Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 24, No 18S (June 20 Supplement), 2006: 12029
© 2006 American Society of Clinical Oncology

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Abstract

Gemcitabine (G) given as a prolonged infusion in patients (pts) with advanced solid tumors: A phase I study with intra-pt dose escalation (DE) and pharmacokinetic (PK) / pharmacodynamic (PD) analysis

CRLCC Paul Papin, Angers, France; CHU, Angers, France

12029

Background: Optimizing drug delivery based on pharmacokinetic data is an important research issue. Previous studies have demonstrated a pharmacological advantage for infusions of G with a fixed dose rate to maximize cellular accumulation of G active metabolite (GTP), despite high interindividual PK variability. Methods: To develop a PK-guided G dosing schedule, we conducted an intra-pt G DE trial to determine: (1) maximum tolerated dose level (MTD) and dose-limiting toxicity (DLT), (2) plasma G and peripheral mononuclear cell GTP post-infusion levels. G was administered over 150 min on day 1, 8 and 15, q4w. The initial dose level (DL) was 1000 mg/m², escalated by 250 mg/m² every cycle (cy) if no limiting toxicity occurred. Results: From 09/2003, 30 pts entered the study. Pts’ characteristics: 16 men/14 women; median age 66 years (49–81); tumor type: pancreas (10 pts), lung (7 pts), others (13 pts); prior chemotherapy (15 pts). A total of 109 cy were given (median: 3 cy/pt). Tolerance: Number of pts/DL: DL1 = 7 pts, DL2 = 5 pts, DL3 = 11 pts, DL4 = 5 pts, DL5 = 2 pts. Main reasons for stopping DE were: disease progression/early death (15 pts), DLT (4 pts), investigator’s decision (8 pts). DLT were: haematological (1 pt), asthenia (2 pts) and infection (1 pt). Most common grade (gr) 1–2/3–4 toxicities (% cy) included: nausea/vomiting (38%/2%), asthenia (56%/11%), neutropenia (29%/27%) and thrombocytopenia (42%/1%). Activity: 26 pts are evaluable (radiological assessment every 3 cycles) showing 5 partial response (2 unconfirmed), 7 stabilization and 14 progression. Conclusions: The main reason for DE failure was early progression, stressing the importance of an early individual dose adjustment. PK and PK/PD correlation analyses are ongoing to confirm our hypothesis.

No significant financial relationships to disclose.