17-AAG in Treating Patients With Metastatic Prostate Cancer That Did Not Respond to Previous Hormone Therapy

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00118092
• Collaborator: (none)
• Enrollment: 17
• Location: 1
• Arm: 1
• Duration (Months): 37
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This phase II trial is studying how well 17-AAG works in treating patients with metastatic prostate cancer that did not respond to previous hormone therapy. Drugs used in chemotherapy, such as 17-AAG, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Prostate; Recurrent Prostate Cancer; Stage IV Prostate Cancer	Drug: tanespimycin; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the prostate-specific antigen (PSA) response in patients with hormone-refractory metastatic prostate cancer treated with 17-N-allylamino-17-demethoxygeldanamycin (17-AAG).

SECONDARY OBJECTIVES:

1. Determine the overall survival and disease-free survival rate in patients treated with this drug.

2. Determine the safety profile of this drug in these patients. III. Determine the duration of PSA response and PSA control in patients treated with this drug.

3. Determine the partial and complete response rates in patients with measurable disease treated with this drug.

4. Correlate changes in expression levels of interleukin-6, maspin, and NF-kappaB in serum and tissue with cancer and treatment-related outcomes in patients treated with this drug.

OUTLINE: This is a multicenter study. Patients receive 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) IV over 2-6 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 2 additional courses of treatment beyond documentation of CR.

After completion of study treatment, patients are followed every 3 months for 1 year and then every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 16-28 patients will be accrued for this study within 20 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) in Patients With Hormone-Refractory Metastatic Prostate Cancer
• Study Start Date: Jan 1, 2005
• Actual Primary Completion Date: May 1, 2006
• Actual Study Completion Date: Feb 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (tanespimycin) Patients receive 17-N-allylamino 17-demethoxygeldanamycin (17-AAG) IV over 2-6 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 2 additional courses of treatment beyond documentation of CR.	Drug: tanespimycin; Given IV; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. PSA Response as Defined by the Recommendations of the Prostate-Specific Antigen Working Group [Up to 1 year]

   Normalization: PSA ≤4.0 ng/ml. This must be confirmed by a second PSA value measured when patient returns in 4-6 weeks. This qualifies as a CR response. > > 50% decline: A 50% decline in PSA value from baseline which must be confirmed by a second PSA value measured when patient returns in 4-6 weeks later. This qualifies as a PR response.> > Progression: A 25% or greater increase over baseline and an increase in the PSA level by at least 5 ng/mL, which is confirmed by a second value obtained approximately one week later. In addition, radiographic scans are required to confirm that a disease progression is by PSA only.

Secondary Outcome Measures

1. Proportion of Overall Responses [Up to 3 years]

   Confirmed response rate was defined using Response Evaluation Criteria In Solid Tumors (RECIST). A confirmed response is defined as a complete response (CR) or partial response (PR) observed on subsequent scans at least 4 weeks apart. Confirmed response rate was estimated by the number of successes divided by the total number of evaluable patients. Complete Response (CR) is defined as the disappearance of all target lesions. Partial Response (PR) is defined as a 30% decrease in sum of longest diameter of target lesions. The proportion of confirmed responses will be estimated by the number of patients with confirmed responses divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.

2. Overall Survival [From registration to death due to any cause, assessed up to 3 years]

   Overall survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.

3. Disease-free Survival [From registration to documentation of disease progression, assessed up to 3 years]

   Disease-free survival time is defined as the time from registration to documentation of disease progression. If a patient dies without a documentation of disease progression, the patient will be considered to have had progressed at the time of their death. In patients who have achieved a PSA response, we will assess the time to PSA progression. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression on day 1 post-registration. The distribution of disease-free survival time will be estimated using the method of Kaplan-Meier.

4. Duration of PSA Response and PSA Control [From PSA response to time of progression, assessed up to 1 year]

   The distribution of this response duration will be estimated using the method of Kaplan-Meier. In patients whose PSA has declined from baseline by at least 30 %, "duration of PSA response" will be defined as the time from PSA response to time of progression. If a patient goes on to alternate therapy, they will be censored at the date they end treatment on this study. "Duration of PSA Control" is defined as the time from the date of the first 30% decline in PSA until an inflection point is identified. Inflection point is defined as the time to first consistent PSA increase, the point at which PSA began what becomes a continuous increase > (retrospectively identified). The inflection point is the point at which disease control could assume to be lost.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the prostate

• Metastatic disease

• Measurable or evaluable disease

• Prostate-specific antigen (PSA) ≥ 5 ng/mL OR new areas of bony metastases on bone scan are required for patients with no measurable disease

• Objective disease progression OR rising PSA despite receiving androgen deprivation therapy and undergoing antiandrogen withdrawal

• Patients with a rising PSA must have 2 successive elevations (measured ≥ 1 week apart)

• Must be castrate (testosterone < 50 ng/mL)

• Luteinizing hormone-releasing hormone agonist therapy must be continued during study participation to maintain castrate levels of testosterone

• Must have received ≥ 1 prior chemotherapy regimen for metastatic disease

• No known brain metastases requiring active therapy

• Previously treated asymptomatic brain metastases allowed

• Performance status - ECOG 0-2

• At least 12 weeks

• Absolute neutrophil count ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• Hemoglobin ≥ 8.0 g/dL

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)

• SGOT and/or SGPT ≤ 2.5 times ULN AND alkaline phosphatase normal

• Alkaline phosphatase ≤ 4 times ULN AND SGOT and/or SGPT normal

• Creatinine clearance ≥ 60 mL/min

• Creatinine normal

• QTc < 450 msec for male patients

• LVEF > 40% by MUGA

• EF normal by MUGA if prior anthracycline therapy

• No congenital long QT syndrome

• No left bundle branch block

• Deep venous thrombosis or other clinically significant thromboembolic event within the past 6 months allowed provided patient is clinically stable on anticoagulation therapy

• No history of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)

• No myocardial infarction within the past year

• No cerebrovascular accident or transient ischemic attack within the past 6 months

• No New York Heart Association class III or IV congestive heart failure

• No poorly controlled angina

• No uncontrolled dysrhythmia or dysrhythmias requiring medication

• No active ischemic heart disease within the past 12 months

• No other significant cardiac disease

• Pulmonary embolus allowed within the past 6 months provided patient is clinically stable on anticoagulation therapy

• Fertile patients must use effective contraception

• Willing and able to provide blood samples

• No serious allergy (i.e., hypotension, dyspnea, anaphylaxis, or edema) to eggs

• No other concurrent malignancy or history of a curatively treated malignancy with a survival prognosis of < 5 years

• No known HIV positivity

• No active infection

• No other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would preclude study participation

• At least 4 weeks since prior flutamide (6 weeks for bicalutamide or nilutamide)

• At least 28 days since prior radiotherapy

• No prior radiotherapy field that included the heart (e.g., mantle)

• More than 6 months since prior coronary or peripheral artery bypass grafting

• More than 28 days since prior investigational agents for prostate cancer

• No concurrent agents that interact with cytochrome P450 3A4

• No concurrent warfarin for anticoagulation

• Concurrent low molecular weight heparin injection allowed

• No concurrent medications that would prolong QTc

• No other concurrent antineoplastic agents

• Concurrent zoledronate for bone metastases or hypercalcemia allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Elisabeth Heath, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00118092
• Other Study ID Numbers: NCI-2012-01466; NCI-2012-01466; MAYO-MC0453; NCI-6651; CDR0000433492; MC0453; 6651; N01CM62205
• First Posted: Jul 11, 2005
• Last Update Posted: Apr 18, 2017
• Last Verified: Mar 1, 2017

• Additional relevant MeSH terms: Prostatic Neoplasms

Study Results

Participant Flow

Arm/Group Title	Treatment (Tanespimycin)
Arm/Group Description	Patients receive 300 mg/m^2 17-N-allylamino 17-demethoxygeldanamycin (17-AAG) IV over 2-6 hours on days 1, 8, and 15. > Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	17
COMPLETED	15
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Tanespimycin)
Arm/Group Description	Patients receive 300 mg/m^2 17-N-allylamino 17-demethoxygeldanamycin (17-AAG) IV over 2-6 hours on days 1, 8, and 15. > Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Participants	15
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	68
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	15 100%
Region of Enrollment (participants) [Number]
United States	15 100%

Outcome Measures

1. Primary Outcome

Title	PSA Response as Defined by the Recommendations of the Prostate-Specific Antigen Working Group
Description	Normalization: PSA ≤4.0 ng/ml. This must be confirmed by a second PSA value measured when patient returns in 4-6 weeks. This qualifies as a CR response. > > 50% decline: A 50% decline in PSA value from baseline which must be confirmed by a second PSA value measured when patient returns in 4-6 weeks later. This qualifies as a PR response.> > Progression: A 25% or greater increase over baseline and an increase in the PSA level by at least 5 ng/mL, which is confirmed by a second value obtained approximately one week later. In addition, radiographic scans are required to confirm that a disease progression is by PSA only.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

All 15 eligible patients that started treatment were evaluated.

Arm/Group Title	Treatment (Tanespimycin)
Arm/Group Description	Patients receive 300 mg/m^2 17-N-allylamino 17-demethoxygeldanamycin (17-AAG) IV over 2-6 hours on days 1, 8, and 15. > Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	15
Number [participants]	0 0%

2. Secondary Outcome

Title	Proportion of Overall Responses
Description	Confirmed response rate was defined using Response Evaluation Criteria In Solid Tumors (RECIST). A confirmed response is defined as a complete response (CR) or partial response (PR) observed on subsequent scans at least 4 weeks apart. Confirmed response rate was estimated by the number of successes divided by the total number of evaluable patients. Complete Response (CR) is defined as the disappearance of all target lesions. Partial Response (PR) is defined as a 30% decrease in sum of longest diameter of target lesions. The proportion of confirmed responses will be estimated by the number of patients with confirmed responses divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

All 15 eligible patients that started treatment were evaluated.

Arm/Group Title	Treatment (Tanespimycin)
Arm/Group Description	Patients receive 300 mg/m^2 17-N-allylamino 17-demethoxygeldanamycin (17-AAG) IV over 2-6 hours on days 1, 8, and 15. > Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	15
Number (95% Confidence Interval) [percentage of responses]	0

3. Secondary Outcome

Title	Overall Survival
Description	Overall survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.
Time Frame	From registration to death due to any cause, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

All 15 eligible patients that started treatment were evaluated.

Arm/Group Title	Treatment (Tanespimycin)
Arm/Group Description	Patients receive 300 mg/m^2 17-N-allylamino 17-demethoxygeldanamycin (17-AAG) IV over 2-6 hours on days 1, 8, and 15. > Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	15
Median (95% Confidence Interval) [months]	9.4

4. Secondary Outcome

Title	Disease-free Survival
Description	Disease-free survival time is defined as the time from registration to documentation of disease progression. If a patient dies without a documentation of disease progression, the patient will be considered to have had progressed at the time of their death. In patients who have achieved a PSA response, we will assess the time to PSA progression. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression on day 1 post-registration. The distribution of disease-free survival time will be estimated using the method of Kaplan-Meier.
Time Frame	From registration to documentation of disease progression, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

All 15 eligible patients that started treatment were evaluated.

Arm/Group Title	Treatment (Tanespimycin)
Arm/Group Description	Patients receive 300 mg/m^2 17-N-allylamino 17-demethoxygeldanamycin (17-AAG) IV over 2-6 hours on days 1, 8, and 15. > Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	15
Median (95% Confidence Interval) [months]	1.8

5. Secondary Outcome

Title	Duration of PSA Response and PSA Control
Description	The distribution of this response duration will be estimated using the method of Kaplan-Meier. In patients whose PSA has declined from baseline by at least 30 %, "duration of PSA response" will be defined as the time from PSA response to time of progression. If a patient goes on to alternate therapy, they will be censored at the date they end treatment on this study. "Duration of PSA Control" is defined as the time from the date of the first 30% decline in PSA until an inflection point is identified. Inflection point is defined as the time to first consistent PSA increase, the point at which PSA began what becomes a continuous increase > (retrospectively identified). The inflection point is the point at which disease control could assume to be lost.
Time Frame	From PSA response to time of progression, assessed up to 1 year

Outcome Measure Data

Analysis Population Description

No participants with PSA response or PSA control.

Arm/Group Title	Treatment (Tanespimycin)
Arm/Group Description	Patients receive 300 mg/m^2 17-N-allylamino 17-demethoxygeldanamycin (17-AAG) IV over 2-6 hours on days 1, 8, and 15. > Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

Adverse Events

Arm/Group Title	Treatment (Tanespimycin)
Arm/Group Description	Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Treatment (Tanespimycin)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Tanespimycin)
	Affected / at Risk (%)	# Events
Total	2/17 (11.8%)
Investigations
Neutrophil count decreased	1/17 (5.9%)	2
Vascular disorders
Thrombosis	1/17 (5.9%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Tanespimycin)
	Affected / at Risk (%)	# Events
Total	16/17 (94.1%)
Blood and lymphatic system disorders
Hemoglobin decreased	14/17 (82.4%)	19
Cardiac disorders
Premature ventricular contractions	1/17 (5.9%)	2
Sinus arrhythmia	1/17 (5.9%)	1
Sinus bradycardia	1/17 (5.9%)	1
Supraventricular extrasystoles	3/17 (17.6%)	4
Eye disorders
Vision blurred	1/17 (5.9%)	1
Gastrointestinal disorders
Abdominal pain	3/17 (17.6%)	4
Constipation	4/17 (23.5%)	4
Diarrhea	6/17 (35.3%)	6
Flatulence	1/17 (5.9%)	1
Mucositis oral	1/17 (5.9%)	1
Nausea	8/17 (47.1%)	10
Vomiting	4/17 (23.5%)	6
General disorders
Fatigue	10/17 (58.8%)	15
Fever	1/17 (5.9%)	1
Infections and infestations
Sinusitis	1/17 (5.9%)	1
Skin infection	1/17 (5.9%)	1
Investigations
Alanine aminotransferase increased	4/17 (23.5%)	6
Alkaline phosphatase increased	7/17 (41.2%)	10
Aspartate aminotransferase increased	8/17 (47.1%)	10
Electrocardiogram QTc interval prolonged	2/17 (11.8%)	2
Leukocyte count decreased	2/17 (11.8%)	3
Lymphocyte count decreased	5/17 (29.4%)	5
Neutrophil count decreased	1/17 (5.9%)	1
Platelet count decreased	4/17 (23.5%)	6
Weight loss	2/17 (11.8%)	2
Metabolism and nutrition disorders
Anorexia	6/17 (35.3%)	7
Blood glucose increased	7/17 (41.2%)	13
Dehydration	1/17 (5.9%)	1
Serum albumin decreased	8/17 (47.1%)	11
Serum calcium decreased	3/17 (17.6%)	5
Serum phosphate decreased	1/17 (5.9%)	2
Serum potassium decreased	1/17 (5.9%)	1
Serum sodium decreased	2/17 (11.8%)	2
Musculoskeletal and connective tissue disorders
Back pain	4/17 (23.5%)	4
Bone pain	2/17 (11.8%)	2
Muscle weakness	1/17 (5.9%)	1
Myalgia	1/17 (5.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/17 (5.9%)	1
Nervous system disorders
Headache	2/17 (11.8%)	3
Peripheral motor neuropathy	1/17 (5.9%)	1
Peripheral sensory neuropathy	1/17 (5.9%)	1
Psychiatric disorders
Anxiety	1/17 (5.9%)	1
Renal and urinary disorders
Hemorrhage urinary tract	1/17 (5.9%)	1
Urinary frequency	1/17 (5.9%)	2
Respiratory, thoracic and mediastinal disorders
Cough	1/17 (5.9%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/17 (5.9%)	1
Body odor	3/17 (17.6%)	4
Skin hyperpigmentation	1/17 (5.9%)	1
Vascular disorders
Flushing	1/17 (5.9%)	1

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.