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The rationale for conducting this study lies in the premise that if indeed the reason for a limited response of Kaposi's sarcoma lesions and other advanced malignancies to chemotherapy is attributable to a high expression of P-glycoprotein, then, by inhibiting this pump, tumor kill would be enhanced and response rates as well as duration of responses would also increase. Doxil is chosen since recent studies have shown that it is superior to combination chemotherapy with ABV or BV. Doxil is also known to be active in other malignancies such as breast and ovarian cancer (34,35). PSC 833 is chosen since it has been found to reverse P-gp in vitro and in vivo, is non-immunosuppressive, and has been shown in recent Phase 1 studies to be well tolerated.
There are yet no human studies reported on Doxil pharmacokinetics when combined with MDR modulators. Preclinical data shows that pharmacokinetics of Doxil, unlike free doxorubicin, is minimally affected by the addition of PSC 833 (36). Enhanced tumor toxicity was observed when PSC 833 was combined with Doxil. Since doxorubicin, the active agent in Doxil, is metabolized by the same cytochrome P450, interactions between these 2 agents may have very significant clinical implications. The purpose of this study is to assess the toxicity and determine the maximum tolerated dose of Doxil when combined with PSC 833 in the treatment of AIDS-KS and other advanced malignancies.
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Inclusion and exclusion criteria
INCLUSION CRITERIA
EXCLUSION CRITERIA
Pregnant or breast feeding patients as radioactive tracer material and chemotherapy will be used in this protocol.
Active opportunistic infections requiring antibiotic treatment.
Treatment with radiation or electron beam therapy, interferon or cytotoxic therapy within the preceding 4 weeks.
Clinically significant history of congestive heart failure.
Patients who have moderate to severe sensory and motor peripheral neuropathy.
Any patient currently receiving treatment with any of the following agents which cannot be discontinued at a specified time relative to PSC 833 administration. All of these drugs are well substantiated to interact with cyclosporin A:
The following drugs must not be administered for 48 hours before PSC 833 is started, during the course of its administration, or up to 48 hours after the last dose of PSC 833 in a cycle:
Calcium channel blockers: diltiazem, nicardipine, verapamil Antifungals: fluconazole (dose <200 mg/day allowed), itraconazole, ketoconazole Antibiotics: clarithromycin, erythromycin Others: metoclopramide,bromocriptine, danazol
The following drugs must not be administered in the 14 days before PSC 833 is started or during the course of its administration. They may be restarted immediately after the last dose of PSC 833:
Antibiotics: nafcillin, rifampin Anticonvulsants: carbamazepine, phenobarbital, phenytoin Others: octreotide, ticlopidine
14 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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