P1.09 - Phase I clinical study of intratumoral injection of Clostridium novyi-NT spores in patients with advanced cancer

Abstract

ABSTRACT Background: Intratumoral injection of Clostridium novyi-NT (attenuated strain of Clostridium) induced a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model and in companion dogs bearing spontaneous solid tumors. Furthermore, intratumoral injection can plausibly induce an immune mediated abscopal effect in non-injected tumor sites. Methods: A standard 3 + 3 dose escalation Phase 1 study of a single intratumoral injection of C.novyi-NT was designed to determine the DLTs, MTD and preliminary activity in adult patients with advanced cancers and superficially located tumors (1-12 cm in size). The SOFA score and temperature are used to guide antibiotic usage. Results: To date, a total of 5 patients (women, n = 3; men, n = 2) with advanced sarcomas (leiomyosarcoma, n = 2; chondrosarcoma, n = 1; carcinosarcoma, n = 1; angiosarcoma, n = 1), median age 54 years, have received an intratumoral injection of 1 x104 (n = 3) and 3 x104 spores (n = 2). Evidence of germination has been noted in 3 patients and has consisted of pain in the injected tumor, fever, elevated WBC with a left shift, an elevated C-reactive protein, and necrosis and gas pockets in the injected tumor on radiographic imaging. Treatment-related grade 3 adverse events include leukocytosis, pathologic fracture, pain and respiratory insufficiency. The most significant morbidity was observed in a patient with a large volume of tumor destruction leading to a pathologic fracture of the necrotic right proximal humerus, which required an aggressive orthopedic surgical procedure. Of note histopathology demonstrated extensive tumor necrosis with small foci of residual tumor cells during surgery. Two patients had between 22-24% shrinkage in the injected tumor and an overall response of stable disease at 2 months. Because exploratory cytokine analysis suggests the potential for a systemic response and because abscopal responses were seen in the companion dog studies, the clinical protocol has been amended to include biopsies of both injected and non-injected tumors pre and post C.novyi-NT injection. Conclusions: Intratumoral injection of Clostridium novyi-NT is feasible and has lead to significant destruction of injected tumor masses in the first two doses studied.