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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


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Male
Adenocarcinoma of the Prostate, Stage IIA Prostate Cancer, Stage IIB Prostate Cancer

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Trial Information

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


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 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 Hedgehog antagonist GDC-0449): Patients receive LHRH
analogue comprising leuprolide intramuscularly or goserelin subcutaneously on day 1 and
Hedgehog antagonist GDC-0449 orally once daily 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 or
goserelin as in group 1. 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.

Tissue specimens from radical prostatectomy may be analyzed for differences in hedgehog
signaling, androgen signaling, markers linked to prostate cancer progression, proliferation,
apoptosis, and the expression of androgen-producing enzymes in the tumor microenvironment by
reverse transcriptase-PCR and IHC.

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


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 PSA > 10ng/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/SGOT) / alanine aminotransferase (ALT/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 PT, 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 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

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with GDC-0449

- 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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of patients with =< 5% tumor involvement

Outcome Time Frame:

Up to 8 years

Safety Issue:

No

Principal Investigator

Christopher Logothetis

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2010-01737

NCT ID:

NCT01163084

Start Date:

July 2010

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Prostate
  • Stage IIA Prostate Cancer
  • Stage IIB Prostate Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Prostatic Neoplasms

Name

Location

M D Anderson Cancer CenterHouston, Texas  77030