Clinical trial NCT00003207: Liposomal Doxorubicin and PSC 833 in Treating Patients With AIDS-Related Kaposi's Sarcoma or Other Advanced Cancers
Official title: Phase I Study on Doxil and SDZ PSC 833 in the Treatment of AIDS-Associated Kaposi's Sarcoma and Other Advanced Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Sarcoma
Unspecified Adult Solid Tumor, Protocol Specific
Keywords: unspecified adult solid tumor, protocol specific
AIDS-related Kaposi sarcoma
recurrent Kaposi sarcoma
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-02-16
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: INCLUSION CRITERIA

* 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 cells/ul.
* 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.

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:

  * 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 this study.

Primary outcomes:
measure: Safety profile and tolerability of Doxil in combination with PSC 833
measure: Maximum tolerated dose of Doxil in combination with PSC 833
measure: Dose limiting toxicity of Doxil in combination with PSC 833
Secondary outcomes:
measure: Effects of PSC 833 on Doxil pharmacokinetics
measure: Confirm the MDR expression with immunohistochemistry and functionally, with 99MTc-sestamibi
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Paula M. Fracasso, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: