Phase I trial using toxicity severity weights for dose finding of gemcitabine combined with radiation therapy and subsequent surgery for patients with extremity and trunk soft tissue sarcomas

Abstract

9008 Background: To determine the maximum tolerated dose (MTD) of gemcitabine when provided concurrently with external beam radiation (EBRT) for patients with extremity and superficial trunk soft tissue sarcomas (STS). Methods: Preoperative EBRT (50 Gy, 25 daily fractions Mon-Fri) was given for 5 weeks. Gemcitabine was administered at 10 mg/m2/min on days 1, 8, 22, 29, 43, and 50 at a starting dose of 400 mg/m2 and escalated or de-escalated between cohorts in increments of 100 mg/m2 using a new method based on severity weights for each grade of each of 5 different toxicities (myelosuppression, dermatitis, nausea/vomiting, liver, and fatigue). This toxicity severity weight method (TSWM) is a Bayesian procedure that repeatedly assesses the data to find the dose having mean posterior total toxicity burden (TTB) closest to a clinician-defined target of 3.04. Results: Eighteen (of 36 planned) patients with radiologically measureable intermediate or high-grade STS have been treated; 16 had completed all therapy at analysis. Histologies included MFH (7), unclassified STS (5), synovial STS (3), and liposarcoma (3). The gemcitabine dose has been progressively escalated to 700 mg/m2 at which the current estimated posterior probability of the TTB is 3.19 (analysis of 15 patients). Five patients have completed treatment at 700 mg/m2 with observed grade 3 or 4 toxicities that included: myelosuppresion without fever (n=2), dermatitis in the radiation field (n=1), hepatotoxicity (n=2), and fatigue (n=2). All 16 patients have undergone surgical resection with microscopically negative surgical margins. Pathological complete responses were observed in 4 tumors, 3 additional tumors had ≥95% tumor necrosis. Conclusions: Gemcitabine-based concurrent chemoradiation appears feasible for extremity and trunk STS. The currently targeted MTD is 700 mg/m2, accrual continues. The TSWM permitted efficient and safe dose escalation using weighted assessment of 5 different, clinically relevant toxicities. Observed histologic responses associated with this regimen are encouraging. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly; Schering-Plough Eli Lilly