Metastatic Prostate Cancer
Conditions
Keywords
Prostate Cancer
Brief summary
The purpose of this research study is to determine if the combination of mitoxantrone, prednisone and sorafenib will improve the time to progression of advanced stage metastatic hormone-refractory prostate cancer.
Detailed description
The primary objective of this study is to test the hypothesis that the combination of Mitoxantrone, Prednisone and Sorafenib in taxane-refractory patients with metastatic hormone refractory prostate cancer (mHRPC) will result in an improvement of the median time to progression (TTP). Since the median (i.e 50% of patients) TTP for Mitoxantrone/Prednisone is 3 months, our hypothesis is that 70% will have not progressed at 3 months with this investigational combination. Progression will be assessed by radiologic imaging criteria. The early stopping point is 21 subjects. If 10 or fewer subjects with tumor favorable response are observed when 21 subjects are accrued then the null hypothesis is accepted and the trial is terminated. If 16 or more subjects with tumor favorable response are observed when 21 subjects are accrued then the alternative hypothesis is accepted and the trial is terminated. The probability of early stopping under the null is 0.51, and under the alternative is 0.39. If the trial progresses until 42 subjects are evaluated and 24 or more subjects with favorable response are observed then the null hypothesis is rejected. This design minimizes the average sample number under the null, which is 31.2.
Interventions
DRUGMitoxantrone
Once six patients are accrued at dose level 1, the maximum tolerated dose (MTD) will be assessed by following them through one cycle of treatment. If 2/6 patients experience dose limiting toxicity (DLT) at the 400 mg twice a day (bid) level then the MTD will be defined as 400 mg daily (QD). Additional patients will be enrolled at the MTD for the phase II portion. Dose Level -2, Mitoxantrone 9mg/m2 Dose Level -1 Mitoxantrone 12mg/m2 Dose Level 1 Mitoxantrone 12mg/m2
DRUGPrednisone
Once six patients are accrued at dose level 1, the maximum tolerated dose (MTD) will be assessed by following them through one cycle of treatment. If 2/6 patients experience dose limiting toxicity (DLT) at the 400 mg twice a day (bid) level then the MTD will be defined as 400 mg daily (QD). Additional patients will be enrolled at the MTD for the phase II portion. Dose Level -2, Prednisone 5mg bid Dose Level -1 Prednisone 5mg bid Dose Level 1 Prednisone 5mg bid
DRUGSorafenib
Once six patients are accrued at dose level 1, the maximum tolerated dose (MTD) will be assessed by following them through one cycle of treatment. If 2/6 patients experience dose limiting toxicity (DLT) at the 400 mg twice a day (bid) level then the MTD will be defined as 400 mg daily (QD). Additional patients will be enrolled at the MTD for the phase II portion. Dose Level -2, Sorafenib 400 mg QD Dose Level -1 Sorafenib 400 mg QD Dose Level 1 Sorafenib 400 mg bid
Sponsors
Bayer
Accelerated Community Oncology Research Network
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Voluntary written informed consent * Histopathologic diagnosis of prostatic adenocarcinoma with evidence of progression despite adequate castration (testosterone \< 50 ng/dL) * Progressive disease after taxane-based chemotherapy (docetaxel or paclitaxel, single agent or combination regimens, weekly or every 21 day schedules) * Patients who discontinued taxane- based chemotherapy because of toxicity will be eligible as long as there is evidence of progressive disease * Minimum of 4 weeks period from last chemotherapy infusion to registration (this does not apply to steroid use which is permitted). Estramustine needs to be discontinued at least 6 weeks prior to first day of treatment on protocol * A minimum of 4 weeks off bicalutamide, nilutamide, megestrol acetate ketoconazole, diethylstilbestrol (DES). Minimum of 2 weeks off flutamide * Reductase inhibitors will be allowed if initiated at least 2 months prior to registration * No concurrent investigational therapy * Complementary and Alternative Medicine (CAM) products will be permitted as long as patients have been receiving them for at least 2 months. Initiation of new CAM products while on protocol will be discouraged. * Ongoing androgen deprivation therapy (orchiectomy, gonadotropin-releasing hormone (GnRH) agonist or antagonist) * Adequate bone marrow, liver and renal function as assessed by the following: * Hemoglobin ≥ 9.0 g/dl * Absolute neutrophil count (ANC) ≥ 1,500/mm3 * Platelet count ≥ 100,000/mm3 * Total bilirubin ≤ 1.5 times upper limit of normal (ULN) * ALT and AST ≤ 2.5 times the ULN ( ≤ 5 x ULN for patients with liver involvement) * Creatinine ≤ 1.5 times the ULN * International normalized ratio (INR) \< 1.5 or a Prothrombin (PT)/Partial thromboplastin time (PTT) within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable. * ECOG performance status ≤ 2 * Baseline left ventricular ejection fraction (LVEF) ≥ 50% * Life expectancy ≥ 3 months * Patients must agree to use adequate contraception prior to study entry, during the study and for at least three months after the last administration of sorafenib
Exclusion criteria
* More than one line of prior cytotoxic chemotherapy in the metastatic setting, previous adjuvant chemotherapy will be allowed * No active malignancy other than prostate cancer (except non-melanoma skin cancer) within 5 years of enrollment * Known brain metastases * Cardiac disease: Congestive heart failure \> class II New York Heart Association (NYHA). Patients must not have unstable angina or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months * Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy * Uncontrolled hypertension * Active clinically serious infection \> Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 * Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months * Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose of study drug * Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks of first dose of study drug * Poorly controlled hyperglycemia * Treatment with radiotherapy within 4 weeks or treatment with radiopharmaceuticals within past 8 weeks * Patient has received other investigational drugs within 14 days before enrollment * Serious medical or psychiatric illness likely to interfere with participation in this clinical study * Serious non-healing wound or ulcer * Evidence or history of bleeding diathesis or coagulopathy * Use of St. John's Wort or rifampin * Known or suspected allergy to sorafenib or any agent given in the course of this trial * Any condition that impairs patient's ability to swallow whole pills * Any malabsorption problem
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to Progression (TTP) by Imaging | Radiologic imaging was repeated after every 4 cycles (approximately every 12 weeks) during study treatment. | Time to progression is defined as the time from treatment start until objective tumor progression. The median time to progression is the parameter used to describe TTP. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation of Biochemical Criteria (PSA, Prostate-specific Antigen) With Objective Imaging | PSA was evaluated on day 1 of every cycle (approximately every 3 weeks) during study treatment. Radiologic imaging was repeated after every 4 cycles (approximately every 12 weeks) during study treatment. | The test of association assesses the null hypothesis that the frequency of PSA response is the same for patients with and without a favorable imaging response. PSA response required a 50% reduction of the baseline PSA result that was confirmed three weeks later. Favorable imaging response is defined as stable disease, partial response, or complete response per RECIST guidelines. The Fisher's exact test was used to test this hypothesis. |
| Quality of Life (QoL) | The Patient Care Monitor questionnaire was administered on day 1 of every cycle (approximately every 3 weeks) during study treatment. | The subject answers questions from the following 6 categories: general physical symptoms, treatment side effects, distress, despair, impaired performance, and impaired ambulation. Each question has a scale from 0 through 10, where 0 is not a problem and 10 is as bad as possible. The scores for the 6 categories are combined and normalized, and used to describe overall quality of life. Because normalized scores are created using a look-up index, there is no clearly defined maximum value. In practice, the maximum value for the combined scale is 73.5. |
| Median Overall Survival (OS) | Overall survival was measured from day 1 of treatment until the end of treatment and then every 3 months thereafter until death. | Overall survival is defined as the time from treatment start until death from any cause. The median overall survival time is used to measure OS. |
Countries
United States
Participant flow
Recruitment details
10 community oncology research sites across the US within the ACORN network participated in this study. Enrollment started in May 2007 and was closed in July 2008 after the interim analysis was completed.
Pre-assignment details
Informed consent was obtained from all subjects. All subjects underwent a screening period that could last up to 4 weeks during which pre-study assessments were completed.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib The treatment plan for all subjects was mitoxantrone 12 mg/m2 IV every 21 days; sorafenib 400 mg po bid daily; and prednisone 5 mg po bid daily. | 22 |
| Total | 22 |
Baseline characteristics
| Characteristic | Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 14 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age Continuous | 67 years STANDARD_DEVIATION 9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 20 / 22 |
| serious Total, serious adverse events | 10 / 22 |
Outcome results
Primary
Median Time to Progression (TTP) by Imaging
Time to progression is defined as the time from treatment start until objective tumor progression. The median time to progression is the parameter used to describe TTP.
Time frame: Radiologic imaging was repeated after every 4 cycles (approximately every 12 weeks) during study treatment.
Population: Survival analysis was performed for 22 patients. However, the upper 95% confidence interval for median TTP could not be calculated and so the number of patients analyzed and the upper 95% confidence interval for median TTP could not be entered into the system.
Secondary
Correlation of Biochemical Criteria (PSA, Prostate-specific Antigen) With Objective Imaging
The test of association assesses the null hypothesis that the frequency of PSA response is the same for patients with and without a favorable imaging response. PSA response required a 50% reduction of the baseline PSA result that was confirmed three weeks later. Favorable imaging response is defined as stable disease, partial response, or complete response per RECIST guidelines. The Fisher's exact test was used to test this hypothesis.
Time frame: PSA was evaluated on day 1 of every cycle (approximately every 3 weeks) during study treatment. Radiologic imaging was repeated after every 4 cycles (approximately every 12 weeks) during study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Correlation of Biochemical Criteria (PSA, Prostate-specific Antigen) With Objective Imaging | PSA response (> 50% reduction) | 3 Participants |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Correlation of Biochemical Criteria (PSA, Prostate-specific Antigen) With Objective Imaging | PSA response (< or = 50% reduction) | 6 Participants |
| Imaging Response (Unfavorable) | Correlation of Biochemical Criteria (PSA, Prostate-specific Antigen) With Objective Imaging | PSA response (> 50% reduction) | 0 Participants |
| Imaging Response (Unfavorable) | Correlation of Biochemical Criteria (PSA, Prostate-specific Antigen) With Objective Imaging | PSA response (< or = 50% reduction) | 13 Participants |
Comparison: The test of association of PSA and imaging response tests the null hypothesis that the proportion of cases exhibiting PSA response is the same for patients with and without a favorable imaging response. A 2x2 table was constructed based on the number of the patients in imaging response (favorable and unfavorable) and PSA response (\>50% reduction and \<=50% reduction). The Fisher's exact test was used to test this hypothesis.p-value: 0.55Fisher Exact
Secondary
Median Overall Survival (OS)
Overall survival is defined as the time from treatment start until death from any cause. The median overall survival time is used to measure OS.
Time frame: Overall survival was measured from day 1 of treatment until the end of treatment and then every 3 months thereafter until death.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Median Overall Survival (OS) | 12.32 Months |
Secondary
Quality of Life (QoL)
The subject answers questions from the following 6 categories: general physical symptoms, treatment side effects, distress, despair, impaired performance, and impaired ambulation. Each question has a scale from 0 through 10, where 0 is not a problem and 10 is as bad as possible. The scores for the 6 categories are combined and normalized, and used to describe overall quality of life. Because normalized scores are created using a look-up index, there is no clearly defined maximum value. In practice, the maximum value for the combined scale is 73.5.
Time frame: The Patient Care Monitor questionnaire was administered on day 1 of every cycle (approximately every 3 weeks) during study treatment.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Baseline | 50.21 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Cycle 1 | 49.71 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Cycle 2 | 51.06 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Cycle 3 | 51.20 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Cycle 4 | 51.66 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Cycle 5 | 51.22 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Cycle 6 | 49.73 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Cycle 7 | 49.50 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Cycle 8 | 48.20 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Cycle 9 | 54.34 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Cycle 10 | 55.88 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Cycle 11 | 54.95 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Cycle 12 | 54.02 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | Cycle 13 | 54.65 units on a scale |
| Treatment Group: Mitoxantrone, Prednisone, Plus Sorafenib | Quality of Life (QoL) | End of Study (at treatment discontinuation) | 45.13 units on a scale |