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Phase II Randomized Study of High-Dose Ketoconazole With or Without Alendronate Sodium in Patients With Androgen-Independent Metastastic Adenocarinoma of the Prostate

Phase 2
18 Years
Open (Enrolling)
Stage IV Prostate Cancer, Bone Metastases, Adenocarcinoma of the Prostate, Recurrent Prostate Cancer

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Trial Information

Phase II Randomized Study of High-Dose Ketoconazole With or Without Alendronate Sodium in Patients With Androgen-Independent Metastastic Adenocarinoma of the Prostate

OBJECTIVES: I. Determine whether there is any evidence that ketoconazole plus alendronate
sodium produces acceptable disease responses as compared with ketoconazole alone in patients
with androgen-independent metastatic adenocarcinoma of the prostate.

II. Characterize the pharmacokinetics/pharmacodynamics and assess the bone marrow
concentrations of both agents.

III. Assess matrix metalloproteinase (MMP) inhibition potential of alendronate sodium by
monitoring markers of angiogenesis, MMP breakdown, and changes in hydroxyproline.

PROTOCOL OUTLINE: This is a randomized, open-label study. Patients are randomized to one of
two treatment arms.

Arm I: Patients receive a single oral dose of ketoconazole on day 1. Patients begin taking
ketoconazole 3 times per day on day 8.

Arm II: Patients receive a single oral dose of alendronate sodium on day 1 and a single
oral dose of ketoconazole on day 3. Patients begin taking alendronate sodium once every
morning and ketoconazole 3 times per day on day 8.

Treatment continues on both arms in the absence of unacceptable toxicity or disease
progression. Patients who experience a clinical complete remission (CR) receive treatment
for an additional 60 days beyond documentation of a clinical CR.

Patients are followed every 2 months.


A total of 72 patients (36 per arm) will be accrued for this study within 3 years.

Inclusion Criteria


--Disease Characteristics-- Histologically confirmed adenocarcinoma of the prostate
Androgen independent with at least 1 bone lesion that is felt to be associated with
metastatic disease Refractory disease must be demonstrated after the withdrawal of
flutamide, nilutamide, bicalutamide, or any other antiandrogen Clinically progressive
disease for at least 1 month documented by rising PSA levels, at least 1 new metastatic
deposit on Tc-99 bone scintigraphy, increasing measurable disease, or new areas of
malignant disease Patients with PSA-negative disease (i.e., PSA less than 10 ng/mL) must
have positive CT scans of soft tissue disease that can be used for disease staging, bone
scan, or some other form of documentable disease progression (i.e., rising
carcinoembryonic antigen, prostatic acid phosphatase) Testosterone in the range expected
for castrated males No brain metastases or primary CNS malignancies No unresolved acute
local complications that require urgent local medical therapy (such as severe bone pain,
spinal cord compression, or urinary flow obstruction) --Prior/Concurrent Therapy--
Biologic therapy: Not specified Chemotherapy: No prior ketoconazole for prostate cancer
Endocrine therapy: See Disease Characteristics Treatment with LHRH agonist must continue
for those patients who have not undergone surgical castration If LHRH agonist has been
discontinued, it must be reinstituted with documented disease progression At least 4 weeks
since prior hormonal therapy other than LHRH agonist and recovered Radiotherapy: Prior
radiotherapy to the prostate allowed At least 4 weeks since prior radiotherapy and
recovered Surgery: Prior radical prostatectomy allowed At least 4 weeks since prior
surgery and recovered Other: At least 4 weeks since other prior anti-cancer therapy and
recovered No prior transfusion with strontium chloride Sr 89 and/or samarium Sm 153
lexidronam pentasodium No concurrent phenytoin, theophylline, cisapride, triazolam,
astemizole, loratadine, rifampin, isoniazid, erythromycin, terfenadine, midazolam,
alprazolam, atorvastatin calcium, cerivastatin sodium, dofetilide, lovastatin, pimozide,
simvastatin, or sirolimus No concurrent drugs that decrease gastric acid output or
increase gastric pH (e.g., antacids, cimetidine, ranitidine, or antimuscarinics) No
concurrent warfarin --Patient Characteristics-- Age: 18 and over Performance status: ECOG
0-2 Life expectancy: Greater than 3 months Hematopoietic: Granulocyte count at least
1,000/mm3 Hemoglobin at least 8.0 g/dL (pretreatment transfusion allowed, provided
hemoglobin is maintained for more than 30 days without additional transfusions and/or an
active source of bleeding is identified and treated) Platelet count at least 75,000/mm3
Hepatic: Acute care panel (i.e., electrolytes, BUN) and urinalysis normal Bilirubin no
greater than 1.2 mg/dL ALT less than 2.5 times upper limit of normal AST less than 2.5
times normal Renal: Creatinine no greater than 1.5 mg/dL and no proteinuria present OR
Creatinine clearance greater than 40 mL/min and proteinuria less than 500 mg/day
(proteinuria not an exclusion for patients with stents in place) Cardiovascular: No
history of unstable or newly diagnosed angina pectoris No myocardial infarction within the
past 6 months No New York Heart Association class II-IV congestive heart failure
Pulmonary: No chronic obstructive lung disease requiring oxygen therapy Neurologic: No
uncontrolled seizure activity No history of seizures within the past 10 years Other: No
other prior malignancies within the past 2 years except nonmelanoma skin cancer or
carcinoma in situ of the bladder No other life-threatening illnesses No untreated
infection HIV negative Willingness to travel from home to NIH for follow-up visits

Type of Study:


Study Design:

Primary Purpose: Treatment

Principal Investigator

William D. Figg

Investigator Role:

Study Chair

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

March 1999

Completion Date:

Related Keywords:

  • Stage IV Prostate Cancer
  • Bone Metastases
  • Adenocarcinoma of the Prostate
  • Recurrent Prostate Cancer
  • adenocarcinoma of the prostate
  • adult solid tumor
  • body system/site cancer
  • bone metastases
  • cancer
  • cellular diagnosis, prostate cancer
  • genetic condition
  • male reproductive cancer
  • metastatic cancer
  • prostate cancer
  • recurrent prostate cancer
  • site, metastatic cancer
  • solid tumor
  • stage IV prostate cancer
  • stage, prostate cancer
  • unclassified/other cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Prostatic Neoplasms
  • Neoplasm Metastasis
  • Bone Neoplasms
  • Bone Marrow Diseases



Medicine Branch Bethesda, Maryland  20892