Calcitriol, Ketoconazole, and Dexamethasone in Treating Patients With Metastatic or Unresectable Solid Tumors

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of calcitriol when administered with ketoconazole and dexamethasone in patients with metastatic or unresectable solid tumors.

Secondary

• Determine the tolerability and toxic effects of this regimen in these patients.
• Determine tumor response in patients treated with this regimen.
• Determine the pharmacokinetics of calcitriol and dexamethasone with or without ketoconazole in these patients.
• Determine the pharmacodynamics of this regimen, in terms of CYP24 expression and activity and vitamin D receptor expression in peripheral blood mononuclear cells, in these patients.

OUTLINE: This is a dose-escalation study of calcitriol.

Patients receive oral dexamethasone twice daily beginning on day 0 and oral ketoconazole 3 times daily beginning on day 4. Patients also receive oral calcitriol once daily on days 1-3 of each week. Treatment continues in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of calcitriol until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

After completion of study treatment, patients are followed for up to 30 days.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed solid tumor

• Metastatic or unresectable disease
• Standard curative or reliable palliative therapy is no longer effective OR does not exist
• Brain metastases allowed provided they have been treated with surgery or radiotherapy AND are stable

PATIENT CHARACTERISTICS:

Performance status

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy

• More than 3 months

Hematopoietic

• WBC ≥ 3,000/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Hemoglobin ≥ 8 g/dL
• Platelet count ≥ 75,000/mm^3

Hepatic

• AST/ALT ≤ 2.5 times upper limit of normal
• Bilirubin normal
• No unstable or uncompensated hepatic disease

Renal

• Creatinine ≤ 2 mg/dL
• No unstable or uncompensated renal disease
• No history of kidney, urethral, or bladder stones within the past 5 years

Cardiovascular

• Ejection fraction ≥ 30%
• No symptomatic congestive heart failure
• No significant arrhythmias
• No myocardial infarction within the past 3 months
• No unstable angina pectoris
• No unstable or uncompensated cardiac disease
• No other significant heart disease

Pulmonary

• No unstable or uncompensated respiratory disease

Immunologic

• No known severe hypersensitivity to ketoconazole or calcitriol or any of the excipients of these products
• No history of allergic reaction attributed to compounds of similar chemical or biological composition to the study drugs
• No ongoing or active infection

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception prior to, during, and for 3 months after completion of study treatment
• Able to receive oral medication
• No sperm donation during and for ≥ 3 months after completion of study treatment
• No evidence of significant clinical disorder or laboratory finding that would preclude study participation
• No other severe or uncontrolled systemic disease
• No psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent prophylactic growth factors, including filgrastim (G-CSF) or sargramostim (GM-CSF)

Chemotherapy

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

• Any number of prior chemotherapy regimens allowed

Endocrine therapy

• No concurrent systemic glucocorticoid therapy > physiologic replacement doses

Radiotherapy

• See Disease Characteristics
• Any number of prior radiotherapy regimens allowed

Surgery

• See Disease Characteristics
• Recovered from prior major surgery
• Concurrent surgery allowed provided ≥ 7 days has passed since the last dose of ketoconazole (ketoconazole may be restarted after adequate wound healing)

Other

• Recovered from prior anticancer therapy

• Alopecia allowed
• More than 30 days since prior nonapproved or investigational agents
• More than 7 days since prior and no concurrent thiazides
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent digoxin or calcium supplementation
• No concurrent proton pump inhibitor or H2 blockers
• No concurrent medications that would alter the levels of ketoconazole and/or calcitriol, including the following:

• Phenytoin
• Carbamazepine
• Barbiturates (e.g., phenobarbital)
• Rifampin
• Hypericum perforatum (St. John's wort)
• No concurrent drugs that would be significantly impaired in a clinically important way by ketoconazole
• No other concurrent investigational or commercial agents or therapies for this malignancy