Carboxyamidotriazole and Ketoconazole in Treating Patients With Advanced Cancers

Study Overview
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Brief Summary
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Phase I trial to study the effectiveness of carboxyamidotriazole and ketoconazole in treating patients with advanced cancers. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

Detailed Description
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OBJECTIVES: I. Determine the maximum tolerated dose of carboxyamidotriazole (CAI) in combination with ketoconazole in patients with advanced malignancies. II. Evaluate the toxic effects, safety, and efficacy of CAI in combination with ketoconazole. III. Determine the modulatory effects of ketoconazole on the pharmacokinetic profile of CAI. IV. Determine a pharmacodynamic model for CAI and ketoconazole with respect to potential gastrointestinal, hematologic, and neurotoxicities. OUTLINE: This is a dose escalation study. Patients receive oral carboxyamidotriazole (CAI) as a test dose on day 1. Patients receive oral ketoconazole on day 7, followed by CAI plus ketoconazole on day 8. CAI and ketoconazole are administered in combination on day 1 and days 3-28 of the first course. Ketoconazole is administered alone on day 2 of the first course. Subsequent courses begin at 28 day intervals in the absence of disease progression or unacceptable toxic effects. Cohorts of 3 patients are evaluated at each dose level prior to dose escalation. If one of three patients within a cohort experiences dose limiting toxicity (DLT), that dose level is expanded to incorporate six patients. If two or more patients experience DLT, the next lower dose is declared to be the maximum tolerated dose.

Official Title
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A Phase I Investigation of Carboxyamido-triazole (CAI) Modulated by Ketoconozole In Patients With Advanced Malignancies

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: carboxyamidotriazole
* Drug: chemotherapy
* Drug: ketoconazole


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically proven refractory or recurrent nonhematologic malignancies Measurable or evaluable disease by radiographic or clinical examination PATIENT CHARACTERISTICS: Age: 18 and over Performance Status: Karnofsky 70-100% Absolute neutrophil count at least 2,000/mm3 Platelet count at least 100,000/mm3 Bilirubin no greater than 1.5 mg/dL SGOT and SGPT no greater than 2.5 times upper limit of normal Albumin at least 3 g/dL Creatinine no greater than 1.5 mg/dL OR creatinine clearance greater than 60 mL/min No concurrent neurotoxicities greater than grade 1 from previous chemotherapy No concurrent neuropathy greater than grade 1 Not pregnant Effective contraceptive method must be used by fertile patients during and up to 2 months after study No serious uncontrolled medical illness No history of active inflammatory bowel disease, ileus, or other chronic malabsorption syndromes PRIOR CONCURRENT THERAPY: No concurrent isoniazid No concurrent rifampin At least 4 weeks since chemotherapy At least 6 weeks since nitrosoureas therapy At least 3 months since suramin therapy No prior carboxyamidotriazole No concurrent steroids (except dose required for adrenal insufficiency) No concurrent tamoxifen No prior radiotherapy within 4 weeks of study No prior total gastrectomy or total ileocolectomy No concurrent therapy with H2 antagonists, barbiturates, calcium channel blockers, terfenadine, astemizole, cisapride, digitoxin, quinidine, amiodarone, carbamazepine, imipramine, or antacids No concurrent erythromycin

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral carboxyamidotriazole (CAI) as a test dose on day 1. Patients receive oral ketoconazole on day 7, followed by CAI plus ketoconazole on day 8. CAI and ketoconazole are administered in combination on day 1 and days 3-28 of the first course. Ketoconazole is administered alone on day 2 of the first course. Subsequent courses begin at 28 day intervals in the absence of disease progression or unacceptable toxic effects. Cohorts of 3 patients are evaluated at each dose level prior to dose escalation. If one of three patients within a cohort experiences dose limiting toxicity (DLT), that dose level is expanded to incorporate six patients. If two or more patients experience DLT, the next lower dose is declared to be the maximum tolerated dose. | Drug: carboxyamidotriazole<br> <br> Drug: chemotherapy<br> <br> Drug: ketoconazole<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 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