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

Phase 1

Terminated

Conditions: Stage IIB Prostate Cancer AJCC v7
Prostate Adenocarcinoma
Stage IIA Prostate Cancer AJCC v7

Interventions: Drug: Goserelin Acetate
Drug: Leuprolide Acetate
Other: Laboratory Biomarker Analysis
Drug: Vismodegib

Registration Number: NCT01163084

Lead Sponsor: National Cancer Institute (NCI)

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.

Detailed Description: PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

I. 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.

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

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

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

V. 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: Male

Target Recruitment: 10

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II (leuprolide acetate, goserelin acetate)	Leuprolide 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.
Arm I (leuprolide acetate, goserelin acetate, vismodegib)	Leuprolide Acetate	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.
Arm II (leuprolide acetate, goserelin 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.
Arm I (leuprolide acetate, goserelin acetate, vismodegib)	Laboratory Biomarker Analysis	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.
Arm I (leuprolide acetate, goserelin acetate, vismodegib)	Goserelin Acetate	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.
Arm I (leuprolide acetate, goserelin acetate, vismodegib)	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.

Primary Outcome Measures

Name	Time	Method
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.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (5): University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States
University of Michigan Comprehensive Cancer Center
🇺🇸
Ann Arbor, Michigan, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
M D Anderson Cancer Center
🇺🇸
Houston, Texas, United States