Castration Resistant Prostate Cancer, Pain, Prostate Cancer, Prostatic Neoplasms
Conditions
Keywords
prostate cancer, castration resistant prostate cancer, bone pain, CRPC
Brief summary
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.
Interventions
DRUGcabozantinib
Tablets taken orally once daily.
DRUGmitoxantrone
Given by IV once every 3 weeks.
DRUGprednisone
Taken twice a day orally by mouth. Commercially-obtained prednisone tablets will be over-encapsulated in order to blind identity.
Sponsors
Exelixis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Response at Week 6 Confirmed at Week 12, Week 12 Reported | Pain response was measured at Week 6 and Week 12 by self-reports of subjects | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bone Scan Response (BSR) | BSR was measured at the end of Week 12 as determined by the IRF | 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. |
| Overall Survival (OS) | OS was measured at the time of randomization until 78 deaths | 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. |
Countries
Australia, Canada, Ireland, United Kingdom, United States
Participant flow
Recruitment details
First patient enrolled: 15 March 2012, Data cut off date: 06 October 2014. The study was terminated by the Sponsor after 119 subjects were enrolled which was less than the planned sample size of 246 subjects.
Participants by arm
| Arm | Count |
|---|---|
| Cabozantinib Subjects randomized to the cabozantinib arm will also receive placebo mitoxantrone injections (color-matched with methylene blue) and placebo prednisone capsules.
Cabozantinib (XL184) 60 mg tablets taken orally once daily and mitoxantrone-matched placebo infusion every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily. | 61 |
| Mitoxantrone/Prednisone Subjects randomized to the mitoxantrone + prednisone arm will also receive placebo cabozantinib tablets.
Mitoxantrone (12mg/m\^2) given by IV once every 3 weeks (maximum of 10 infusions) plus prednisone-matched placebo capsules orally twice daily. | 58 |
| Total | 119 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 15 |
| Overall Study | No longer receiving clinical benefit | 36 | 28 |
| Overall Study | No study treatment given | 1 | 1 |
| Overall Study | Other | 1 | 3 |
| Overall Study | Withdrawal by Subject | 5 | 8 |
Baseline characteristics
| Characteristic | Cabozantinib | Mitoxantrone/Prednisone | Total |
|---|---|---|---|
| Age, Customized 65 to <75 years | 30 participants | 26 participants | 56 participants |
| Age, Customized <65 years | 24 participants | 26 participants | 50 participants |
| Age, Customized 75 to <85 years | 7 participants | 6 participants | 13 participants |
| Bone-scan lesion area (BSLA) | 72865.0 mm^2 | 72702.5 mm^2 | 72865.0 mm^2 |
| ECOG Performance Status (per IVRS/IWRS) 0-1 (normal to symptoms, but ambulatory) | 53 participants | 52 participants | 105 participants |
| ECOG Performance Status (per IVRS/IWRS) ≥2 (ambulatory to incapable of self-care/death) | 8 participants | 6 participants | 14 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants | 57 Participants | 114 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Geographic Region Asia | 9 participants | 9 participants | 18 participants |
| Geographic Region Europe | 8 participants | 13 participants | 21 participants |
| Geographic Region North America | 44 participants | 36 participants | 80 participants |
| Gleason score at diagnosis (Primary + Secondary) 7 | 17 participants | 21 participants | 38 participants |
| Gleason score at diagnosis (Primary + Secondary) <7 | 2 participants | 4 participants | 6 participants |
| Gleason score at diagnosis (Primary + Secondary) >7 | 40 participants | 28 participants | 68 participants |
| Gleason score at diagnosis (Primary + Secondary) Missing | 0 participants | 1 participants | 1 participants |
| Gleason score at diagnosis (Primary + Secondary) Unknown | 2 participants | 4 participants | 6 participants |
| Number of prior anticancer agents 2 | 0 Participants | 3 Participants | 3 Participants |
| Number of prior anticancer agents 3 | 6 Participants | 4 Participants | 10 Participants |
| Number of prior anticancer agents 4 | 20 Participants | 14 Participants | 34 Participants |
| Number of prior anticancer agents ≥5 | 35 Participants | 37 Participants | 72 Participants |
| Pain score (BPI Item 3) during Run-In Stage 4-5 | 10 participants | 15 participants | 25 participants |
| Pain score (BPI Item 3) during Run-In Stage >5-6 | 22 participants | 13 participants | 35 participants |
| Pain score (BPI Item 3) during Run-In Stage >6-7 | 18 participants | 15 participants | 33 participants |
| Pain score (BPI Item 3) during Run-In Stage >7-8 | 11 participants | 15 participants | 26 participants |
| Pain score (BPI Item 3) during Run-In Stage | 6.00 units on a scale | 6.14 units on a scale | 6.00 units on a scale |
| Prior cabazitaxel (per IVRS/IWRS) No | 36 Participants | 34 Participants | 70 Participants |
| Prior cabazitaxel (per IVRS/IWRS) Yes | 25 Participants | 24 Participants | 49 Participants |
| Prior prostate surgery/procedure Bilateral orchiectomy | 4 participants | 2 participants | 6 participants |
| Prior prostate surgery/procedure Cyrosurgery | 0 participants | 1 participants | 1 participants |
| Prior prostate surgery/procedure Other | 55 participants | 52 participants | 107 participants |
| Prior prostate surgery/procedure Radical prostatectomy - with | 17 participants | 13 participants | 30 participants |
| Prior prostate surgery/procedure Radical prostatectomy - without | 3 participants | 2 participants | 5 participants |
| Prior prostate surgery/procedure Transurethral resection of the prostate (TURP) | 8 participants | 6 participants | 14 participants |
| Race/Ethnicity, Customized American Indian/Alaska Native | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized Black/African-American | 8 participants | 3 participants | 11 participants |
| Race/Ethnicity, Customized Multiple | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Not Reported | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 49 participants | 51 participants | 100 participants |
| Randomization Stratification Factors (per IVRS/IWRS) ECOG = 0-1 and prior cabazitaxel: no | 35 participants | 34 participants | 69 participants |
| Randomization Stratification Factors (per IVRS/IWRS) ECOG = 0-1 and prior cabazitaxel: yes | 18 participants | 18 participants | 36 participants |
| Randomization Stratification Factors (per IVRS/IWRS) ECOG ≥ 2 and prior cabazitaxel: no | 1 participants | 0 participants | 1 participants |
| Randomization Stratification Factors (per IVRS/IWRS) ECOG ≥ 2 and prior cabazitaxel: yes | 7 participants | 6 participants | 13 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 61 Participants | 58 Participants | 119 Participants |
| Sites of prostate cancer metastasis Bone | 61 participants | 58 participants | 119 participants |
| Sites of prostate cancer metastasis Lymph node | 29 participants | 18 participants | 47 participants |
| Sites of prostate cancer metastasis Other soft tissue | 7 participants | 3 participants | 10 participants |
| Sites of prostate cancer metastasis Visceral (soft tissue; liver) | 8 participants | 8 participants | 16 participants |
| Sites of prostate cancer metastasis Visceral (soft tissue; lung) | 2 participants | 5 participants | 7 participants |
| Time from initial diagnosis to randomization | 4.7 years | 5.3 years | 5.0 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 60 / 60 | 57 / 57 |
| serious Total, serious adverse events | 16 / 60 | 15 / 57 |
Outcome results
Primary
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.
Time frame: Pain response was measured at Week 6 and Week 12 by self-reports of subjects
Population: The primary analysis of pain response was based on the Intent to Treat (ITT) population of 119 participants (61 cabozantinib, 58 mitoxantrone plus prednisone).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib | Pain Response at Week 6 Confirmed at Week 12, Week 12 Reported | 15 percentage of responders |
| Mitoxantrone/Prednisone | Pain Response at Week 6 Confirmed at Week 12, Week 12 Reported | 17 percentage of responders |
p-value: 0.773Cochran-Mantel-Haenszel
Secondary
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.
Time frame: BSR was measured at the end of Week 12 as determined by the IRF
Population: Analysis was conducted on the randomized ITT population (61 cabozantinib, 58 mitoxantrone plus prednisone) for BSR at Week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib | Bone Scan Response (BSR) | 31 percentage of responders |
| Mitoxantrone/Prednisone | Bone Scan Response (BSR) | 5.2 percentage of responders |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
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.
Time frame: OS was measured at the time of randomization until 78 deaths
Population: The Intent to Treat (ITT) population was used and included 119 randomized subjects (61 cabozantinib, 58 mitoxantrone plus prednisone) at the time of primary analysis (data cut off date: 06 October 2014).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabozantinib | Overall Survival (OS) | 9.0 months |
| Mitoxantrone/Prednisone | Overall Survival (OS) | 7.9 months |
p-value: 0.12195% CI: [0.44, 1.1]Log Rank