Epirubicin dose escalation in the treatment of soft tissue sarcoma

Abstract

9034 Background: Epirubicin (Epi), a topoisomerase II-targeted anthracycline, has been used safely in doses ranging from 75–160 mg/m2 for the treatment of patients (pts) with soft tissue sarcoma (STS). We performed a pharmacokinetic (PK) dose-response study in pts with unresectable or metastatic STS. Methods: Previously untreated patients (PS 0–1) were given Epi 75 mg/m2. 11 serial blood samples were obtained in 24 hrs after a 10 min Epi IV infusion. Epi concentrations were determined using a validated LC-MS assay and Epi area under the concentration-time curve (EAUC) was calculated. After 2 cycles of chemotherapy pts with EAUC<2133 (ng-hr/ml) and progressive disease (PD) were dose escalated in order to achieve a target EAUC of 3200 ng-hr/ml. Further patient accrual required 4 responses by RECIST criteria in 14 patients treated by dose escalation Results: A total of 18 pts (9 male, 9 female, median age 54 years) were enrolled. Treatment with Epi 75 mg/m2 produced a median EAUC= 1538(range 1140–3677). 3 pts treated with Epi 75 mg/m2 had AUC>2133 and could not be dose escalated, 1 pt died before response could be assessed. 13 pts had dose escalation; PK values are available for 11 pts. Median EAUC was 3125 (range 2533 - 3619). Toxicities included Grade III/IV hematologic toxicity in 8 pts and G.I. Grade III toxicity in 4 pts. . No responses by RECIST criteria occured at 75mg/m2 . 9 pts had PD, but 1 pt had minor response (MR), 4 had stable disease (SD), 1 of theses was negative by PET scan. Dose escalation produced 1 partial response (PR), 5 SD with 3 PET neg, and 5 PD. All pts with SD or minimal response (MR) at the lower dose had at least SD or MR at the higher dose. 1 pt with AUC<2133 ng.h/mL was PET negative vs 1 PR, 3 PET negative with AUC>2133. Conclusions: EAUC increased linearly with dose increases, however, there was substantial inter-patient variability in the doses required to achieve the desired EAUC. Doses of Epi that result in EAUC<2133 appear inadequate. Further study is indicated if PET criteria are proven to be reliable to judge response. Epi dose escalation produced significant clinical responses in some STS pts with notable hematological / GI toxicities Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pharmacia