A PHASE I STUDY OF IRINOTECAN (CPT-11) WITH PHARMACOKINETIC MODULATION BY CYCLOSPORINE A AND PHENOBARBITAL
I. Determine the maximum tolerated dose of irinotecan (CPT-11) when infused weekly with
cyclosporine (CYSP) in patients with solid tumors or lymphoma refractory to standard
II. Determine whether CYSP modulates the pharmacokinetics and pharmacodynamics of CPT-11 and
its active metabolite, SN-38.
III. Determine whether phenobarbital modulates the pharmacokinetics and pharmacodynamics of
CPT-11 and SN-38.
OUTLINE: This is a dose escalation study of irinotecan. Patients are stratified according to
Part I: Patients receive cyclosporine IV over 6 hours and irinotecan IV over 90 minutes
weekly for 4 weeks. Courses repeat every 6 weeks in the absence of unacceptable toxicity or
disease progression. Cohorts of 3-12 patients receive escalating doses of irinotecan until
the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which at
least one third of patients experience dose limiting toxicity (DLT).
Part IIA: If the DLT is diarrhea in part I, then part IIA is opened. Patients receive oral
phenobarbital, cyclosporine as in part I, and irinotecan at the MTD from part I. Dose
escalation occurs as in part I to determine a new MTD. If the DLT continues to be diarrhea,
the study is closed. Part IIB: If the DLT is neutropenia in part I, then part IIB is opened.
Patients receive cyclosporine as in part I and escalating doses of irinotecan to determine a
Part III: If the DLT is neutropenia in part IIA or any DLT in part IIB, patients receive
phenobarbital, cyclosporine, and irinotecan at the MTD determined as in part IIA or part
IIB. Dose escalation continues until a new MTD is determined.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Mark J. Ratain, MD
University of Chicago
United States: Food and Drug Administration
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