Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	18 and over	Other	RPCI-I-33204 NCT00238225

Objectives

Primary

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

Secondary

1. Determine the tolerability and toxic effects of this regimen in these patients.
2. Determine tumor response in patients treated with this regimen.
3. Determine the pharmacokinetics of calcitriol and dexamethasone with or without ketoconazole in these patients.
4. 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.

Entry Criteria

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

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

Patient Characteristics:

Performance status

• ECOG 0-2

  OR

• Karnofsky 60-100%

Life expectancy

• More than 3 months

Hematopoietic

• WBC ≥ 3,000/mm³
• Absolute neutrophil count ≥ 1,500/mm³
• Hemoglobin ≥ 8 g/dL
• Platelet count ≥ 75,000/mm³

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

Expected Enrollment

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

Outcomes

Maximum tolerated dose (MTD) of calcitriol

Pharmacokinetics of calcitriol and dexamethasone with or without ketoconazole

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.

Trial Contact Information

Trial Lead Organizations

Roswell Park Cancer Institute

Donald Trump, MD, Principal investigator		Ph: 716-845-3499; 800-685-6825 Email: donald.trump@roswellpark.org

Registry Information
Official Title		A Phase I Study of Oral Calcitriol in Combination with Ketoconazole in Refractory Advanced Malignancies
Trial Start Date		2004-11-03
Registered in ClinicalTrials.gov		NCT00238225
Date Submitted to PDQ		2005-07-22
Information Last Verified		2006-08-16
NCI Grant/Contract Number		CA16056

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