Prostate Cancer
Conditions
Keywords
Prostate cancer, metastatic disease
Brief summary
This is a multi-centre, phase II, open-label, two-stage design, single-arm study in patients with hormone-refractory prostate cancer (HRPC) with advanced (rising PSA) and/or metastatic disease and who have had prior anti-androgen therapy. The study will further explore the efficacy of E7389 by enrollment of patients into two strata: those who have had no prior systemic chemotherapy for their disease (except for mitoxantrone and estramustine), and those who failed no more than one previous chemotherapeutic regimen with tubulin-binding agents such as docetaxel.
Interventions
DRUGE7389
Intravenous 1.4 mg/m2 on a 3-week course.
Sponsors
Eisai Inc.
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
1. Males with histologically proven adenocarcinoma of the prostate that has progressed (ie. a minimum of 3 consecutive rises in Prostate Specific Antigen (PSA) (with the last value ≥ 4 ng/mL) taken at least 1 week apart prior to study entry) despite castration or maintenance of castrate-level testosterone (defined as serum testosterone ≤ .50 ng/dL or 1.7 nmol/L), or progressed during non-hormonal chemotherapy. Note: Patients previously treated with an antiandrogen must have disease progression documented after antiandrogen withdrawal. Those who have not undergone orchiectomy must continue medical castration with a gonadotropin-releasing hormone analog. At least 4 weeks must have elapsed between the withdrawal of antiandrogens (6 weeks in the case of nilutamide or bicalutamide and four weeks in the case of flutamide or other secondary hormonal therapy) and enrollment, so as to avoid the possibility of confounding results of the response due to antiandrogen withdrawal. 2. Patients must fulfill one of the following two criteria to be stratified: * No prior chemotherapy (except mitoxantrone or estramustine) for advanced and/or metastatic disease as defined in inclusion criteria #1. * Failure of no more than one previous chemotherapeutic regimen with tubulin binding agents such as docetaxel. 3. Resolution of all chemotherapy or radiation-related toxicities to less than grade 2 severity, except neuropathy and alopecia 4. Age ≥ 18 years. 5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2. 6. Life expectancy of ≥ 3 months. 7. Adequate renal function as evidenced by serum creatinine ≤ 1.5 times upper limits of normal (ULN) or calculated creatinine clearance ≥ 40 mL/minute (min) per the Cockcroft and Gault formula. 8. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L, hemoglobin ≥ 9.0 g/dL (or 5.5 mmol/L), and platelet count ≥ 100 x 10\^9/L. Adequate liver function as evidenced by bilirubin ≤ 1.5 x ULN, alanine transaminase (ALT), and aspartate transaminase (AST) ≤ 3 x ULN (in the case of liver metastases ≤ 5 x ULN). 9. Patients willing and able to complete the VAS (Visual Analog Scale). 10. Patients willing and able to comply with the study protocol for the duration of the study. 11. Written informed consent prior to any study-specific screening procedures with the understanding that the patient may withdraw consent at any time without prejudice.
Exclusion criteria
1. Patients who have received chemotherapy, radiation, or experimental therapy within 4 weeks of start of E7389 treatment 2. Radiation therapy encompassing ≥30% of marrow or treatment with radioactive strontium 3. Patients who require therapeutic anti-coagulant therapy with warfarin or related compounds; (mini dose warfarin or related compounds are permitted). 4. Severe / uncontrolled intercurrent illness/infection. 5. Significant cardiovascular impairment (history of congestive heart failure \> NYHA grade II, unstable angina or myocardial infarction within the past six months, or serious cardiac arrhythmia) 6. Patients with organ allografts. 7. Patients with known immunosuppression such as positive HIV status. 8. Patients who have had a prior malignancy, other than nonmelanoma skin cancer, unless the prior malignancy was diagnosed and definitively treated ≥ 5 years previously with no subsequent evidence of recurrence. 9. Patients with pre-existing neuropathy \> Grade 2 10. Patients with brain or subdural metastases are not eligible, except if they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least two weeks before starting treatment with E7389. 11. Patients with meningeal carcinomatosis. 12. Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical derivative. 13. Patients who participated in a prior E7389 clinical trial. 14. Patients with other significant disease or disorders that, in the Investigator's opinion, would exclude the patient from the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Prostate Specific Antigen (PSA) Response Rate Based on Bubley Criteria | 12 months | Bubley Criteria: Patients must have progressive disease to enter study. For outcomes, PSA response must show at least 50% decrease. Duration of response is the time from \>50% decrease from baseline to when there is a 50% decrease in nadir. PSA progressive disease- 25% increase from baseline or increase of 5 ng/mL along with measureable disease Stable disease- decline of less than 50% and not more than 25% increase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Prostate Specific Antigen Response Based on Bubley Criteria | 12 months. | Duration of response is the time from \>50% decrease from baseline to when there is a 50% decrease in nadir. |
| Progression Free Survival | 12 months | From the date study treatment was initiated until the earliest date of the first PSA assessment that determined progressive disease, or the death of death if death occurred without disease progression. |
| Overall Survival | 12 months | — |
| Best Objective Tumor Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | 12 months | Based on Response Evaluation Criteria in Solid Tumors (RECIST), consisting of complete response (CR) plus partial response (PR). Defined as the best response from the start of treatment until disease progression or recurrence. Lesions measured by computed tomography (CT) scan and magnetic resonance imaging (MRI). Objective response rate: complete response (CR-disappearance of all lesions)+ partial response (PR-30% decrease in lesion diameter), Progressive Disease (PD-20% increase in lesion diameter), stable disease (SD-neither shrinkage nor increase of lesions). |
Countries
United States
Participant flow
Recruitment details
This study was recruited at 22 centers in U.S, UK, Spain and Hungary during the period of Feb 2006 to May 2009.
Participants by arm
| Arm | Count |
|---|---|
| E7389 Intravenous 1.4 mg/m2 E7389 intravenous 1.4 mg/m2 on a 3-week course | 108 |
| Total | 108 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 24 |
| Overall Study | Not Otherwise Specified | 4 |
| Overall Study | Physician Decision | 9 |
| Overall Study | Progressive Disease | 65 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | E7389 Intravenous 1.4 mg/m2 |
|---|---|
| Age, Continuous | 71.0 years STANDARD_DEVIATION 9.36 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants |
| Race/Ethnicity, Customized Asian | 3 participants |
| Race/Ethnicity, Customized Black or African American | 6 participants |
| Race/Ethnicity, Customized More than one race | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants |
| Race/Ethnicity, Customized Other | 5 participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 participants |
| Race/Ethnicity, Customized White | 94 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 108 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 107 / 108 |
| serious Total, serious adverse events | 34 / 108 |
Outcome results
Primary
Objective Prostate Specific Antigen (PSA) Response Rate Based on Bubley Criteria
Bubley Criteria: Patients must have progressive disease to enter study. For outcomes, PSA response must show at least 50% decrease. Duration of response is the time from \>50% decrease from baseline to when there is a 50% decrease in nadir. PSA progressive disease- 25% increase from baseline or increase of 5 ng/mL along with measureable disease Stable disease- decline of less than 50% and not more than 25% increase.
Time frame: 12 months
Population: Per Protocol Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E7389 Intravenous 1.4 mg/m2 | Objective Prostate Specific Antigen (PSA) Response Rate Based on Bubley Criteria | Response | 16.2 Percentage of Participants |
| E7389 Intravenous 1.4 mg/m2 | Objective Prostate Specific Antigen (PSA) Response Rate Based on Bubley Criteria | Stable Disease | 52.4 Percentage of Participants |
| E7389 Intravenous 1.4 mg/m2 | Objective Prostate Specific Antigen (PSA) Response Rate Based on Bubley Criteria | Progressive Disease | 29.5 Percentage of Participants |
| E7389 Intravenous 1.4 mg/m2 | Objective Prostate Specific Antigen (PSA) Response Rate Based on Bubley Criteria | Unknown/Not Evaluated | 1.9 Percentage of Participants |
Secondary
Best Objective Tumor Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) Criteria
Based on Response Evaluation Criteria in Solid Tumors (RECIST), consisting of complete response (CR) plus partial response (PR). Defined as the best response from the start of treatment until disease progression or recurrence. Lesions measured by computed tomography (CT) scan and magnetic resonance imaging (MRI). Objective response rate: complete response (CR-disappearance of all lesions)+ partial response (PR-30% decrease in lesion diameter), Progressive Disease (PD-20% increase in lesion diameter), stable disease (SD-neither shrinkage nor increase of lesions).
Time frame: 12 months
Population: Per Protocol Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| E7389 Intravenous 1.4 mg/m2 | Best Objective Tumor Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | Complete Response | 0 Percentage of Participants |
| E7389 Intravenous 1.4 mg/m2 | Best Objective Tumor Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | Partial Response | 8.1 Percentage of Participants |
| E7389 Intravenous 1.4 mg/m2 | Best Objective Tumor Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | Stable Disease | 72.6 Percentage of Participants |
| E7389 Intravenous 1.4 mg/m2 | Best Objective Tumor Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | Progressive Disease | 8.1 Percentage of Participants |
| E7389 Intravenous 1.4 mg/m2 | Best Objective Tumor Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | Unknown | 11.3 Percentage of Participants |
| E7389 Intravenous 1.4 mg/m2 | Best Objective Tumor Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | Patients with measureable tumors | 59 Percentage of Participants |
Secondary
Duration of Prostate Specific Antigen Response Based on Bubley Criteria
Duration of response is the time from \>50% decrease from baseline to when there is a 50% decrease in nadir.
Time frame: 12 months.
Population: Per Protocol Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| E7389 Intravenous 1.4 mg/m2 | Duration of Prostate Specific Antigen Response Based on Bubley Criteria | 96 Days |
Secondary
Overall Survival
Time frame: 12 months
Population: Intent to Treat Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| E7389 Intravenous 1.4 mg/m2 | Overall Survival | 567 Days |
Secondary
Progression Free Survival
From the date study treatment was initiated until the earliest date of the first PSA assessment that determined progressive disease, or the death of death if death occurred without disease progression.
Time frame: 12 months
Population: Per Protocol Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| E7389 Intravenous 1.4 mg/m2 | Progression Free Survival | 64 Days |