A Phase I Study of Oral Calcitriol in Combination With Ketoconazole in Refractory Advanced Malignancies
18 Years
N/A
Both
Unspecified Adult Solid Tumor, Protocol Specific
Trial Information
A Phase I Study of Oral Calcitriol in Combination With Ketoconazole in Refractory Advanced Malignancies
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.
Inclusion 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
Type of Study:
Interventional
Study Design:
Primary Purpose: Treatment
Outcome Measure:
Maximum tolerated dose (MTD) of calcitriol
Safety Issue:
Yes
Principal Investigator
Donald L. Trump, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Roswell Park Cancer Institute
Authority:
United States: Federal Government
Study ID:
I 33204
NCT ID:
NCT00238225
Start Date:
November 2004
Completion Date:
Related Keywords:
- Unspecified Adult Solid Tumor, Protocol Specific
- unspecified adult solid tumor, protocol specific
Name | Location |
|---|---|
| Roswell Park Cancer Institute | Buffalo, New York 14263 |
