R-(-)-Gossypol and Androgen Ablation Therapy in Treating Patients With Newly Diagnosed Metastatic Prostate Cancer

A Phase II Study of AT101, to Abrogate BCL-2 Mediated Resistance to Androgen Ablation Therapy in Patients With Newly Diagnosed Stage D2 Prostate Cancer

This phase II trial is studying how well giving gossypol together with androgen ablation therapy works in treating patients with newly diagnosed metastatic prostate cancer. Gossypol may stop the growth of tumor cells by blocking blood flow to the tumor. Androgens can cause the growth of prostate tumor cells. Luteinizing hormone-releasing hormone agonists and drugs, such as bicalutamide, may lessen the amount of androgens made by the body. Giving gossypol together with androgen ablation therapy may be an effective treatment for prostate cancer

Study Overview

• Status: Completed
• Conditions: Adenocarcinoma of the Prostate; Stage IV Prostate Cancer
• Intervention / Treatment: Drug: AT-101; Drug: Bicalutamide; Other: LHRH agent

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the percentage of patients with newly diagnosed metastatic prostate cancer who demonstrate undetectable prostate-specific antigen (PSA) (< 0.2 ng/mL) at 7 months when treated with R-(-)-gossypol (AT-101) and androgen ablation therapy.

SECONDARY OBJECTIVES:

I. To determine the safety of this regimen in these patients. II. To determine the percentage of patients with PSA >= 4.0 ng/mL, overall PSA < 4.0 ng/mL, and a PSA >= 0.2 ng/mL but < 4.0 ng/mL during the first 7 months of therapy.

OUTLINE:

Patients receive R-(-)-gossypol orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. Patients may receive bicalutamide PO QD beginning 6 weeks before the initiation of R-(-)-gossypol and continuing after completion of treatment, at the discretion of the treating physician.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria

• Histologically proven adenocarcinoma of the prostate with clinical stage D2 disease defined by soft tissue or bony metastasis.
• Patients must have elevated PSA ≥ 5 ng/ml within 12 weeks prior to registration. Androgen ablation therapy, which must include an LHRH agonist, will begin 6 weeks prior to initiation of AT101.
• Patients are allowed prior local therapy with radiation or surgery. Patients must not have received more than 12 months of androgen ablation therapy or antiandrogen therapy in the adjuvant/neoadjuvant setting and no prior androgen ablation therapy for metastatic disease, beyond the six week induction period prior to initiation of AT101. Patients with prior adjuvant/neoadjuvant androgen ablation therapy must have completed such therapy at least 12 months prior.
• Must be 18 years old or older.
• Life expectancy of greater than 6 months.
• ECOG performance status ≤ 2.

• Patients must have normal organ and marrow function as defined below:

  • leukocytes ≥ 3,000/mcL
  • absolute neutrophil count ≥ 1,500/mcL
  • platelets ≥ 100,000/mcL
  • total bilirubin within normal institutional limits
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal
  • creatinine within normal institutional limits OR
  • creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
• There must be no plans to receive concomitant chemotherapy or radiation therapy during the study period. Baseline and on study PSA values must be obtained from the same reference laboratory.
• The effects of AT101 on the developing human fetus at the recommended therapeutic dose are unknown. For this reason men and/or their partners must agree to use adequate contraception, (including hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation.

Exclusion Criteria

• Patients who have had radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Patients may not be receiving any other investigational agents.
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AT101 or other agents used in the study.
• Patients with bilateral orchiectomy are not eligible.
• Patients presenting with acute cord compression are not eligible.
• History of bowel obstruction or GI dismotility disorder.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain AT-101 tablets.
• Requirement for routine use of hematopoietic growth factors (including granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, or interleukin-11) or platelet transfusions to maintain absolute neutrophil counts or platelets counts above the required thresholds for study entry.
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AT-101.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: AT101 (R-(-)-gossypol acetic acid); Patients will receive Hormone therapy with at least one LHRH agent (Leuprolide Acetate or Goserelin) for 6 weeks and include bicalutamide. Patients will begin AT101 daily at 6 weeks for 3 weeks of every 4 weeks (4 weeks - 1 cycle) and continue for 8 cycles of combined therapy (combined AT101, and LHRH agonist). After 8 cycles patients will continue hormonal therapy.

Drug: AT-101; AT101 will be administered orally 20 mg/day for 21 days of a 28 day cycle.; Other Names: R-(-)-gossypol acetic acid; Drug: Bicalutamide; Daily bicalutamide 50 mg po is encouraged for the first month of LHRH agonist therapy to prevent a flare. Continued bicalutamide use is optional. Bicalutamide will be administered orally at a dose of 50 mg po daily, Day 1 to 28 of each cycle.; Other Names: Casodex; CDX; Other: LHRH agent; An LHRH agonist(Leuprolide Acetate or Goserelin)can be administered at standard dosing appropriate to the agent used.; Other Names: Leutinizing Hormone Receptor Hormone agonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of Patients With Undetectable Prostate-specific Antigen (PSA) (< 0.2 ng/mL) at End of 7 Cycles	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage of Patients With PSA ≥ 0.2 ng/mL But < 4.0 ng/mL	3 years
Percentage of Patients With Overall PSA < 4.0 ng/mL	3 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Robert DiPaola, Rutgers Cancer Institute of New Jersey

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: April 24, 2008
• First Submitted That Met QC Criteria: April 24, 2008
• First Posted (Estimate): April 25, 2008

Study Record Updates

• Last Update Posted (Estimate): December 18, 2014
• Last Update Submitted That Met QC Criteria: December 17, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: stage IV prostate cancer; adenocarcinoma of the prostate; prostate Cancer; newly diagnosed stage IV prostate cancer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Adenocarcinoma; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Phytogenic; Anti-Bacterial Agents; Hormone Antagonists; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Androgen Antagonists; Contraceptive Agents, Male; Spermatocidal Agents; Antispermatogenic Agents; Hormones; Bicalutamide; Acetic Acid; Gossypol; Gossypol acetic acid
• Other Study ID Numbers: NCI-2009-00264; N01CM62201 (U.S. NIH Grant/Contract); U01CA132194 (U.S. NIH Grant/Contract); U01CA062491 (U.S. NIH Grant/Contract); 8014 (NCI/CTEP); 080707 (Other Identifier: CINJ)