Calcitriol, Ketoconazole, and Dexamethasone in Treating Patients With Metastatic or Unresectable Solid Tumors
Information source: National Cancer Institute (NCI)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Unspecified Adult Solid Tumor, Protocol Specific
Intervention: calcitriol (Drug); dexamethasone (Drug); ketoconazole (Drug)
Phase: Phase 1
Status: Completed
Sponsored by: Roswell Park Cancer Institute Official(s) and/or principal investigator(s):
Donald L. Trump, MD, Principal Investigator, Affiliation: Roswell Park Cancer Institute
Summary
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.
Clinical Details
Official title: A Phase I Study of Oral Calcitriol in Combination With Ketoconazole in Refractory Advanced Malignancies
Study design: Treatment
Primary outcome: Maximum tolerated dose (MTD) of calcitriol
Secondary outcome: Pharmacokinetics of calcitriol and dexamethasone with or without ketoconazole
Detailed description:
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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
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
Locations and Contacts
Roswell Park Cancer Institute, Buffalo, New York 14263-0001, United States
Additional Information
Clinical trial summary from the National Cancer Institute's PDQ® database
Starting date: November 2004
Last updated: May 23, 2008
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