Prostate Cancer
Conditions
Keywords
Castration resistant, Prostate cancer, Metastatic, First-line, Treatment naive, Rapidly cycling, Non-cross resistant
Brief summary
The purpose of this study is to determine the clinical benefits of using a rapidly cycling, non-cross reactive regimen of FDA-approved prostate cancer therapeutic agents in the management of castration resistant prostate cancer. The hypothesis is that the identification of optimal combinations and sequencing of therapies can help prevent or delay the development of therapeutic drug resistance, and can be safely tolerated.
Detailed description
This phase II clinical trial will explore the efficacy of rapidly cycling non-cross reactive treatment therapies in the treatment of patients with newly diagnosed mCRPC. The primary hypothesis is that the best chance of eliminating or controlling disease is when the cancer is treatment naïve, and has not yet developed therapeutic resistance. By finding an optimal drug deployment strategy of already approved and available treatments for mCRPC, the researchers believe providers can more effectively treat an intrinsically heterogeneous disease, delay/prevent drug resistance, as well as minimize treatment toxicity. All of the treatment agents selected have well-defined individual toxicity profiles from large phase III trials, but there is limited clinical data about the toxicity profiles of these drugs in combinations. While each agent is generally well tolerated, toxicities remain a significant concern given the older age of the typical mCRPC patient, the comorbid conditions common to this patient population, as well as those borne from previous chronic androgen deprivation therapy. Each drug in the proposed treatment regimen will be used at their FDA-approved dosing and indication, with the exception of cabazitaxel, which will be used prior to disease demonstration of docetaxel failure, and in combination with carboplatin. The proposed sequencing is rationally designed, and based on each drug's distinct mechanisms of action as well as their toxicity profiles. The rapidly-cycling treatment regimen contains three, separate, consecutive treatment modules, each lasting 3 months: 1. Abiraterone; 2. Cabazitaxel + Carboplatin; 3. Enzalutamide + Radium-223. Therapeutic agents are delivered as non-cross reactive combinations, in order to achieve optimal therapeutic dosing at each cycle and decrease possibility of significant adverse effects. To the researcher knowledge, no study has evaluated the use of rapidly cycling, non-cross reactive therapies for the treatment of mCRPC. The hypothesis is that the identification of optimal combinations and sequencing of rapidly cycling non-cross reactive therapies can help prevent or delay the development of therapeutic drug resistance, and can be safely tolerated. Primary objective is to evaluate the time to disease progression after completion of all modules of the rapidly-cycling, non-cross reactive regimen in patients with mCRPC. Secondary objectives are to evaluate overall survival, prostate-specific antigen (PSA) response rate with each treatment module, changes to alkaline phosphatase level, and assess safety of the rapidly-cycling, non-cross reactive regimen. Additional exploratory objective are to evaluate the correlation of a peripheral whole-blood RNA signature with clinical outcome measures during and after treatment, and to evaluate changes to AR-V7 expression in CTCs with different treatment modalities and clinical outcomes.
Interventions
DRUGAbiraterone acetate
Abiraterone acetate 1000 mg PO daily
DRUGPrednisone
5 mg PO twice a day
50 kBq/kg IV monthly
DRUGcabazitaxel
25 mg/m2 IV every 3 weeks
DRUGCarboplatin
Carboplatin AUC 4 IV every 3 weeks
DRUGEnzalutamide
160 mg PO daily
Sponsors
Sanofi
Bayer
Icahn School of Medicine at Mount Sinai
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
* Histologically or cytologically confirmed adenocarcinoma of the prostate * Metastatic castrate resistant prostate cancer, defined by progressive disease based on either rising PSA, new bone metastases, or progression of measurable disease on standard imaging, according to PCWG2 guidelines, despite androgen deprivation therapy * Ongoing androgen deprivation therapy with a GnRH analogue, GnRH antagonist, or bilateral orchiectomy * ECOG performance status 0-1 * Serum testosterone level \< 50 ng/dL * Absolute neutrophil count \> 1,500/μL, platelet count \> 100,000/μL, and hemoglobin \> 9 g/dL * Creatinine \< 2 mg/dL * Total bilirubin \< 1 times the upper limit of normal, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 1.5 times the upper limit of normal
Exclusion criteria
* History of uncontrolled seizure disorder * Clinically significant cardiovascular disease including: 1. Myocardial infarction or uncontrolled angina within 6 months 2. Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients with history of congestive heart failure NYHA class 3 or 4 in the past 3. Uncontrolled hypertension as indicated by a resting systolic blood pressure \> 170 mmHg or diastolic blood pressure \> 105 mmHg at the screening visit * Have used or plan to use from 30 days prior to enrollment through the end of the study medication known to lower the seizure threshold or prolong the QT interval * Major surgery within 4 weeks of enrollment * Radiation therapy within 4 weeks of enrollment * Prior use of abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, carboplatin, or radium-223 for the treatment of castration-resistant disease * Prior docetaxel use in the hormone-sensitive disease setting is allowed, but must be completed ≥ 4 weeks prior to enrollment * Prior sipuleucel-T use is allowed, but must be completed ≥ 4 weeks prior to enrollment * Concurrent use of zoledronic acid or denosumab is allowed on study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Disease Progression | 47.8 months | Time to disease progression, as determined by either PSA or radiographic progression, after completion of all modules of the rapidly-cycling, non-cross reactive regimen in patients with mCRPC. Time to progression (TTP) is defined as beginning with the time the first dose of PCD regimen is administered until disease progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Rate of Survival | 40 months | Overall rate of survival at 40 months. Overall rate of Survival as defined by likelihood that a participant on the study is still alive at 40 months follow up |
| Number of Participants With PSA Response Rate >90% | up to 36 weeks | PSA response rate - \>90% decrease in PSA compared to baseline |
| Number of Participants With PSA Response Rate >=50% | up to 36 weeks | Number of participants with PSA response rate \>=50% decrease in PSA compared to baseline |
| Overall Survival (OS) | 47.8 months | Overall survival defined as the time of study entry to death from any cause. |
| Number of Participants With Stable PSA as Compared to Baseline | up to 36 weeks | Participants with a 50% PSA decline from their baseline PSA level will be considered responders, provided objective tumor measurements are stable or also demonstrate response. Participants with a 25% PSA increase from their baseline PSA will be considered nonresponders. Participants that do not meet criteria for responder or nonresponder, will be considered to have stable disease. |
| Number of Participants With Normal Alkaline Phosphatase Levels | baseline and 36 weeks | Number of participants who converted from elevated to normal range of alkaline phosphatase levels at 9 months from baseline |
| Number of Participants With PSA Progression Compared to Baseline. | up to 36 weeks | PSA changes was reported globally using a waterfall plot for each module. In participants who have a decline in PSA value from baseline, progression is defined by: * An increase in PSA by 25% above the nadir, AND * An increase in PSA by a minimum of 2 ng/ml, or an increase in PSA to the pre-treatment PSA value, AND * Confirmation by a second PSA at least 3 weeks apart, AND * Occur following at least 12 weeks of therapy, AND * There is no objective evidence of disease response. In participants whose PSA value from baseline has not declined from baseline, progression is defined by: * An increase in PSA by 25% above either the pre-treatment level, or the nadir PSA level (whichever is lowest), AND * An increase in PSA by a minimum of 2 ng/ml, AND * Confirmation by a second PSA at least 3 weeks apart, AND * Occur following at least 12 weeks of therapy, AND * There is no objective evidence of disease response. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intensive, Non-Cross Reactive Therapy Prostate Cancer Rapidly cycling, Intensive, Non-Cross Reactive Therapy (PRINT) Rapidly cycling, consecutive treatment modules: 1. Abiraterone acetate 1000 mg PO daily; 2. Cabazitaxel 25 mg/m2 IV every 3 weeks + Carboplatin AUC 4 IV every 3 weeks; 3. Enzalutamide 160 mg PO daily + Radium-223 kg IV monthly and Prednisone: 5 mg PO twice a day | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Medical Insurance Barriers | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Intensive, Non-Cross Reactive Therapy |
|---|---|
| Age, Continuous | 69 years |
| Alkaline phosphatase Elevated (>126 IU/L) | 13 Participants |
| Alkaline phosphatase Normal (<=126 IU/L) | 27 Participants |
| Alkaline phosphatase | 98 IU/L |
| Eastern Cooperative Oncology Group (ECOG) 0 | 27 Participants |
| Eastern Cooperative Oncology Group (ECOG) 1 | 10 Participants |
| Eastern Cooperative Oncology Group (ECOG) unknown | 3 Participants |
| Gleason score <=6 | 5 Participants |
| Gleason score 7 | 10 Participants |
| Gleason score >=8 | 21 Participants |
| Gleason score Unknown | 4 Participants |
| Prostate-specific antigen (PSA) | 9.6 ng/mL |
| Race/Ethnicity, Customized Amerian Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 10 Participants |
| Race/Ethnicity, Customized Hispanic | 7 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 1 Participants |
| Race/Ethnicity, Customized White | 21 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 40 Participants |
| Sites of metastasis Bone | 29 Participants |
| Sites of metastasis Liver | 0 Participants |
| Sites of metastasis Lung | 1 Participants |
| Sites of metastasis Lymph node | 13 Participants |
| Sites of metastasis Other | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 33 |
| other Total, other adverse events | 18 / 33 |
| serious Total, serious adverse events | 10 / 33 |
Outcome results
Primary
Time to Disease Progression
Time to disease progression, as determined by either PSA or radiographic progression, after completion of all modules of the rapidly-cycling, non-cross reactive regimen in patients with mCRPC. Time to progression (TTP) is defined as beginning with the time the first dose of PCD regimen is administered until disease progression.
Time frame: 47.8 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intensive, Non-Cross Reactive Therapy | Time to Disease Progression | 15.2 weeks |
Secondary
Number of Participants With Normal Alkaline Phosphatase Levels
Number of participants who converted from elevated to normal range of alkaline phosphatase levels at 9 months from baseline
Time frame: baseline and 36 weeks
Population: Data for those with elevated alkaline phosphatase levels at baseline and with results available at 36 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intensive, Non-Cross Reactive Therapy | Number of Participants With Normal Alkaline Phosphatase Levels | 8 Participants |
Secondary
Number of Participants With PSA Progression Compared to Baseline.
PSA changes was reported globally using a waterfall plot for each module. In participants who have a decline in PSA value from baseline, progression is defined by: * An increase in PSA by 25% above the nadir, AND * An increase in PSA by a minimum of 2 ng/ml, or an increase in PSA to the pre-treatment PSA value, AND * Confirmation by a second PSA at least 3 weeks apart, AND * Occur following at least 12 weeks of therapy, AND * There is no objective evidence of disease response. In participants whose PSA value from baseline has not declined from baseline, progression is defined by: * An increase in PSA by 25% above either the pre-treatment level, or the nadir PSA level (whichever is lowest), AND * An increase in PSA by a minimum of 2 ng/ml, AND * Confirmation by a second PSA at least 3 weeks apart, AND * Occur following at least 12 weeks of therapy, AND * There is no objective evidence of disease response.
Time frame: up to 36 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Intensive, Non-Cross Reactive Therapy | Number of Participants With PSA Progression Compared to Baseline. | after module 1, 12 weeks | 4 Participants |
| Intensive, Non-Cross Reactive Therapy | Number of Participants With PSA Progression Compared to Baseline. | after module 2, 24 weeks | 4 Participants |
| Intensive, Non-Cross Reactive Therapy | Number of Participants With PSA Progression Compared to Baseline. | after module 3, 36 weeks | 0 Participants |
Secondary
Number of Participants With PSA Response Rate >=50%
Number of participants with PSA response rate \>=50% decrease in PSA compared to baseline
Time frame: up to 36 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Intensive, Non-Cross Reactive Therapy | Number of Participants With PSA Response Rate >=50% | after module 1, 12 weeks | 27 Participants |
| Intensive, Non-Cross Reactive Therapy | Number of Participants With PSA Response Rate >=50% | after module 2, 24 weeks | 28 Participants |
| Intensive, Non-Cross Reactive Therapy | Number of Participants With PSA Response Rate >=50% | after module 3, 36 weeks | 32 Participants |
Secondary
Number of Participants With PSA Response Rate >90%
PSA response rate - \>90% decrease in PSA compared to baseline
Time frame: up to 36 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Intensive, Non-Cross Reactive Therapy | Number of Participants With PSA Response Rate >90% | after module 1, 12 weeks | 11 Participants |
| Intensive, Non-Cross Reactive Therapy | Number of Participants With PSA Response Rate >90% | after module 2, 24 weeks | 14 Participants |
| Intensive, Non-Cross Reactive Therapy | Number of Participants With PSA Response Rate >90% | after module 3, 36 weeks | 20 Participants |
Secondary
Number of Participants With Stable PSA as Compared to Baseline
Participants with a 50% PSA decline from their baseline PSA level will be considered responders, provided objective tumor measurements are stable or also demonstrate response. Participants with a 25% PSA increase from their baseline PSA will be considered nonresponders. Participants that do not meet criteria for responder or nonresponder, will be considered to have stable disease.
Time frame: up to 36 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Intensive, Non-Cross Reactive Therapy | Number of Participants With Stable PSA as Compared to Baseline | after module 1, 12 weeks | 2 Participants |
| Intensive, Non-Cross Reactive Therapy | Number of Participants With Stable PSA as Compared to Baseline | after module 2, 24 weeks | 1 Participants |
| Intensive, Non-Cross Reactive Therapy | Number of Participants With Stable PSA as Compared to Baseline | after module 3, 36 weeks | 1 Participants |
Secondary
Overall Rate of Survival
Overall rate of survival at 40 months. Overall rate of Survival as defined by likelihood that a participant on the study is still alive at 40 months follow up
Time frame: 40 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intensive, Non-Cross Reactive Therapy | Overall Rate of Survival | 63 percent |
Secondary
Overall Survival (OS)
Overall survival defined as the time of study entry to death from any cause.
Time frame: 47.8 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intensive, Non-Cross Reactive Therapy | Overall Survival (OS) | NA weeks |