Safety andpharmacokinetics of high-dose gefitinib in patients with solid tumors: results of a phase I study
Mitchell E. Gross, Lawrence Leichman,ElizabethS.Lowe, Alan Swaisland, David B.Agus
Address for correspondence and reprints:
Mitchell Gross, MD, PhD
USC Westside Cancer Center
Center for Applied Molecular Medicine
Tel: +1 310-272-7640
Fax: +1 310-272-7656
Email:
Journal: Cancer Chemotherapy and Pharmacology
Online Resource
Additional eligibility criteria
Adequate liver function was defined as: total bilirubin ≤2 mg/dL, aspartate aminotransferase/alanine aminotransferase activity ≤2.5 times upper limit of normal (ULN) or ≤5 times ULN for liver metastasis. Adequate renal function was defined as: creatinine ≤1.5mg/dL or creatinine clearance ≥60mL/min for levels above ULN (measured by the Cockcroft-Gault method[23]. Adequate bone marrow function was defined as: white blood cell count total ≥3,000/μL or absolute neutrophil count ≥1,500/μL, platelets ≥100,000/μL. Female patients whose ovarian cancer was non-measurable required two CA-125 levels >65IU/mL measured ≥2 weeks apart and patients with non-measurable prostate cancer progression while on stable doses of androgen deprivation therapy required prostate-specific antigen levels ≥5 ng/mL on two separate occasions ≥2 weeks apart.
Patients were excluded if they had: evidence of another severe or uncontrolled systemic disease; clinically active interstitial lung disease; co-existing malignancies or malignancies diagnosed within ≤5 years (except basal cell carcinoma or cervical cancer in situ); history of known risk factors for QT-related problems or pre-existing conditions known to be causally associated with prolonged QT interval corrected using Bazett’s formula. Other exclusion criteria were: history of hypersensitivity to the study drug; gastrointestinal disease affecting drug administration/absorption; pregnancy or breastfeeding; incomplete healing from previous oncologic or other major surgery; any unresolved chronic toxicity > Common Toxicity Criteria (CTC) grade 2 from prior anticancer therapy; evidence of other significant clinical or laboratory finding making it undesirable for participation; and newly diagnosed central nervous system metastases not treated with surgery and/or radiation. All females and fertile male patients had to use adequate contraceptive methods during the study.
Treatment with a biologically targeted or an investigational drug was required to have ceased at least 30 days prior to entering the study. Patients who had received prior chemotherapy or radiation therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) before study initiation were excluded, as were those who received cytochrome P450 inhibitors or inducers for 2 weeks (12 weeks for fluoxetine) prior to gefitinib treatment or during the study; and those who used medications known to prolong QTc. Apart from gefitinib, no systemic treatment or radiotherapy known to have an effect on solid tumors could be used during this study (except for patients with prostate cancer, who remained on androgen-deprivation therapy to maintain castrate levels of testosterone).
Dose escalation scheme
Upon completion of cycle 1 by all patients in each cohort, the safety and pharmacokinetic data were reviewed by the Study Cohort Review Committee (representatives from the Study Sponsor and the principal investigators) who decided whether or not to advance to the next cohort. If no patients experienced dose-limiting toxicity (DLT) at the first dose level, then three patients were enrolled at the next dose level. If one of three patients experienced DLT, then three more patients were accrued at the same dose level. If none of these additional patients experienced DLT, then the dose was escalated for the subsequent three patients. Dose escalation was terminated when at least two patients experienced a DLT at a given dose level.
Dose delays and reductions
To allow a patient to recover from CTCgrade 2 or 3 diarrhea, or grade 3 or 4 rash, liver transaminase, or bilirubin toxicities, the gefitinib dose could be reduced or held. Patients were withdrawn from the study for CTCgrade 4 diarrhea. For cohorts 1–6 and 7–10 the dose could be reduced by 250 mg and 500mg, respectively, and a maximum of two dose reductions and/or consecutive held doses were permitted. If toxicity was resolved to ≤CTCgrade 1 at the next due dose in patients with CTCgrade 2 diarrhea, the dose was resumed (cohorts 1–6) or decreased (cohorts 7–10), and if toxicity continued as CTCgrade 2 the dose was held (cohorts 1–10). For patients in cohorts 1–10 with CTCgrade 3 diarrhea, the dose was reduced at the next due dose (if resolved to ≤CTCgrade 1) and held (if continued as CTCgrade 2 or 3). For patients in cohorts 1–10 with CTC grade 3 or 4 rash, liver transaminase, or bilirubin toxicity, the dose was held at the next due dose (if continued as CTCgrade 3 or 4) and if the event recurred after full dosing the dose was reduced at the next due dose (CTCgrade≤2) and held (if continued as CTC grade 3 or 4).
Patients also received anti-diarrheal therapy for grade 2 and 3 diarrhea, and any grade3 or 4 toxicities or clinically significant lower grade toxicities were managed at the investigators’ discretion.
Reference
1. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16: 31–41
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