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

Study Overview
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Brief Summary
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RATIONALE: Calcitriol may cause solid tumor cells to look more like normal cells, and to grow and spread more slowly. Ketoconazole and dexamethasone may help calcitriol work better by making tumor cells more sensitive to the drug. Giving calcitriol together with ketoconazole and dexamethasone may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of calcitriol when given together with ketoconazole and dexamethasone in treating patients with metastatic or unresectable solid tumors.

Detailed Description
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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.

Official Title
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A Phase I Study of Oral Calcitriol in Combination With Ketoconazole in Refractory Advanced Malignancies

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Dietary Supplement: calcitriol
* Drug: dexamethasone
* Drug: ketoconazole


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Dietary Supplement: calcitriol|nan|
|Drug: dexamethasone|nan|
|Drug: ketoconazole|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of calcitriol |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of calcitriol and dexamethasone with or without ketoconazole |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific