Clinical trial NCT01163084: Leuprolide Acetate or Goserelin Acetate With or Without Vismodegib Followed by Surgery in Treating Patients With Locally Advanced Prostate Cancer
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Prostate Adenocarcinoma
Stage IIA Prostate Cancer AJCC v7
Stage IIB Prostate Cancer AJCC v7
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-07-15
Enrollment: 10
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of Patients With =< 5% Tumor Involvement
timeFrame: Baseline up to 4 months or radical prostatectomy, whichever comes first
Secondary outcomes:
Other outcomes:
measure: Differences in Relapse Rates by PSA Levels (Biochemical)
timeFrame: Date of surgery, then every 6 months, up to 8 years
measure: Time to PSA (Biochemical) Progression, Defined as PSA Recurrence
timeFrame: From the date of surgery and elevated post operative PSA concentration, assessed up to 8 years
measure: 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
timeFrame: From the date of surgery and elevated post operative PSA concentration, assessed up to 8 years
measure: Proportion of Patients With PSA =< 0.2 ng/mL
timeFrame: Up to 8 years
measure: Differences in the Rate of Positive Surgical Margins Between the Two Groups
timeFrame: Baseline to up to 8 years
measure: Differences in Relapse Rates by Bone Scan/Computed Tomography Scan (Objective)
timeFrame: Baseline to up to 8 years
measure: Proportion of Patients Expressing Differences in Hedgehog, Androgen Signaling and Related Genes Markers
timeFrame: Up to 8 years
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Christopher Logothetis
role: PRINCIPAL_INVESTIGATOR
References:
citation: Karlou M, Tzelepi V, Efstathiou E. Therapeutic targeting of the prostate cancer microenvironment. Nat Rev Urol. 2010 Sep;7(9):494-509. doi: 10.1038/nrurol.2010.134.