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
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
Biopsy proven advanced cancer, for whom no better therapy exists.
Enrollment of patients with breast cancer, lymphoma, renal cell cancer or ovarian cancer
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
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.