Ketoconazole, Hydrocortisone, and GM-CSF in Treating Patients With Progressive Prostate Cancer After Hormone Therapy

Phase II Trial to Assess the Activity of Ketoconazole Plus GM-CSF in Patients With Prostate Cancer Progressive After Androgen Deprivation

RATIONALE: Androgens can cause the growth of prostate cancer cells. Drugs, such as ketoconazole, may stop the adrenal glands from making androgens. GM-CSF may help ketoconazole work better by making tumor cells more sensitive to the drug. Giving ketoconazole together with hydrocortisone and GM-CSF may be an effective treatment for prostate cancer.

PURPOSE: This phase II trial is studying how well giving ketoconazole together with hydrocortisone and GM-CSF works in treating patients with progressive prostate cancer after hormone therapy.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: therapeutic hydrocortisone; Drug: ketoconazole; Biological: sargramostim

Detailed Description

OBJECTIVES:

Primary

• Evaluate the effect of ketoconazole, hydrocortisone, and sargramostim (GM-CSF) on time to clinical progression in patients with prostate cancer that has progressed on primary hormonal therapy.

Secondary

• Evaluate the objective response frequency in patients treated with this regimen.
• Investigate the safety of this regimen.

OUTLINE: This is an open-label, nonrandomized study.

Patients receive oral ketoconazole three times daily and oral hydrocortisone twice daily on days 1-28 and sargramostim (GM-CSF) subcutaneously on days 15-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

PROJECTED ACCRUAL: A total of 48 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115
      • UCSF Comprehensive Cancer Center
    • San Francisco, California, United States, 94121
      • Veterans Affairs Medical Center - San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 120 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the prostate

• Progressive disease after androgen deprivation AND meets 1 of the following criteria:

  • Measurable disease

    • Measurable lesions ≥ 10 mm with spiral CT
    • Up to 5 lesions per organ and 10 lesions total should be identified as target lesions

  • No measurable disease

    • Patients with prostate-specific antigen (PSA)-only disease must have an elevated PSA

      • PSA evidence for progressive disease consists of a PSA level of ≥ 5 ng/mL that has risen on ≥ 2 successive occasions, ≥ 2 weeks apart
    • Patients with a positive bone scan must also have an elevated PSA

• Patients who received prior antiandrogen as a part of primary androgen ablation therapy must demonstrate disease progression after discontinuation of the antiandrogen

  • Disease progression after antiandrogen withdrawal is defined as 2 consecutive rising PSA values obtained ≥ 2 weeks apart, or documented osseous or soft tissue progression

    • Patients receiving flutamide must have had ≥ 1 of the PSA values obtained ≥ 4 weeks after flutamide discontinuation
    • Patients receiving bicalutamide or nilutamide must have had ≥ 1 of the PSA values obtained ≥ 6 weeks after antiandrogen discontinuation
• Testosterone < 50 ng/dL
• PSA ≥ 5 ng/mL

PATIENT CHARACTERISTICS:

• Karnofsky performance status 60-100%
• No serious intercurrent infections or nonmalignant uncontrolled medical illnesses
• No psychiatric illnesses OR social situations that would limit compliance
• No active or uncontrolled autoimmune disease
• ALT and AST normal
• Bilirubin normal
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Creatinine ≤ 1.5 times upper limit or normal (ULN)
• Hemoglobin ≥ 8 g/dL

• No other currently active malignancy except for nonmelanoma skin cancer

  • No currently active malignancy defined as therapy completed with ≤ 30% risk of relapse

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Patients must continue primary androgen deprivation therapy with a luteinizing-hormone releasing-hormone (LHRH) analogue if they have not undergone orchiectomy

• No prior systemic chemotherapy for prostate cancer

  • All other systemic chemotherapy must have been completed ≥ 2 years prior to study
• No other concurrent chemotherapy, immunotherapy, or radiotherapy
• Major surgery or radiation therapy completed ≥ 4 weeks prior to study
• No other concurrent corticosteroids, including routine use antiemetics
• No prior ketoconazole, aminoglutethimide, or corticosteroids for treatment of progressive prostate cancer
• No prior immunotherapy (e.g., vaccines or sargramostim GM-CSF)
• Patients receiving any other hormonal therapy (e.g., megestrol, finasteride, herbal product known to decrease PSA levels [e.g., saw palmetto or PC-SPES], or any systemic corticosteroid) must discontinue the agent ≥ 4 weeks prior to enrollment and progressive disease must be documented after discontinuation

• No initiation of bisphosphonate therapy within 1 month prior to starting study therapy

  • Patients on stable doses that show tumor progression are allowed to continue bisphosphonate

• No concurrent supplements or complementary medicines/botanicals, except any combination of the following:

  • Conventional multivitamin supplements
  • Selenium
  • Lycopene
  • Soy supplements
  • Vitamin E
• At least 8 weeks since prior radiopharmaceuticals (strontium chloride Sr 89, samarium Sm 153 lexidronam pentasodium)
• No other concurrent investigational or commercial anticancer agents or therapies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time to progression

Secondary Outcome Measures

Outcome Measure
Response rate as measured by prostate-specific antigen and objective parameters
Frequency of grades 3-4 toxicity
Pattern of immune response as measured by immunohistochemistry

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Charles Ryan, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start: April 1, 2004
• Primary Completion (Actual): November 1, 2007
• Study Completion (Actual): December 1, 2007

Study Registration Dates

• First Submitted: March 29, 2006
• First Submitted That Met QC Criteria: March 29, 2006
• First Posted (Estimate): April 3, 2006

Study Record Updates

• Last Update Posted (Actual): August 5, 2019
• Last Update Submitted That Met QC Criteria: August 1, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: recurrent prostate cancer; adenocarcinoma of the prostate
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Immunologic Factors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Ketoconazole; Sargramostim; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate
• Other Study ID Numbers: 035516; UCSF-H45860-23833-02

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No