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.
- Histologically documented malignancy refractory to standard treatment or for which no
standard treatment exists, or biopsy proven Kaposi's sarcoma with mucocutaneous
lesions numbering 10 or more or a documented visceral KS lesion with at least 2
assessable cutaneous lesions.
- A life expectancy of >4 months.
- Patients with prior chemotherapy and Doxil exposure are eligible
- Age >=18
- Karnofsky score of >=70%
- Hemoglobin >=8 g/dl, neutrophil count >=1000 cells/ul and platelet count of >=75,000
- Creatinine clearance of .=50 ml/min or creatinine of <=2.0mg/dl, SGOT <=2X the
institutional normal and bilirubin <1.5X institutional normal
- Written informed consent has been obtained from the patient.
- 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:
- Agents increasing serum concentrations of CsA
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
- Agents decreasing serum concentrations of CsA
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
- Hypersensitivity to Doxil or cyclosporin A
- Any patient, who, in the judgment of the investigator, may not be able to complete