A Phase I Study of Infusional Chemotherapy With the P-Glycoprotein Antagonist PSC 833
Information source: National Institutes of Health Clinical Center (CC)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Breast Cancer; Kidney Neoplasm; Lymphoma; Neoplasm Metastasis; Ovarian Cancer
Intervention: PSC 833 (Drug)
Phase: Phase 1
Status: Completed
Sponsored by: National Cancer Institute (NCI)
Summary
The clinical study entitled "A Phase I Study of Infusional Chemotherapy with the
P-glycoprotein Antagonist PSC 833" seeks to determine the maximum tolerated dose for a
proposed P-glycoprotein antagonist, PSC 833. 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 vinblastine, and to determine how the drug affects the pharmacokinetics of vinblastine.
PSC 833 will most likely reduce the clearance of vinblastine, as reported for the parent
compound, cyclosporine. This effect will increase the area under the curve (AUC) of
vinblastine, may increase toxicity, and requires that the escalation scheme for PSC 833 be a
conservative one. Initially, a 120 hour infusion of vinblastine will be given alone. Then 8
days of PSC 833 will follow to allow monitoring of adverse effects of PSC 833 alone. This
first cycle of vinblastine will be given in the absence of PSC 833; in second and subsequent
cycles 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.
Clinical Details
Official title: A Phase I Study of Infusional Chemotherapy With the P-Glycoprotein Antagonist PSC 833
Study design: Treatment, Safety Study
Detailed description:
The clinical study entitled "A Phase I Study of Infusional Chemotherapy with the
P-glycoprotein Antagonist PSC 833" seeks to determine the maximum tolerated dose for a
proposed P-glycoprotein antagonist, PSC 833. 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 vinblastine, and to determine how the drug affects the pharmacokinetics of vinblastine.
PSC 833 will most likely reduce the clearance of vinblastine, as reported for the parent
compound, cyclosporine. This effect will increase the area under the curve (AUC) of
vinblastine, may increase toxicity, and requires that the escalation scheme for PSC 833 be a
conservative one. Initially, a 120 hour infusion of vinblastine will be given alone. Then 8
days of PSC 833 will follow to allow monitoring of adverse effects of PSC 833 alone. This
first cycle of vinblastine will be given in the absence of PSC 833; in second and subsequent
cycles 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.
Eligibility
Minimum age: N/A.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Biopsy proven metastatic cancer, for whom no better therapy exists. All patients are
eligible. Enrollment of patients with kidney, breast, ovarian cancers, and lymphomas is
encouraged.
A life expectancy of at least 16 weeks, and a performance status (Karnofsky scale) of 70%
or greater. Patients without rapidly growing disease.
Any prior therapy except for previous bone marrow transplantation.
WBC greater than 3,000/mm3 and ACG greater than 1,000/mm3; platelets greater than
100,000/mm3.
Creatinine Clearance greater than 50 ml/min; bilirubin less than 1. 5 mg/dl; SGOT less than
70u/L; SGPT less than 80u/L.
A signed informed consent and geographic accessibility for the patient to return for follow
up and treatment.
No history of brain metastases.
Not currently receiving treatment with the following agents or any other agent known to
significantly interact with cyclosporine, and 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 symptomatic peripheral neuropathy (grade 2 or greater arising from prior vinca alkaloid
therapy).
No positive serology for HIV.
No ongoing pregnancy or unwillingness to practice adequate contraception.
Locations and Contacts
National Cancer Institute (NCI), Bethesda, Maryland 20892, United States
Additional Information
Related publications: Yahanda AM, Alder KM, Fisher GA, Brophy NA, Halsey J, Hardy RI, Gosland MP, Lum BL, Sikic BI. Phase I trial of etoposide with cyclosporine as a modulator of multidrug resistance. J Clin Oncol. 1992 Oct;10(10):1624-34. Samuels BL, Mick R, Vogelzang NJ, Williams SF, Schilsky RL, Safa AR, O'Brien SM, Ratain MJ. Modulation of vinblastine resistance with cyclosporine: a phase I study. Clin Pharmacol Ther. 1993 Oct;54(4):421-9. Piwnica-Worms D, Chiu ML, Budding M, Kronauge JF, Kramer RA, Croop JM. Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex. Cancer Res. 1993 Mar 1;53(5):977-84.
Starting date: September 1992
Ending date: June 2002
Last updated: March 3, 2008
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