Liposomal Doxorubicin and PSC 833 in Treating Patients With AIDS-Related Kaposi's Sarcoma or Other Advanced Cancers

Unspecified Adult Solid Tumor, Protocol Specific Clinical Trial

Official title:

Phase I Study on Doxil and SDZ PSC 833 in the Treatment of AIDS-Associated Kaposi's Sarcoma and Other Advanced Malignancies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00003207
• Other study ID #: CDR0000066062
• Secondary ID: WU-106NCI-T97-00
• Status: Completed
• Phase: Phase 1
• First received: November 1, 1999
• Last updated: April 11, 2013
• Start date: March 1998
• Est. completion date: July 2002

Study information

• Verified date: April 2013
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Adminstration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: July 2002
• Est. primary completion date: July 2002
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Sarcoma
• Sarcoma, Kaposi
• Unspecified Adult Solid Tumor, Protocol Specific

Intervention

Drug:
• pegylated liposomal doxorubicin hydrochloride

• PSC 833

Locations

Country	Name	City	State
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Washington University School of Medicine	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety profile and tolerability of Doxil in combination with PSC 833	Each cycle is 2 weeks long and can continue until disease progression, toxicity, or patient decision		Yes
Primary	Maximum tolerated dose of Doxil in combination with PSC 833			Yes
Primary	Dose limiting toxicity of Doxil in combination with PSC 833			Yes
Secondary	Effects of PSC 833 on Doxil pharmacokinetics			No
Secondary	Confirm the MDR expression with immunohistochemistry and functionally, with 99MTc-sestamibi			No