Pharmacokinetic (Pk) And Pharmacodynamic (Pd) Study Of The Combination Of Docetaxel (Doc) And Oxaliplatin (Ox) In Patients (Pts) With Advanced Solid Tumors

2546 Background: A phase I clinical trial was conducted to determine the maximum-tolerated dose (MTD) of docetaxel (Doc) and oxaliplatin (Ox) in pts with advanced solid tumors. As part of this phase I study, pharmacokinetic (PK) and pharmacodynamic (PD) studies of Doc and Ox were performed. Methods: In the phase I study, Ox was administered on day 1 and Doc was administered on days 1 and 8, with cycles repeated every 21 days. The cohorts studied were (Ox/Doc) 75/35, 90/35, 105/35, 120/35, 130/35, 130/40, 130/45, 130/50 mg/m2. PK studies of Ox and Doc were performed on day 1 of cycle 1. Serial plasma samples were obtained from 0 to 24 h for Ox and Doc. Total and ultrafiltrate (UF) platinum (Pt) plasma conc of Ox were determined by flameless atomic absorption spectrophotometry (FAAS). Doc plasma conc were determined by liquid chromatography mass spectrometry (LC-MS). Area under the plasma conc versus time curves (AUC) for Doc and total and UF Pt conc were calculated using the log-trapezoidal method. Results: The phase II recommended dose (P2RD) was Ox/Doc at 130/35 mg/m2. Dose-limiting toxicities (DLT) were observed on cohorts (co) 5 through 8 and included grade 3 diarrhea in 3 pts (1 pt in co 5, 2 pts in co 8), grade 3 fatigue in 2 pts (co 6 and 7) and grade 4 neutropenia in 1 pt (co 8). PK results from Ox/Doc at 120/35 to 130/50 mg/m2 are presented in the table. Conclusions: A 2 to 3-fold increases in UF Pt AUC and the ratio of UF Pt AUC to total Pt AUC was associated with the combination of Doc at doses of ≥ 40 mg/m2 (P > 0.05). This data suggests that Doc at doses of ≥ 40 mg/m2 displaces Ox from plasma proteins and increases the exposure of active-unbound Ox. The alteration in UF Pt AUC was consistent with the DLTs and P2RD. The clinical significance of the interactions between Ox and Doc needs to be further evaluated in phase II studies. Cohort Ox Dose (mg/m2) Doc Dose (mg/m2) Number of Pts Doc AUC (ng/mL·h) Total Pt AUC (μg/mL·h) UF Pt AUC (μg/mL·h) Ratio of UF Pt AUC to Total Pt AUC 4 120 35 3 1,132 ± 340 36.1±11.3 1.4 ± 0.6 0.04 ± 0.01 5 (P2RD) 130 35 6 1,111 ± 265 32.0±11.3 1.5 ± 1.4 0.05 ± 0.04 6 130 40 6 1,618 ± 968 39.4±12.3 3.9 ± 2.1 0.09 ± 0.04 7 130 45 4 1,580 ± 280 41.4±6.7 4.2 ± 0.4 0.10 ± 0.03 8 130 50 3 1,738 ± 252 38.2±5.5 4.8 ± 1.6 0.12 ± 0.03 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis