MDV3100 in the last 2 weeks; or with any other type of cytotoxic or investigational anticancer agent in the last 2 weeks. Radiation therapy in the last 4 weeks (includes radiation targeting bone metastases), radionuclide treatment in the last 6 weeks, or radiation therapy to the thoracic cavity (unless radiation targets bone metastases) in the past 3 months. Treatment with serotonergic psychiatric medication(s) in the last 2 weeks (5 weeks for fluoxetine). Known brain metastases or uncontrolled epidural disease. Requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or FXa (coagulation factor X) inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin (above low dose levels for cardioprotection per local applicable guidelines), low-dose warfarin (≤ 1 mg/day), and prophylactic low molecular weight heparin are permitted. Uncontrolled, significant intercurrent illness including, but not limited to, cardiovascular disorders, gastrointestinal disorders, active infections, non-healing wounds, recent surgery. Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon of red blood, or other signs indicative of pulmonary hemorrhage in the last 3 months, or history of other significant bleeding in the past 6 months. Cavitating pulmonary lesion(s) or a lesion invading or encasing a major blood vessel. Corrected QT interval (QTc) > 500 ms in the last 4 weeks. Unable to swallow capsules or tablets or tolerate infusions. Previously-identified allergy or hypersensitivity to components of the study treatment formulations investigator or designee. History of another malignancy (except non-melanoma skin cancer, adequately treated stage I colon cancer, superficial transitional carcinoma of the bladder) in the past 2 years.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cabozantinib<br>Subjects randomized to the cabozantinib arm will also receive placebo mitoxantrone injections (color-matched with methylene blue) and placebo prednisone capsules. There will be a maximum of 10 infusions for mitoxantrone placebo. | Drug: cabozantinib<br>* Tablets taken orally once daily.<br>|
| Active Comparator: Mitoxantrone/prednisone<br>Subjects randomized to the mitoxantrone + prednisone arm will also receive placebo cabozantinib tablets. There will be a maximum of 10 infusions for mitoxantrone. | Drug: mitoxantrone<br>* Given by IV once every 3 weeks.<br>Drug: prednisone<br>* Taken twice a day orally by mouth. Commercially-obtained prednisone tablets will be over-encapsulated in order to blind identity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain Response at Week 6 Confirmed at Week 12, Week 12 Reported | The pre-specified primary analysis of Pain Response at Week 6 confirmed at Week 12 was defined as ≥ 30% from baseline in the average daily worst pain intensity score during a 7-day reporting period, with neither a concomitant increase in average daily use of any opioid narcotic type, nor addition of any new opioid narcotic type, relative to baseline. Pain Progression at a given time point is defined as ≥ 30% increase compared with baseline in the average daily worst pain intensity score during a 7-day reporting period or either an increase in the average daily use of any type of opioid narcotic or addition of a new opioid narcotic type compared with baseline. | Pain response was measured at Week 6 and Week 12 by self-reports of subjects | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone Scan Response (BSR) | BSR is defined as >=30% in the bone scan lesion area (BSLA) compared with baseline. Bones scans were evaluated by an independent radiology facility (IRF) for response. | BSR was measured at the end of Week 12 as determined by the IRF | 
| Overall Survival (OS) | OS was defined as the time from randomization to the date of death (due to any cause). Participants that had not died were censored at last known date alive. The analyses for OS occurred after 78/196 deaths (40% of the total required for the pre-specified primary analysis of OS). The data cut-off date was 06 October 2014. Median OS was calculated using Kaplan-Meier estimates. | OS was measured at the time of randomization until 78 deaths | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRPC, prostate cancer, castration resistant prostate cancer, bone pain