Leuprolide Acetate or Goserelin Acetate With or Without Vismodegib Followed by Surgery in Treating Patients With Locally Advanced Prostate Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT01163084
• Collaborator: (none)
• Enrollment: 10
• Locations: 5
• Arms: 2
• Actual Duration (Months): 22.8
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This randomized phase I/II trial studies giving leuprolide acetate or goserelin acetate together with or without vismodegib followed by surgery to see how well they work in treating patients with prostate cancer that has spread from where it started to nearby tissue or lymph nodes. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as leuprolide acetate or goserelin acetate, may lessen the amount of androgens made by the body. Vismodegib may slow the growth of tumor cells. Giving antihormone therapy together with vismodegib may be an effective treatment for prostate cancer.

Condition or Disease	Intervention/Treatment	Phase
Prostate Adenocarcinoma; Stage IIA Prostate Cancer AJCC v7; Stage IIB Prostate Cancer AJCC v7	Drug: Goserelin Acetate; Other: Laboratory Biomarker Analysis; Drug: Leuprolide Acetate; Drug: Vismodegib	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the difference in less than or equal to 5% tumor involvement between patients between the two arms.

SECONDARY OBJECTIVES:

1. To assess differences in hedgehog signaling, androgen signaling, markers linked to high grade prostate cancer (PCa) progression, proliferation, apoptosis, and the expression of androgen producing enzymes in the tumor microenvironment between the two arms.

2. To assess safety of preoperative GDC-0449 (vismodegib) in combination with luteinizing hormone-releasing hormone (LHRH).

3. To assess the difference in proportion of patients with negative disease surgical margins between the two arms.

4. To collect and archive tissue from the primary tumor, bone marrow and blood (serum, plasma), bone marrow aspirate for future study.

5. To assess difference in relapse rate (biochemical, objective) and time to progression.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (androgen-ablation therapy and vismodegib): Patients receive LHRH analogue comprising leuprolide acetate intramuscularly (IM) or goserelin acetate subcutaneously (SC) on day 1 and vismodegib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 16 weeks in the absence of disease progression or unacceptable toxicity.

ARM II (androgen-ablation therapy): Patients receive LHRH analogue comprising leuprolide acetate or goserelin acetate as in Arm I. Treatment repeats every 28 days for up to 16 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients undergo radical prostatectomy.

After completion of study therapy, patients are followed up every 6 months for up to 8 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase Ib/II Study of Preoperative GDC-0449 and Androgen Ablation Compared to Androgen Ablation Alone Followed by Radical Prostatectomy for Select Patients With Locally Advanced Adenocarcinoma of the Prostate
• Actual Study Start Date: Jul 9, 2010
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (leuprolide acetate, goserelin acetate, vismodegib) Patients receive LHRH analogue comprising leuprolide acetate IM or goserelin acetate SC on day 1 and vismodegib PO QD on days 1-28. Treatment repeats every 28 days for up to 16 weeks in the absence of disease progression or unacceptable toxicity.	Drug: Goserelin Acetate; Given SC; Other Names: ZDX Zoladex ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Leuprolide Acetate; Given IM; Other Names: A-43818 Abbott 43818 Abbott-43818 Carcinil Depo-Eligard Eligard Enanton Enantone Enantone-Gyn Ginecrin LEUP Leuplin Leuprorelin Acetate Lucrin Lucrin Depot Lupron Lupron Depot Lupron Depot-3 Month Lupron Depot-4 Month Lupron Depot-Ped Procren Procrin Prostap TAP-144 Trenantone Uno-Enantone Viadur ; Drug: Vismodegib; Given PO; Other Names: Erivedge GDC-0449 Hedgehog Antagonist GDC-0449
Active Comparator: Arm II (leuprolide acetate, goserelin acetate) Patients receive LHRH analogue comprising leuprolide acetate or goserelin acetate as in Arm I. Treatment repeats every 28 days for up to 16 weeks in the absence of disease progression or unacceptable toxicity.	Drug: Goserelin Acetate; Given SC; Other Names: ZDX Zoladex ; Drug: Leuprolide Acetate; Given IM; Other Names: A-43818 Abbott 43818 Abbott-43818 Carcinil Depo-Eligard Eligard Enanton Enantone Enantone-Gyn Ginecrin LEUP Leuplin Leuprorelin Acetate Lucrin Lucrin Depot Lupron Lupron Depot Lupron Depot-3 Month Lupron Depot-4 Month Lupron Depot-Ped Procren Procrin Prostap TAP-144 Trenantone Uno-Enantone Viadur

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients With =< 5% Tumor Involvement [Baseline up to 4 months or radical prostatectomy, whichever comes first]

   Each patient's pathologic staging will be assessed from the samples collected from prostatectomy. Will be descriptively summarized. Two-sided Chi-Square test will be used to provide the test of significance between the 2 groups of LHRHa versus LHRHa plus vismodegib.

Other Outcome Measures

1. Differences in Relapse Rates by PSA Levels (Biochemical) [Date of surgery, then every 6 months, up to 8 years]

   Will be descriptively summarized.

2. Time to PSA (Biochemical) Progression, Defined as PSA Recurrence [From the date of surgery and elevated post operative PSA concentration, assessed up to 8 years]

   Will be descriptively summarized. PSA recurrence is defined as two (2) serial measureable rises in PSA concentration above the undetectable level with the standard assay (> 0.1 ng/mL).

3. Time to PSA (Clinical) Progression, Defined as a Serial Rise in PSA Concentration in the Presence of Castrate Serum Testosterone Concentration or Radiographic Evidence of Progression [From the date of surgery and elevated post operative PSA concentration, assessed up to 8 years]

   Will be descriptively summarized. PSA recurrence is defined as two (2) serial measureable rises in PSA concentration above the undetectable level with the standard assay (> 0.1 ng/mL).

4. Proportion of Patients With PSA =< 0.2 ng/mL [Up to 8 years]

   Will be descriptively summarized.

5. Differences in the Rate of Positive Surgical Margins Between the Two Groups [Baseline to up to 8 years]

   Will be descriptively summarized.

6. Differences in Relapse Rates by Bone Scan/Computed Tomography Scan (Objective) [Baseline to up to 8 years]

   Will be descriptively summarized.

7. Proportion of Patients Expressing Differences in Hedgehog, Androgen Signaling and Related Genes Markers [Up to 8 years]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have histologic proof of prostatic adenocarcinoma via a minimum of 6 core biopsy samples

• Clinical stage T1c or T2 with high-grade disease (Gleason's 8-10) on initial biopsy and prostate specific antigen (PSA) > 10 ng/ml, or clinical stage T2b-T2c with Gleason's grade >= 7

• No evidence of metastatic disease as determined by imaging

• Initial therapy with antiandrogen treatment is allowed but must be within 4 weeks prior to study enrollment

• Appropriate surgical candidate for radical prostatectomy and an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Absence of major co-morbidity as determined by the treating physician

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >=100,000/mcL

• Total bilirubin within normal institutional limits

• Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal

• Creatinine within normal institutional limits OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

• Patients must have prothrombin time (PT), partial thromboplastin time (PTT) and fibrinogen levels within institutional normal limits and no history of substantial non-iatrogenic bleeding diathesis

• Men and their female partners must agree to use two forms of contraception (i.e., barrier contraception and one other method of contraception) during study treatment and for at least 12 months post-treatment

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Histologic variants in the primary tumor (histologic variants other than adenocarcinoma)

• Patients who have had chemotherapy or radiotherapy for prostate cancer prior to entering the study

• Patients who have received prior treatment with GDC-0449

• Patients may not be receiving any other investigational agents

• Patients receiving previous androgen ablation or current androgen ablation of greater than 4 week's duration

• Patients who are not appropriate surgical candidates for radical prostatectomy based on the evaluation of co-existent medical diseases and competing causes of death (such as but not limited to, unstable angina, myocardial infarction within the previous 6 months, or use of ongoing maintenance therapy for life-threatening ventricular arrhythmia, uncontrolled hypertension)

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to GDC-0449 or LHRH analogues

• Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible

• Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow capsules

• Patients with clinically important (in the opinion of the treating physician) history of liver disease, including viral or other hepatitis or cirrhosis are ineligible

• Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study

• 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

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

• Patients with prior malignancy if there is an increased chance (>= 30%) of relapse in the following five years (in the opinion of the treating physician)

• Patients who have received systemic treatment for cancer within the last 6 months

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
2	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
3	Duke University Medical Center	Durham	North Carolina	United States	27710
4	M D Anderson Cancer Center	Houston	Texas	United States	77030
5	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Christopher Logothetis, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01163084
• Other Study ID Numbers: NCI-2010-01737; NCI-2010-01737; CDR0000670590; 2009-0473; 8384; N01CM00039; N01CM62202; P30CA016672; U01CA062461; U01CA062491
• First Posted: Jul 15, 2010
• Last Update Posted: Feb 28, 2019
• Last Verified: Feb 1, 2019

• Additional relevant MeSH terms: Prostatic Neoplasms; Adenocarcinoma; Leuprolide; Goserelin

Study Results

Participant Flow

Recruitment Details	Participants were recruited by physicians in the Genitourinary Medical Oncology Clinic and Urology clinic.
Pre-assignment Detail	10 participants started but only 9 were randomized

Arm/Group Title	Group A- GDC-0449 and Androgen Ablation (LHRHa)	Group B- Androgren Ablation (LHRHa) Alone
Arm/Group Description	Group A will receive 150mg GDC-0449 daily for 3 months prior to radical prostatectomy.	Patients will receive an LHRHa (monthly injection or three-month injection) for a maximum of 4 months before a prostatectomy is performed.
Period Title: Overall Study
STARTED	4	5
COMPLETED	4	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Group A- GDC-0449 and Androgen Ablation (LHRHa)	Group- B Androgren Ablation (LHRHa) Alone	Total
Arm/Group Description	Group A will receive 150mg GDC-0449 daily for 3 months prior to radical prostatectomy.	Patients will receive an LHRHa (monthly injection or three-month injection) for a maximum of 4 months before a prostatectomy is performed.	Total of all reporting groups
Overall Participants	4	5	9
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	2 50%	4 80%	6 66.7%
>=65 years	2 50%	1 20%	3 33.3%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	63	63	63
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	4 100%	5 100%	9 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 20%	1 11.1%
Not Hispanic or Latino	3 75%	1 20%	4 44.4%
Unknown or Not Reported	1 25%	3 60%	4 44.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	3 75%	4 80%	7 77.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 25%	1 20%	2 22.2%
Region of Enrollment (participants) [Number]
United States	4 100%	5 100%	9 100%

Outcome Measures

1. Primary Outcome

Title	Proportion of Patients With =< 5% Tumor Involvement
Description	Each patient's pathologic staging will be assessed from the samples collected from prostatectomy. Will be descriptively summarized. Two-sided Chi-Square test will be used to provide the test of significance between the 2 groups of LHRHa versus LHRHa plus vismodegib.
Time Frame	Baseline up to 4 months or radical prostatectomy, whichever comes first

Outcome Measure Data

Analysis Population Description

Results was not determined.

Arm/Group Title	Group A-GDC-0449 and Androgen Ablation (LHRHa	Group B Androgen Ablation (LHRHa) Alone
Arm/Group Description	Group A will receive 150mg GDC-0449 daily for 3 months prior to radical prostatectomy	Patients will receive an LHRHa (monthly injection or three-month injection) for a maximum of 4 months before a prostatectomy is performed.
Measure Participants	0	0

2. Other Pre-specified Outcome

Title	Differences in Relapse Rates by PSA Levels (Biochemical)
Description	Will be descriptively summarized.
Time Frame	Date of surgery, then every 6 months, up to 8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Other Pre-specified Outcome

Title	Time to PSA (Biochemical) Progression, Defined as PSA Recurrence
Description	Will be descriptively summarized. PSA recurrence is defined as two (2) serial measureable rises in PSA concentration above the undetectable level with the standard assay (> 0.1 ng/mL).
Time Frame	From the date of surgery and elevated post operative PSA concentration, assessed up to 8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	Time to PSA (Clinical) Progression, Defined as a Serial Rise in PSA Concentration in the Presence of Castrate Serum Testosterone Concentration or Radiographic Evidence of Progression
Description	Will be descriptively summarized. PSA recurrence is defined as two (2) serial measureable rises in PSA concentration above the undetectable level with the standard assay (> 0.1 ng/mL).
Time Frame	From the date of surgery and elevated post operative PSA concentration, assessed up to 8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	Proportion of Patients With PSA =< 0.2 ng/mL
Description	Will be descriptively summarized.
Time Frame	Up to 8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Differences in the Rate of Positive Surgical Margins Between the Two Groups
Description	Will be descriptively summarized.
Time Frame	Baseline to up to 8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Differences in Relapse Rates by Bone Scan/Computed Tomography Scan (Objective)
Description	Will be descriptively summarized.
Time Frame	Baseline to up to 8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Proportion of Patients Expressing Differences in Hedgehog, Androgen Signaling and Related Genes Markers
Time Frame	Up to 8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	During on-study tests/visits that occur every 4 weeks for all participants until the follow up visit after radical prostatectomy, assessed up to 5 months.
Adverse Event Reporting Description	All adverse events reported as routine part of a clinical trial.
Arm/Group Title	Group A- GDC-0449 and Androgen Ablation (LHRHa)		Group B- Androgren Ablation (LHRHa) Alone
Arm/Group Description	Group A will receive 150mg GDC-0449 daily for 3 months prior to radical prostatectomy.		Patients will receive an LHRHa (monthly injection or three-month injection) for a maximum of 4 months before a prostatectomy is performed.
All Cause Mortality
	Group A- GDC-0449 and Androgen Ablation (LHRHa)		Group B- Androgren Ablation (LHRHa) Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/5 (0%)
Serious Adverse Events
	Group A- GDC-0449 and Androgen Ablation (LHRHa)		Group B- Androgren Ablation (LHRHa) Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Group A- GDC-0449 and Androgen Ablation (LHRHa)		Group B- Androgren Ablation (LHRHa) Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		5/5 (100%)
Blood and lymphatic system disorders
Anemia	1/4 (25%)		3/5 (60%)
Edema Limbs	0/4 (0%)		1/5 (20%)
Eye disorders
Watering eyes	1/4 (25%)		0/5 (0%)
Gastrointestinal disorders
Constipation	1/4 (25%)		0/5 (0%)
General disorders
Fatigue	4/4 (100%)		2/5 (40%)
Pain	0/4 (0%)		1/5 (20%)
Investigations
Cholesterol, high	2/4 (50%)		1/5 (20%)
Metabolism and nutrition disorders
Hyperglycemia	1/4 (25%)		1/5 (20%)
Hyperuricemia	1/4 (25%)		1/5 (20%)
Hypokalemia	2/4 (50%)		0/5 (0%)
Hypophosphatemia	1/4 (25%)		4/5 (80%)
Musculoskeletal and connective tissue disorders
Back Pain	0/4 (0%)		1/5 (20%)
Myalgia	3/4 (75%)		0/5 (0%)
Pain in extremity	0/4 (0%)		1/5 (20%)
Nervous system disorders
Dysgeusia	2/4 (50%)		0/5 (0%)
Headache	1/4 (25%)		0/5 (0%)
Spasticity	1/4 (25%)		0/5 (0%)
Psychiatric disorders
Depression	0/4 (0%)		1/5 (20%)
Renal and urinary disorders
Proteinuria	1/4 (25%)		0/5 (0%)
Urinal frequency	0/4 (0%)		1/5 (20%)
Respiratory, thoracic and mediastinal disorders
Allergic Rhinitis	1/4 (25%)		0/5 (0%)
Skin and subcutaneous tissue disorders
Rash acneiform	1/4 (25%)		0/5 (0%)
Rash pustular	0/4 (0%)		1/5 (20%)
Dry Skin	1/4 (25%)		0/5 (0%)
Vascular disorders
Hot flashes	2/4 (50%)		4/5 (80%)
Hypertension	1/4 (25%)		0/5 (0%)
hypotension	1/4 (25%)		0/5 (0%)

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.