Prostate Cancer Metastatic
Conditions
Keywords
Prostate, Cancer, Metastatic
Brief summary
The purpose of this study is to look at the effects of cabozantinib on castrate-resistant prostate cancer metastatic (cancer that has spread to other parts of the body) to the bone and to learn about any side effects caused by taking cabozantinib.
Detailed description
A significant proportion of patients with prostate cancer develop metastatic disease, which most commonly affects the skeleton. Bone metastases are the cause of significant morbidity and mortality in these patients, and require long-term management. Study participants in this research study will have a diagnosis of castration-resistant prostate cancer metastatic to bone. Cabozantinib is not approved by the United States Food and Drug Administration (FDA) to treat people for castration-resistant prostate cancer metastatic to bone or for any other type of cancer. Giving cabozantinib to human cancer patients is experimental. Cabozantinib is currently being given to patients on other studies. Cabozantinib is known to have anti-tumor effects and to reduce bone metastases based on early clinical studies in prostate cancer and other cancers. The drug is known to have side effects. The most common side effects were fatigue, diarrhea, anorexia, rash, and palmar-plantar erythrodysesthesia (PPE) syndrome. To date, it is not known if cabozantinib is safe and/or effective.
Interventions
DRUGCabozantinib
Cabozantinib is available in capsule form. The dose is 60 mg daily by mouth. Subjects with disease progression at 6 weeks who do not have significant toxicities may remain on therapy for an additional six weeks until a progression is confirmed. Further study drug administration beyond 12 weeks will be at the discretion of the investigator provided that the subject does not have disease progression, does not have unacceptable side effects, does not withdraw from study, or does not have a medical condition or illness that renders the subject unacceptable to receive further study drug.
Sponsors
Exelixis
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically and radiologically confirmed castrate-resistant prostate cancer metastatic to bone * Bone metastases which are accessible for biopsy under CT guidance. * Willingness to undergo sequential biopsy of bone lesions. * No prior standard chemotherapy for metastatic disease (neoadjuvant, adjuvant and hormonal treatments are excluded). * Participant must have discontinued antiandrogen therapy at least 4 weeks (for flutamide and megestrol acetate) or 6 weeks (for bicalutamide or nilutamide) prior to the first dose of XL184. Participants currently on LHRH or GnRH agonists can be maintained on these agents. * Greater than or equal to 18 years old on day of consent * Participants must be able to care for themselves * Adequate organ and bone marrow function * Participants must be capable of understanding and complying with the protocol requirements and has signed the informed consent document. * Men capable of sexual activity will be required to agree to use a condom during sexual contact with women having the potential to bear children during their participation in the study and for six months after participation.
Exclusion criteria
* Prior therapy with cabozantinib * Any other type of investigational agent within 28 days before the first dose of study treatment or 5 half-lives of the compound or active metabolite, whichever is longer * No radiation therapy within 14 days of study treatment. No radionuclide treatment within two months. * No known brain metastases. * Test results that measure how quickly blood clots need to be adequate for the study * Participants who require concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). Low dose aspirin (≤ 81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted. * Participants must not have uncontrolled significant illness including but not limited to: ongoing or active infection requiring systemic treatment, symptomatic congestive heart failure, uncontrolled hypertension , history of hypertensive emergency (e.g.encephalopathy) or hypertensive urgency within 6 months of study treatment, clinically significant wounds including osteonecrosis, history of organ transplant, unstable angina pectoris, stroke within 3 months of study drug, heart attack within 3 months of study drug, development of clots within blood vessels within 6 months of study drug, bleeding from distended veins within 3 months of study drug, any other severe or life threatening hemorrhage/bleeding, major surgery within 4 weeks of study treatment, clinically significant cardiac arrhythmias, history of bowel obstruction within 6 months of study drug or unresolved malabsorption syndrome, untreated bone fracture including tumor-related pathologic fracture, anticipated need for major surgery during the period of the study. * Corrected QT interval, as measured by an ECG, must be within acceptable protocol limits within 28 days of entering the study * Unable to swallow capsules * Unable to undergo MRI * History of another malignant disease within two years with the exception of superficial skin or bladder cancer which has been completely resected or carcinoma in situ without evidence of invasion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Remain Progression-free at 12 Weeks | 12 weeks after participant initiates study | Efficacy will be measured by the proportion of participants who remain progression-free at 12 weeks after initiation of the study. RECIST 1.1 will be used to measure progression. Progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or the appearance of one or more new lesions. Kaplan-Meier methods will be used to report progression-free survival. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Fold Change in Bone Metabolism Biomarker Expression With Cabozantinib | 18 months | Mean fold change in markers of bone metabolism in bone and serum with cabozantinib. Bone biomarkers include Osteocalcin, NTx, TRAcP, BMP2, SOST, BAP, CICP |
| Progression-free Survival | 12 weeks | The percentage of participants alive without progression at 12 weeks |
| Response Proportion in Both Soft Tissue and Bone Disease. | 18 months | The percentage of participants that respond in soft tissue and bone disease. |
| Incidence of Adverse Events (AEs) Related to Treatment | 18 months | The incidence of grades 1-3 AEs, by CTCAE 4.0 category, either possibly, probably or definitely related to treatment. The NCI Common Terminology Criteria for Adverse Events (CTCAE) is a descriptive terminology which can be utilized for AE reporting. |
| The Number of Patients That Are Progression Free by PSA | 12 weeks | The number of patients that are progression free by PSA at 12 weeks |
| Median Time to PSA Progression | 18 months | — |
| Duration of Response. | 18 months | Duration of response in soft tissue and bone. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cabozantinib (XL184) Cabozantinib is available in capsule form. The dose is 60 mg daily by mouth. Subjects with disease progression at 6 weeks who do not have significant toxicities may remain on therapy for an additional six weeks until a progression is confirmed. Further study drug administration beyond 12 weeks will be at the discretion of the investigator provided that the subject does not have disease progression, does not have unacceptable side effects, does not withdraw from study, or does not have a medical condition or illness that renders the subject unacceptable to receive further study drug. | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | 25 patients enrolled, 3 were not treated | 3 |
Baseline characteristics
| Characteristic | Cabozantinib (XL184) |
|---|---|
| Age, Continuous | 67 years |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 22 / 22 |
| serious Total, serious adverse events | 16 / 22 |
Outcome results
Primary
Percentage of Participants Who Remain Progression-free at 12 Weeks
Efficacy will be measured by the proportion of participants who remain progression-free at 12 weeks after initiation of the study. RECIST 1.1 will be used to measure progression. Progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or the appearance of one or more new lesions. Kaplan-Meier methods will be used to report progression-free survival.
Time frame: 12 weeks after participant initiates study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib (XL184) | Percentage of Participants Who Remain Progression-free at 12 Weeks | 77.3 Percentage of participants |
Secondary
Duration of Response.
Duration of response in soft tissue and bone.
Time frame: 18 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cabozantinib (XL184) | Duration of Response. | Soft Tissue (only one responder) | 9 weeks |
| Cabozantinib (XL184) | Duration of Response. | Bone | 18 weeks |
Secondary
Incidence of Adverse Events (AEs) Related to Treatment
The incidence of grades 1-3 AEs, by CTCAE 4.0 category, either possibly, probably or definitely related to treatment. The NCI Common Terminology Criteria for Adverse Events (CTCAE) is a descriptive terminology which can be utilized for AE reporting.
Time frame: 18 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Blood and Lymphatic System | 10 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Cardiac | 2 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Ear and Labyrinth | 2 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Endocrine | 4 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Eye | 1 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Gastrointestinal | 68 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | General and Administrative Site Conditions | 18 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Immune System | 1 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Infections | 7 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Injury | 2 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Investigations | 78 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Metabolism and Nutrition | 29 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Musculoskeletal and Soft Tissue | 8 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Nervous System | 19 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Psychiatric | 2 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Renal and Urinary | 12 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Reproductive and Breast | 1 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Respiratory, Thoracic and Mediastinal | 17 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Skin and Subcutaneous | 24 adverse events reported |
| Cabozantinib (XL184) | Incidence of Adverse Events (AEs) Related to Treatment | Vascular | 11 adverse events reported |
Secondary
Mean Fold Change in Bone Metabolism Biomarker Expression With Cabozantinib
Mean fold change in markers of bone metabolism in bone and serum with cabozantinib. Bone biomarkers include Osteocalcin, NTx, TRAcP, BMP2, SOST, BAP, CICP
Time frame: 18 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cabozantinib (XL184) | Mean Fold Change in Bone Metabolism Biomarker Expression With Cabozantinib | Osteocalcin | -3.3 unitless | Standard Deviation 5.8 |
| Cabozantinib (XL184) | Mean Fold Change in Bone Metabolism Biomarker Expression With Cabozantinib | NTx | 0.5 unitless | Standard Deviation 15.4 |
| Cabozantinib (XL184) | Mean Fold Change in Bone Metabolism Biomarker Expression With Cabozantinib | TRAcP | -0.1 unitless | Standard Deviation 2.4 |
| Cabozantinib (XL184) | Mean Fold Change in Bone Metabolism Biomarker Expression With Cabozantinib | BMP2 | 65.5 unitless | Standard Deviation 49.1 |
| Cabozantinib (XL184) | Mean Fold Change in Bone Metabolism Biomarker Expression With Cabozantinib | SOST | -29.8 unitless | Standard Deviation 94.5 |
| Cabozantinib (XL184) | Mean Fold Change in Bone Metabolism Biomarker Expression With Cabozantinib | BAP | -1.36 unitless | Standard Deviation 56.6 |
| Cabozantinib (XL184) | Mean Fold Change in Bone Metabolism Biomarker Expression With Cabozantinib | CICP | 4.8 unitless | Standard Deviation 80.6 |
Secondary
Median Time to PSA Progression
Time frame: 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabozantinib (XL184) | Median Time to PSA Progression | 6 weeks |
Secondary
Progression-free Survival
The percentage of participants alive without progression at 12 weeks
Time frame: 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib (XL184) | Progression-free Survival | 89.5 percentage of participants |
Secondary
Response Proportion in Both Soft Tissue and Bone Disease.
The percentage of participants that respond in soft tissue and bone disease.
Time frame: 18 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cabozantinib (XL184) | Response Proportion in Both Soft Tissue and Bone Disease. | Bone Disease | 59 percentage of participants |
| Cabozantinib (XL184) | Response Proportion in Both Soft Tissue and Bone Disease. | Soft Tissue | 5 percentage of participants |
Secondary
The Number of Patients That Are Progression Free by PSA
The number of patients that are progression free by PSA at 12 weeks
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cabozantinib (XL184) | The Number of Patients That Are Progression Free by PSA | 8 Participants |