(P 160) NEOADJUVANT PHARMACOLOGICAL ASCORBATE WITH CONCURRENT RADIATION IN LOCALLY ADVANCED SOFT-TISSUE SARCOMA OF EXTREMITY/TRUNK AND RETROPERITONEUM

Objective: High-risk extremity/trunk and retroperitoneal soft tissue sarcoma (STS) are frequently treated with neoadjuvant radiation followed by surgical resection. Pharmacological ascorbate (plasma levels ≥20 mM) is hypothesized to have anti-tumor properties via the development of redox species and H2O2 and has shown to have synergistic effect with radiation in sarcoma pre-clinical models. Recent clinical trials in pancreatic, ovarian and non-small cell lung cancer have demonstrated increased anti-tumor activity when ascorbate is administered as an adjunct to chemoradiation. In this phase IB/II trial, treatment with pharmacological ascorbate with concurrent EBRT in STS was assessed for safety and response.

Methods: The trial was conducted as a single stage design to detect ≥95% pathological tumor necrosis rate of 30% relative to a historical control of 10% in patients treated with EBRT alone. The design called for 25 patients to be enrolled; safety was evaluated in the first 6 patients. All patients had tumor size >5cm and were either grade 2 or higher or recurrent grade 1. Ascorbate was dosed at 75 gm IV three times weekly, and EBRT at 45-50 Gy in 25 fractions. Resection of the tumor was performed 4-6 weeks after completion of EBRT. Blood samples were collected prior to study, during treatment, after completion of EBRT, and prior to resection. Immune cell studies were performed in peripheral blood and resected STS tumor specimens.

Results: A total of 25 patients with locally advanced STS of the extremities or retroperitoneum were treated per protocol. No dose-limiting toxicity was observed with this combination. Three of 25 patient tumors (12%) developed necrosis of ≥95%. Ascorbate related adverse events included grade 3 hypertension in 2 out of 25 patients (8%) and grade 3 anemia in one patient (4%). Radiation related adverse events included grade 3 lymphopenia in four patients (16%) and grade 4 lymphopenia in one patient (4%). A significant association for activated effector CD4 (p=< 0.01) and CD8 T cells (p=0.02) was evidenced, such that higher levels in the blood were related to higher levels in the tumor.

Conclusion: Pharmacological ascorbate with concurrent EBRT in treatment of STS is safe and well tolerated, with 95% or greater pathological necrosis noted in 12% of patients. A statistically significant increase in ≥95% pathological response rate was not evidenced (p=0.46). Peripheral blood activated effector CD4 and CD8 T cells are a surrogate for tumor infiltration in patients treated with this combination.