A Phase I Study of Infusional Paclitaxel With the P-Glycoprotein Antagonist PSC 833
A Phase I Study of Infusional Paclitaxel With the P-Glycoprotein Antagonist PSC 833
This is a dosage escalation study to estimate the maximum tolerated dose of drug resistance
 inhibitor PSC 833 given in combination with paclitaxel. Groups of 3 to 6 patients receive
 continuous-infusion paclitaxel for 5 days and oral PSC 833 for 6-7 days, following paclitaxel
 on the first course, then beginning 3 days prior to paclitaxel on subsequent courses.

 Stable and responding patients are re-treated every 21 days, with paclitaxel dose adjusted to
 maintain an absolute neutrophil count less than 500 for no more than 4 days.
The clinical study entitled "A Phase I Study of Infusional Paclitaxel with the P-glycoprotein
 Antagonist PSC 833" seeks to determine the maximum tolerated dose for the proposed
 P-glycoprotein antagonist, PSC 833, in combination with paclitaxel. PSC 833 is a cyclosporine
 analogue which is purportedly non-nephrotoxic and non-immunosuppressive. It has been shown in
 in vitro studies to enhance chemosensitivity as well as cyclosporine and to be far better at
 increasing intracellular drug accumulation than the concentrations of verapamil which are
 clinically achievable. The purpose of this study is to define the maximum tolerated dose in
 combination with paclitaxel, and to determine how the drug affects the pharmacokinetics of
 paclitaxel. PSC 833 will most likely reduce the clearance of paclitaxel as reported for the
 parent compound, cyclosporine. This effect will increase the area under the curve (AUC) of
 paclitaxel, may increase toxicity, and requires that the escalation scheme for PSC 833 be a
 conservative one. The first cycle of paclitaxel will be given in the absence of PSC 833.
 Subsequently, 7 days of PSC 833 will be given alone to allow monitoring of pharmacokinetics
 and adverse effects of PSC 833 alone. In the second cycle, both agents will be combined.
 Escalation of the PSC 833 will continue until a target concentration is reached, or until the
 maximum tolerated dose is reached. Clinical responses will be monitored in order to provide
 the best possible medical care to our patients.
Biopsy proven advanced cancer, for whom no better therapy exists.

 Enrollment of patients with breast cancer, lymphoma, renal cell cancer or ovarian cancer
 are encouraged.

 Patients with a life expectancy of at least 16 weeks, and a performance status (Karnofsky
 Scale) of 70% or greater. No rapidly growing disease.

 Patients with prior therapy.

 WBC greater than 3,000/mm(3) and AGC greater than 1000/mm(3); platelets greater than
 100,000/mm(3).

 Creatinine clearance greater than 50 ml/min; bilirubin less than 1.5 mg/dl; SGOT less than
 90 u/L; SGPT less than 100 u/L.

 Patients must sign an informed consent and have geographic accessibility to return for
 follow up and treatment.

 No history of brain metastases.

 No patients currently receiving treatment with the following agents or any other agent
 known to significantly interact with cyclosporine, and the treatment cannot be discontinued
 , or changed to another therapeutically equivalent allowable drug: acetazolamide,
 barbiturates, corticosteroids, diltiazem, erythromycin, fluconazole, ketoconazole,
 nicardipine, phenothiazines, phenytoin, rifampin, sulfonamides, trimethoprim, verapamil,
 tamoxifen, progesterone, quinine, quinidine, or amiodarone.

 No patients with a history of coronary artery disease with angina pectoris or history of
 congestive heart failure.

 No patients with a history of cardiac disease, other than angina pectoris or congestive
 heart failure, including patients with arrhythmias or conduction system abnormalities will
 be considered on an individual basis.

 No patients with symptomatic peripheral neuropathy (grade 2 or greater).

 No patients with a positive serology for HIV.

 No patients who are pregnant or unwilling to practice adequate contraception.

 No patients with prior bone marrow transplantation or extensive irradiation resulting in
 compromised bone marrow reserve.