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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00666666
• Collaborator: (none)
• Enrollment: 55
• Locations: 4
• Arm: 1
• Duration (Months): 35
• Patients Per Site: 13.8
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Prostate; Stage IV Prostate Cancer	Drug: AT-101; Drug: Bicalutamide; Other: LHRH agent	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. 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:

1. 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 Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients With Undetectable Prostate-specific Antigen (PSA) (< 0.2 ng/mL) at End of 7 Cycles [3 years]

Secondary Outcome Measures

1. Percentage of Patients With PSA ≥ 0.2 ng/mL But < 4.0 ng/mL [3 years]

2. Percentage of Patients With Overall PSA < 4.0 ng/mL [3 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago	Chicago	Illinois	United States	60637
2	University of Michigan	Ann Arbor	Michigan	United States	48109
3	Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
4	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Robert DiPaola, Rutgers Cancer Institute of New Jersey

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00666666
• Other Study ID Numbers: NCI-2009-00264; 8014; N01CM62201; U01CA062491; U01CA132194; 080707
• First Posted: Apr 25, 2008
• Last Update Posted: Dec 18, 2014
• Last Verified: Aug 1, 2014

• Keywords provided by National Cancer Institute (NCI): prostate Cancer; adenocarcinoma of the prostate; stage IV prostate cancer; newly diagnosed stage IV prostate cancer
• Additional relevant MeSH terms: Prostatic Neoplasms; Adenocarcinoma; Acetic Acid; Bicalutamide; Gossypol acetic acid; Gossypol; Hormones

Study Results

Participant Flow

Recruitment Details	Patients were recruited from April 2008 through July 2010, from four academic medical centers.
Pre-assignment Detail	There are no pre-assignment requirements.

Arm/Group Title	AT101 (R-(-)-Gossypol Acetic Acid)
Arm/Group Description	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. AT-101 : AT101 will be administered orally 20 mg/day for 21 days of a 28 day cycle. 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. LHRH agent : An LHRH agonist(Leuprolide Acetate or Goserelin)can be administered at standard dosing appropriate to the agent used.
Period Title: Overall Study
STARTED	55
COMPLETED	55
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	AT101 (R-(-)-Gossypol Acetic Acid)
Arm/Group Description
Overall Participants	55
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	32 58.2%
>=65 years	23 41.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.58 (8.925)
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	61.5
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	55 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	55 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	6 10.9%
White	49 89.1%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	55 100%
Gleason Score (participants) [Number]
Gleason Score 6	1 1.8%
Gleason Score 7	13 23.6%
Gleason Score 8	12 21.8%
Gleason Score 9	24 43.6%
Gleason Score 10	3 5.5%
Not assessed	2 3.6%
Metastatic disease (participants) [Number]
Visceral metastases	3 5.5%
Bone/node metastases	52 94.5%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AT101 (R-(-)-Gossypol Acetic Acid)
Arm/Group Description	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. AT-101 : AT101 will be administered orally 20 mg/day for 21 days of a 28 day cycle. 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. LHRH agent : An LHRH agonist(Leuprolide Acetate or Goserelin)can be administered at standard dosing appropriate to the agent used.
Measure Participants	55
Number [percentage of participants]	22 40%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AT101 (R-(-)-Gossypol Acetic Acid)
Arm/Group Description	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. AT-101 : AT101 will be administered orally 20 mg/day for 21 days of a 28 day cycle. 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. LHRH agent : An LHRH agonist(Leuprolide Acetate or Goserelin)can be administered at standard dosing appropriate to the agent used.
Measure Participants	55
Number [percentage of participants]	18 32.7%

3. Secondary Outcome

Title	Percentage of Patients With Overall PSA < 4.0 ng/mL
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AT101 (R-(-)-Gossypol Acetic Acid)
Arm/Group Description	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. AT-101 : AT101 will be administered orally 20 mg/day for 21 days of a 28 day cycle. 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. LHRH agent : An LHRH agonist(Leuprolide Acetate or Goserelin)can be administered at standard dosing appropriate to the agent used.
Measure Participants	55
Number [percentage of participants]	60 109.1%

Adverse Events

Time Frame	8 months
Arm/Group Title	AT101 (R-(-)-Gossypol Acetic Acid)
Arm/Group Description	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. AT-101 : AT101 will be administered orally 20 mg/day for 21 days of a 28 day cycle. 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. LHRH agent : An LHRH agonist(Leuprolide Acetate or Goserelin)can be administered at standard dosing appropriate to the agent used.
All Cause Mortality
	AT101 (R-(-)-Gossypol Acetic Acid)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	AT101 (R-(-)-Gossypol Acetic Acid)
	Affected / at Risk (%)	# Events
Total	13/55 (23.6%)
Eye disorders
Eye disorders - optic neuritis	1/55 (1.8%)	1
Gastrointestinal disorders
Dyspepsia	1/55 (1.8%)	1
Ileus	3/55 (5.5%)	3
Lower gastrointestinal hemorrhage	1/55 (1.8%)	1
Small intestinal obstruction	1/55 (1.8%)	1
Infections and infestations
Infections and infestations - urosepsis	1/55 (1.8%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/55 (1.8%)	1
Bone pain	1/55 (1.8%)	1
Musculoskeletal and connective tissue disorder - left total hip arthroplasty	1/55 (1.8%)	1
Nervous system disorders
Dizziness	1/55 (1.8%)	1
Peripheral motor neuropathy	1/55 (1.8%)	1
Peripheral sensory neuropathy	1/55 (1.8%)	1
Syncope	1/55 (1.8%)	1
Other (Not Including Serious) Adverse Events
	AT101 (R-(-)-Gossypol Acetic Acid)
	Affected / at Risk (%)	# Events
Total	55/55 (100%)
Blood and lymphatic system disorders
Anemia	22/55 (40%)	34
Gastrointestinal disorders
Nausea	20/55 (36.4%)	28
Vomiting	14/55 (25.5%)	22
Constipation	13/55 (23.6%)	14
Diarrhea	12/55 (21.8%)	18
Abdominal pain	8/55 (14.5%)	11
Flatulence	4/55 (7.3%)	4
General disorders
Fatigue	32/55 (58.2%)	42
Edema limbs	5/55 (9.1%)	5
Chills	3/55 (5.5%)	3
Pain	3/55 (5.5%)	3
Investigations
Alanine aminotransferase increased	23/55 (41.8%)	35
Aspartate aminotransferase increased	17/55 (30.9%)	26
Creatinine increased	10/55 (18.2%)	17
Platelet count decreased	6/55 (10.9%)	15
Alkaline phosphatase increased	5/55 (9.1%)	6
White blood cell decreased	5/55 (9.1%)	12
Lymphocyte count decreased	3/55 (5.5%)	9
Metabolism and nutrition disorders
Hyperglycemia	27/55 (49.1%)	42
Anorexia	10/55 (18.2%)	12
Hyperkalemia	8/55 (14.5%)	9
Hypercalcemia	6/55 (10.9%)	10
Hypocalcemia	5/55 (9.1%)	7
Acidosis	4/55 (7.3%)	5
Hyponatremia	3/55 (5.5%)	4
Hypophosphatemia	3/55 (5.5%)	4
Musculoskeletal and connective tissue disorders
Back pain	9/55 (16.4%)	10
Bone pain	7/55 (12.7%)	9
Arthralgia	6/55 (10.9%)	11
Pain in extremity	4/55 (7.3%)	4
Myalgia	3/55 (5.5%)	3
Nervous system disorders
Peripheral sensory neuropathy	19/55 (34.5%)	29
Dizziness	7/55 (12.7%)	8
Headache	6/55 (10.9%)	6
Dysgeusia	3/55 (5.5%)	3
Peripheral motor neuropathy	3/55 (5.5%)	4
Psychiatric disorders
Insomnia	6/55 (10.9%)	6
Depression	3/55 (5.5%)	3
Renal and urinary disorders
Urinary frequency	8/55 (14.5%)	8
Urinary tract pain	3/55 (5.5%)	3
Reproductive system and breast disorders
Erectile dysfunction	6/55 (10.9%)	6
Respiratory, thoracic and mediastinal disorders
Dyspnea	5/55 (9.1%)	7
Cough	3/55 (5.5%)	3
Skin and subcutaneous tissue disorders
Dry skin	8/55 (14.5%)	8
Rash acneiform	3/55 (5.5%)	4
Vascular disorders
Hot flashes	19/55 (34.5%)	22
Hypertension	6/55 (10.9%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.