Prostate Cancer
Conditions
Keywords
adenocarcinoma of the prostate, stage IV prostate cancer, recurrent prostate cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as ABT-751, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. PURPOSE: This phase I/II trial is studying the side effects and best dose of ABT-751 and to see how well it works in treating patients with metastatic prostate cancer that did not respond to hormone therapy.
Detailed description
OBJECTIVES: Primary * Evaluate the safety and efficacy of ABT-751 in patients with androgen-independent, hormone-refractory metastatic prostate cancer and determine the maximum tolerated dose (MTD) and optimal phase II dose of this drug in these patients. Secondary * Determine the objective response rate (partial and complete response) in patients with measurable disease treated with this drug. * Evaluate the effect of this drug on prostate-specific antigen (PSA) response in patients with nonmeasurable disease. * Determine the time to tumor progression in patients treated with this drug. * Determine survival of patients treated with this drug. * Determine the toxicity of this drug in these patients. OUTLINE: This is a phase I, dose-escalation study followed by a phase II study. * Phase I: Patients receive oral ABT-751 twice daily on days 1-7 and 15-21. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of ABT-751 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 50 additional patients may be treated at the recommended phase II dose (RPTD) which is the dose level at the maximally administered dose. * Phase II: Patients receive ABT-751 at the MTD determined in phase I. After completion of study treatment, patients are followed every 3 months for 2 years. PROJECTED ACCRUAL: A total of 53 patients will be accrued for this study.
Interventions
DRUGABT-751
Phase I: Cohort \| Number of Patients \|Dose (mg) ABT-751 (BID) * -1 \| 3-6 \|100 mg BID * 1 \| 3-6 \|125 mg BID * 2 \| 3-6 \|150 mg BID * 3 \| 3-6 \|175 mg BID * 4 \| 3-6 \|200 mg BID Phase II: Patients receive ABT-751 at 125mg po BID for 7 days on, 7 days off (X2) for a 28 day cycle
Sponsors
National Cancer Institute (NCI)
Vanderbilt-Ingram Cancer Center
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
* Patients at least 18 years of age. * Patients must have histologically proven adenocarcinoma of the prostate gland. * Patients must have metastatic disease (e.g. bone metastases, pelvic mass, nodal, liver or lung metastases), with evidence of radiographic progression (including bone scans observed during last treatment) or serologically -Patients with bone-only metastases (i.e. lacking soft tissue or visceral disease) must have a PSA level \> 10 ng/mls. Patients with soft tissue metastases and/or visceral disease must have either measurable disease OR a PSA level \> 10 ng/ml. * Patients must have had prior treatment with bilateral orchiectomy or other primary hormonal therapy (e.g. LHRH therapy, estrogens, etc.) with evidence of treatment failure and simultaneous documentation of a castrate testosterone level (\< 50 ng/dL) NOTE: Patients who have not undergone bilateral orchiectomy must continue LHRH agonist therapy for the duration of this protocol unless this medically contraindicated. * For patients previously treated with flutamide, nilutamide, or bicalutamide: patients must have discontinued flutamide or nilutamide \> 4 weeks prior to randomization (\> 6 weeks for bicalutamide) with no evidence of an anti-androgen withdrawal response (i.e. no decline in serum PSA and/or no improvement in baseline scans). * Patients must have received prior therapy with docetaxel alone or in combination with either prednisone or estramustine. This therapy may have been given in a neoadjuvant, adjuvant or metastatic setting * Patients must not have received radiotherapy \< 3 weeks prior to randomization. If patients have received prior radiotherapy to an evaluable lesion(s), there must be evidence of radiographic progression prior to entry. * Patients must not have received prior Strontium 89, Samarium 153, or other therapeutic radioisotopes. * Patients must have recovered from all systemic toxicities due to prior treatment for prostate cancer (does not include incontinence, impotence, etc. secondary to primary therapy) * The patient must have an ECOG Performance Status of 0-1 * The patient must have adequate hematologic, renal and hepatic function as follows: 1. Hematologic: ANC \> 1200/mm3; hemoglobin \> 9.0 g/dl; platelets \> 100,000/mm3 2. Renal: serum creatinine \< 2.0 mg/dL 3. Hepatic: bilirubin \< 2.5 mg/dL; AST and ALT \< 2.5X upper limit of normal (ULN); \< 5X ULN for patients with hepatic metastases * Sexually-active patients must use a contraceptive method deemed acceptable by the investigator while in the study and for up to 3 months following completion of therapy. * The patient or the patient's legally acceptable representative has voluntarily signed and dated an informed consent approved by and Institutional Review Board prior to any study any study specific procedures. * Patients may be receiving bisphosphonate therapy prior to randomization and continue while receiving protocol therapy, but must not begin treatment with bispohosphonates while receiving protocol therapy. Patients on bisphosphonates must have completed at least 4 weeks of bisphosphonate therapy prior to entry onto study. * Patients with a history of a prior malignancy are eligible provided they were treated with curative intent and have been free of disease for the time period considered appropriate for the specific malignancy.
Exclusion criteria
* No active angina pectoris, uncontrolled hypertension, or known heart disease of New York Heart Association Class III-IV. Patients must not have a history of myocardial infarction, congestive cardiac failure (New York Heart Association Class 3), or coronary angioplasty/stenting \< 6 months prior to entry. * No carcinomatous meningitis or brain metastases. * Any investigational therapy within 4 weeks. * No serious concurrent medical illness or active infection, which, in the opinion of the investigator, would jeopardize the ability of the patient to receive the chemotherapy outlined in this protocol with reasonable safety. * Documented history of allergy to sulfa medications. * Current colchicines treatment * Greater than Grade 1 CTC neurology category findings (Appendix A). * Prior treatment with more than 1 prior chemotherapy regimen.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | up to four weeks | MTD is determined by the 3+3 study design, in which patients are enrolled in cohorts of 3. In any dose cohort, if 1 patient of 3 experience dose-limiting toxicity (DLT), three additional patients will be enrolled at the same dose level. Whenever \>=2 of 6 subjects experience a DLT, then the maximum tolerated dose (MTD) has been exceeded. The MTD is generally one dose below that at which DLT occurs in \>= 2 of 6 subjects in any given cohort. |
| Number of Patients Who Demonstrated Treatment Effectiveness Based on Prostate Specific Antigen (PSA) Response in Non-measurable Disease | after four weeks | Patients with a minimum 50% decline in PSA from pre-treatment baseline, confirmed by a second PSA 4 or more weeks later, measured in nanograms per milliliter of blood. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Objective Response (CR & PR) by RECIST | after four weeks | Number of participants in each best tumor response category, RECIST criteria (v. 1.0: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) \> 30% decrease in sum longest diameter (LD) of target lesions, progressive disease (PD) \> 20% increase in sum LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of smallest sum of the LD of target lesions. |
| Median Time to Tumor Progression | date on study to date of progression | Number of weeks from the date the patient started study drug to the date of the patient's tumor progression documented radiographically or by PSA testing. Tumor progression is measured at baseline and after two 28-day cycles |
| Overall Survival | date on study to date of death from any cause | Number of weeks from the date the patient started study drug to the date of the patient's death. |
| Safety Profile Based on Number of Patients With Worst Grade Toxicities | at 30 days after final treatment dose | Not all participants necessarily have an adverse event, thus not everyone will be accounted for in worst-grade toxicities. Likewise, one participant can potentially have more than one event in various grades 1-5 which accounts for the difference in number of patients analyzed and total number in the worst-grade toxicity tables. Tables represent the number of patients with worst-grade toxicity at each of five grades (grade 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening or disabling, grade 5 = death)following NCI Common Toxicity Criteria |
Countries
United States
Participant flow
Recruitment details
This study began enrolling October 2004 through December 2007.
Pre-assignment details
A total of 34 patients were consented in Phase I and Phase II, 7 of which were not eligible.
Participants by arm
| Arm | Count |
|---|---|
| Phase I/II: ABT-751 Phase I: Patients receive oral ABT-751 twice daily on days 1-7 and 15-21. Phase II: Patients receive ABT-751 at 125mg twice daily, 7 days on, 7 days off (x2)for a 28-day cycle | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | disease progression | 22 |
| Overall Study | other complicating disease | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Phase I/II: ABT-751 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 13 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Age Continuous | 65 years STANDARD_DEVIATION 1 |
| Region of Enrollment United States | 27 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 27 / 27 |
| serious Total, serious adverse events | 7 / 27 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
MTD is determined by the 3+3 study design, in which patients are enrolled in cohorts of 3. In any dose cohort, if 1 patient of 3 experience dose-limiting toxicity (DLT), three additional patients will be enrolled at the same dose level. Whenever \>=2 of 6 subjects experience a DLT, then the maximum tolerated dose (MTD) has been exceeded. The MTD is generally one dose below that at which DLT occurs in \>= 2 of 6 subjects in any given cohort.
Time frame: up to four weeks
Population: Phase I patients who received treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-751 | Maximum Tolerated Dose (MTD) | 125 mg twice a day |
Primary
Number of Patients Who Demonstrated Treatment Effectiveness Based on Prostate Specific Antigen (PSA) Response in Non-measurable Disease
Patients with a minimum 50% decline in PSA from pre-treatment baseline, confirmed by a second PSA 4 or more weeks later, measured in nanograms per milliliter of blood.
Time frame: after four weeks
Population: Men with non-measurable disease: all other lesions, bone lesions, leptomeningeal disease, cystic lesions, abdominal masses that are not followed by imaging techniques
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-751 | Number of Patients Who Demonstrated Treatment Effectiveness Based on Prostate Specific Antigen (PSA) Response in Non-measurable Disease | 0 participants |
Secondary
Median Time to Tumor Progression
Number of weeks from the date the patient started study drug to the date of the patient's tumor progression documented radiographically or by PSA testing. Tumor progression is measured at baseline and after two 28-day cycles
Time frame: date on study to date of progression
Population: Patients who received treatment and who were available for measurement of tumor or who available for PSA testing
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABT-751 | Median Time to Tumor Progression | 4 Weeks |
Secondary
Number of Patients With Objective Response (CR & PR) by RECIST
Number of participants in each best tumor response category, RECIST criteria (v. 1.0: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) \> 30% decrease in sum longest diameter (LD) of target lesions, progressive disease (PD) \> 20% increase in sum LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of smallest sum of the LD of target lesions.
Time frame: after four weeks
Population: Participants with measurable disease who completed at least one cycle of treatment with tumor assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABT-751 | Number of Patients With Objective Response (CR & PR) by RECIST | Complete Response | 0 participants |
| ABT-751 | Number of Patients With Objective Response (CR & PR) by RECIST | Partial Response | 0 participants |
Secondary
Overall Survival
Number of weeks from the date the patient started study drug to the date of the patient's death.
Time frame: date on study to date of death from any cause
Population: At the time of this analysis, all 27 patients were deceased due to progressive prostate cancer.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABT-751 | Overall Survival | 35.3 Weeks |
Secondary
Safety Profile Based on Number of Patients With Worst Grade Toxicities
Not all participants necessarily have an adverse event, thus not everyone will be accounted for in worst-grade toxicities. Likewise, one participant can potentially have more than one event in various grades 1-5 which accounts for the difference in number of patients analyzed and total number in the worst-grade toxicity tables. Tables represent the number of patients with worst-grade toxicity at each of five grades (grade 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening or disabling, grade 5 = death)following NCI Common Toxicity Criteria
Time frame: at 30 days after final treatment dose
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABT-751 | Safety Profile Based on Number of Patients With Worst Grade Toxicities | No. of patients with worst-grade toxicity of 1 | 0 patients |
| ABT-751 | Safety Profile Based on Number of Patients With Worst Grade Toxicities | No. of patients with worst-grade toxicity of 2 | 10 patients |
| ABT-751 | Safety Profile Based on Number of Patients With Worst Grade Toxicities | No. of patients with worst-grade toxicity of 3 | 14 patients |
| ABT-751 | Safety Profile Based on Number of Patients With Worst Grade Toxicities | No. of patients with worst-grade toxicity of 4 | 3 patients |
| ABT-751 | Safety Profile Based on Number of Patients With Worst Grade Toxicities | No. of patients with worst-grade toxicity of 5 | 0 patients |