Castration Resistant Prostate Cancer, Pain, Prostate Cancer, Prostatic Neoplasms
Conditions
Keywords
prostate cancer, castration resistant prostate cancer, bone pain, CRPC
Brief summary
This study will 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.
Interventions
DRUGcabozantinib
Tablets taken orally once-daily
DRUGprednisone
Taken twice a day orally. 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. * Received prior docetaxel (minimum cumulative dose of 225 mg/m2) and either abiraterone or MDV3100 treatment and has evidence of 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. * Capable of understanding and complying with the protocol requirements 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 4 months after the last dose of study treatment.
Exclusion criteria
* Prior treatment with cabozantinib. * 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 within 4 weeks (excluded if to mediastinum) or radionuclide treatment within 6 weeks of randomization. * Known brain metastases or cranial epidural disease. * Requires concomitant treatment, in therapeutic doses, with anticoagulants. * Requires chronic concomitant treatment of strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort). * 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, 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. * QTcF \> 500 ms within 7 days of randomization. * Unable to swallow capsules or tablets. * Previously-identified allergy or hypersensitivity to components of the study treatment formulations. * Another diagnosis of malignancy requiring systemic treatment within 2 years of randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | OS was measured from the time of randomization until 614 events, approximately 24 months after study start | The primary analysis of OS is defined as the time from randomization to death due to any cause. Participants that had not died or were permanently lost to follow-up were censored at the last known date alive. Median OS was calculated using Kaplan-Meier estimates. Analysis for OS was performed after 614 events had occurred. |
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% reduction in the bone scan lesion area (BSLA) compared with baseline. Confirmation of bone scan was not required for response or progression. Bone scans were evaluated by an independent radiology facility (IRF) for response. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Duration of PFS was defined as time from the date of randomization to earlier of date of radiographic progression (bone/andor soft tissue) according to the investigator's assessment or death, assessed for up to approximately 24 months | The exploratory analysis of PFS is the time from randomization to date of first documented radiographic progression (bone and/or soft tissue) according to the investigator's assessment or death. PFS was defined per mRECIST 1.1 and included evaluation of measurable, nonmeasurable, target and nontarget lesions. A Kaplan-Meier analysis was performed to estimate the median duration. |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Ireland, Italy, Netherlands, Puerto Rico, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
First patient enrolled: 02 July 2012 (first subject randomized), Data cut off date: 07 July 2014
Participants by arm
| Arm | Count |
|---|---|
| Cabozantinib Subjects randomized to the cabozantinib arm will also receive placebo-matched prednisone capsules.
Cabozantinib (XL184) 60 mg tablets orally once daily plus prednisone-matched placebo orally twice daily. | 682 |
| Prednisone Subjects randomized to the prednisone arm will also receive placebo-matched cabozantinib.
Prednisone 5 mg capsules orally twice daily plus cabozantinib-matched placebo orally once daily. | 346 |
| Total | 1,028 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 228 | 42 |
| Overall Study | Clinical Deterioration | 227 | 133 |
| Overall Study | Did not receive study treatment | 2 | 3 |
| Overall Study | Dose Held >6 weeks | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 9 | 7 |
| Overall Study | Progressive Disease | 132 | 128 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Sponsor Decision | 2 | 0 |
| Overall Study | Started New Therapy | 1 | 0 |
| Overall Study | Subject Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 18 | 14 |
Baseline characteristics
| Characteristic | Cabozantinib | Prednisone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 517 Participants | 249 Participants | 766 Participants |
| Age, Categorical Between 18 and 65 years | 165 Participants | 97 Participants | 262 Participants |
| Baseline LDH | 230 U/L | 230 U/L | 230 U/L |
| Baseline PSA | 192 μg/L | 195 μg/L | 192 μg/L |
| Baseline serum testosterone (<50 ng/dL) | 677 Participants | 345 Participants | 1022 Participants |
| Bone scan lesion area | 45,635.5 mm^2 | 41,746.0 mm^2 | 44,782.0 mm^2 |
| Brief Pain Inventory (BPI) Item 3 (per CRF) <4 | 389 Participants | 196 Participants | 585 Participants |
| Brief Pain Inventory (BPI) Item 3 (per CRF) ≥4 | 284 Participants | 148 Participants | 432 Participants |
| Brief Pain Inventory (BPI) Item 3 (per CRF) Missing | 9 Participants | 2 Participants | 11 Participants |
| Concomitant prednisone/prednisolone at randomization | 289 Participants | 142 Participants | 431 Participants |
| ECOG Performance Status (per CRF) 0/1 (asymptomatic or symptomatic but ambulatory) | 605 participants | 303 participants | 908 participants |
| ECOG Performance Status (per CRF) 2 (ambulatory but can't carry out work activities) | 76 participants | 43 participants | 119 participants |
| ECOG Performance Status (per CRF) Missing | 1 participants | 0 participants | 1 participants |
| Extent of metastasis Bone | 681 participants | 346 participants | 1027 participants |
| Extent of metastasis Liver | 91 participants | 35 participants | 126 participants |
| Extent of metastasis Lung | 69 participants | 29 participants | 98 participants |
| Extent of metastasis Lymph node | 313 participants | 140 participants | 453 participants |
| Extent of metastasis None | 0 participants | 0 participants | 0 participants |
| Extent of metastasis Other soft tissue | 39 participants | 23 participants | 62 participants |
| Extent of metastasis Visceral | 133 participants | 58 participants | 191 participants |
| No. of prior anticancer agents 2 | 57 participants | 31 participants | 88 participants |
| No. of prior anticancer agents ≥3 | 625 participants | 315 participants | 940 participants |
| Opioid narcotic use within 24 hours (per solicited oploid CRF) | 454 Participants | 228 Participants | 682 Participants |
| Prior cabazitaxel (per CRF) No | 421 Participants | 214 Participants | 635 Participants |
| Prior cabazitaxel (per CRF) Yes | 261 Participants | 132 Participants | 393 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 6 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 146 Participants | 74 Participants | 220 Participants |
| Race (NIH/OMB) White | 520 Participants | 265 Participants | 785 Participants |
| Region of Enrollment Australia | 35 Participants | 27 Participants | 62 Participants |
| Region of Enrollment Europe | 528 Participants | 256 Participants | 784 Participants |
| Region of Enrollment North America | 119 Participants | 63 Participants | 182 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 682 Participants | 346 Participants | 1028 Participants |
| Time from diagnosis to study entry | 6.68 years | 6.98 years | 6.83 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 675 / 681 | 332 / 342 |
| serious Total, serious adverse events | 420 / 681 | 181 / 342 |
Outcome results
Primary
Overall Survival (OS)
The primary analysis of OS is defined as the time from randomization to death due to any cause. Participants that had not died or were permanently lost to follow-up were censored at the last known date alive. Median OS was calculated using Kaplan-Meier estimates. Analysis for OS was performed after 614 events had occurred.
Time frame: OS was measured from the time of randomization until 614 events, approximately 24 months after study start
Population: The Intent to Treat (ITT) population was used and included 1028 randomized subjects (682 cabozantinib, 346 prednisone).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabozantinib | Overall Survival (OS) | 11.0 months |
| Prednisone | Overall Survival (OS) | 9.8 months |
p-value: 0.21395% CI: [0.76, 1.06]Log Rank
Secondary
Bone Scan Response (BSR)
BSR is defined as \>=30% reduction in the bone scan lesion area (BSLA) compared with baseline. Confirmation of bone scan was not required for response or progression. Bone 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 ITT population (682 cabozantinib, 346 prednisone) for Bone Scan Response (BSR) at Week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib | Bone Scan Response (BSR) | 42 percentage of participants |
| Prednisone | Bone Scan Response (BSR) | 3 percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel
Other Pre-specified
Progression-free Survival (PFS)
The exploratory analysis of PFS is the time from randomization to date of first documented radiographic progression (bone and/or soft tissue) according to the investigator's assessment or death. PFS was defined per mRECIST 1.1 and included evaluation of measurable, nonmeasurable, target and nontarget lesions. A Kaplan-Meier analysis was performed to estimate the median duration.
Time frame: Duration of PFS was defined as time from the date of randomization to earlier of date of radiographic progression (bone/andor soft tissue) according to the investigator's assessment or death, assessed for up to approximately 24 months
Population: The Intent to Treat (ITT) population was used and include 1028 randomized subjects (682 cabozantinib, 346 prednisone) with a data cut off date of 07 July 2014.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabozantinib | Progression-free Survival (PFS) | 5.6 months |
| Prednisone | Progression-free Survival (PFS) | 2.8 months |
p-value: <0.00195% CI: [0.4, 0.57]Log Rank