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

Phase 1
18 Years
Not Enrolling
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

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



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


- 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

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


- Histologically confirmed solid tumor

- Metastatic or unresectable disease

- Standard curative or reliable palliative therapy is no longer effective OR does not

- Brain metastases allowed provided they have been treated with surgery or radiotherapy
AND are stable


Performance status

- ECOG 0-2 OR

- Karnofsky 60-100%

Life expectancy

- More than 3 months


- WBC ≥ 3,000/mm^3

- Absolute neutrophil count ≥ 1,500/mm^3

- Hemoglobin ≥ 8 g/dL

- Platelet count ≥ 75,000/mm^3


- AST/ALT ≤ 2.5 times upper limit of normal

- Bilirubin normal

- No unstable or uncompensated hepatic disease


- Creatinine ≤ 2 mg/dL

- No unstable or uncompensated renal disease

- No history of kidney, urethral, or bladder stones within the past 5 years


- 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


- No unstable or uncompensated respiratory disease


- 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


- 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


Biologic therapy

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


- 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


- See Disease Characteristics

- Any number of prior radiotherapy regimens allowed


- 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)


- 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

Type of Study:


Study Design:

Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD) of calcitriol

Safety Issue:


Principal Investigator

Donald L. Trump, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Roswell Park Cancer Institute


United States: Federal Government

Study ID:

I 33204



Start Date:

November 2004

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • unspecified adult solid tumor, protocol specific



Roswell Park Cancer InstituteBuffalo, New York  14263