Background: Intratumoral injection of Clostridium novyi-NT (C. novyi-NT), an attenuated strain of Clostridium, induced a microscopically precise response, which was restricted to tumor tissue in a ...rat orthotopic brain tumor model, in companion dogs bearing spontaneous solid tumors and in the first patient treated on a Phase 1 human clinical trial (Roberts et al, Sci Transl Med. 2014). C. novyi-NT lyses malignant cells by secreting lipases, proteases, other hydrolytic enzymes, and recruiting inflammatory cells to tumors eliciting anti-tumor immune responses in animals. Furthermore, intratumoral injection can plausibly induce an immune mediated abscopal effect in non-injected tumor sites. Material and Methods: The objectives of this Phase 1 study using the 3+3 dose escalation design were to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and preliminary activity of C. novyi-NT when administered as a single intratumoral injection. Adult patients with advanced cancers and at least one accessible, superficial tumor mass (1-12 cm in size) that did not involve bone, were eligible. Results: To date, a total of 19 patients (women, n = 10; men, n = 9) with advanced cancers (sarcoma, n = 10; carcinoma, n = 7; melanoma, n = 1; chordoma, n = 1), median age 55 years, have received an intratumoral injection ranging from 1 x 104 to 100x 104 spores in 5 dose levels. Evidence of C. novyi-NT germination has been noted in all dose levels in 8 (42%) patients and has consisted of pain in the injected tumor, fever, elevated WBC with a leftshift, an elevated C-reactive protein, tumor necrosis and gas pockets in the injected tumor on radiographic imaging. One DLT (Grade 4 sepsis) was observed on the dose level 4. Grade 3 treatment-related adverse events included respiratory insufficiency and pathologic fracture of right humerus. Anticancer activity was observed in all 8 patients where C. novyi-NT germination resulted in extensive, in some cases, complete central necrosis of the injected tumor. Two patients had between 22-24% shrinkage in the injected tumor based on RECIST assessment. Five out of 7 patients who were evaluated at Month 2 had an overall response of stable disease, 2 out of the 7 patients had progressive disease. One patient had stable disease at Month 4. Correlative studies for predictors of immune response included pre and post treatment biopsies from injected and non-injected lesions, serum cytokine analysis, and immunophenotyping of patients' circulating lymphocyte. Conclusions: A single dose of intratumoral injection of Clostridium novyi-NT is feasible and has promising anticancer activity. A study of PD1 antibody with Clostridium novyi-NT has been designed.
Materials and methods: A retrospective review was carried out in patients with pancreatic adenocarcinoma at Siteman Cancer Center, who had received nab-paclitaxel monotherapy after experiencing ...disease progression on standard treatments between 2010 and 2012.
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