ABT-751 in Treating Patients With Metastatic Prostate Cancer That Did Not Respond to Hormone Therapy

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.

• ABT-751 (Drug): 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

Primary outcomes

• 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 outcomes

• 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

Sex: Male, ages: 18 Years to any

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.

Participant flow

Outcome results

• Maximum Tolerated Dose (MTD) (Primary), Number, mg twice a day: ABT-751 125
• Number of Patients With Objective Response (CR & PR) by RECIST (Secondary), Number, participants: Phase I/11: ABT-751 0
• Median Time to Tumor Progression (Secondary), Median, Weeks: Phase I/II: ABT-751 4 (3.83 to 4.17)
• Overall Survival (Secondary), Median, Weeks: Phase I/II: ABT-751 35.3 (26.4 to 44.2)
• Safety Profile Based on Number of Patients With Worst Grade Toxicities (Secondary), Number, patients: Phase I/II: ABT-751 0
• Number of Patients Who Demonstrated Treatment Effectiveness Based on Prostate Specific Antigen (PSA) Response in Non-measurable Disease (Primary), Number, participants: Phase I/11: ABT-751 0

Adverse events

Serious adverse events by term

Other adverse events by term

• Jeff Sosman, MD, Principal investigator, Vanderbilt-Ingram Cancer Center