KRAS-LODER for Pancreatic Cancer
According to the American Cancer Society, the estimated new cases and deaths from pancreatic cancer in the United States in 2020 will be 57,600 and 47,050, respectively. Pancreatic ductal adenocarcinoma is the most common pancreatic neoplasm, responsible for 95% of pancreatic cancer cases. It evolves from a progressive cascade of cellular, morphological and architectural changes, which are associated with somatic mutations in oncogenes and tumor suppressor genes. Most notably, almost all pancreatic ductal adenocarcinomas (PDAC) involve mutations in the KRAS oncogene, with the vast majority of them a gain-of-function mutation at codon 12 of the oncogene. For example, in a total of 68 genomic alterations identified within 21 genes in 18 PDACs with an average number of 3.8 alterations per tumor, K.RIEDMAN, H. SAFRAN, and M RESNICK found (RHODE ISLAND MEDICAL JOURNAL, OCTOBER 2015) that the most common genetic alterations included KRAS (100%), TP53(76%), CDKN2A (29%), SMAD4 (18%) and ATM (12%).
Silenseed developed and manufactured the product called KRAS-LODER, which releases a specific siRNA, designed to silence mutated KRAS (G12X X = D, C, A, R, S, V) continuously for four months within the pancreatic tumor. In pre-clinical in-vitro studies, and in-vivo studies in mice, the Silenseed siG12D drug has been found to effectively lead to cell death, as well as halting of tumor growth.
Phase I: In the years 2011-2015 Silenseed conducted an open label, multicenter, single-time dosing, Phase I study in patients with non-operable, locally advanced pancreatic cancer (LAPC). Patients received KRAS-LODER in a dose escalation design and also received standard-of-care chemotherapy, mostly Gemcitabine, and in a number of instances FOLFIRINOX. Fifteen patients with LAPC were enrolled. Two patients were omitted from the study but followed for safety due to metastatic disease detected on the first day after KRAS-LODER implanting. The study showed a high safety profile. No dose limiting toxicity (DLT) events were observed during the study, and the highest dose administered was well tolerated. Most adverse events were grade 1 and 2, transient, and not related to the study drug or to the study procedure, and no drug-related SAEs were observed.
In all efficacy measures – tumor response, tumor marker decrease, TTM (time to metastasis), progression free survival, and overall survival – we have noted encouraging preliminary results. CT imaging performed 8-12 weeks following the procedure showed no tumor progression in all patients and we’ve noted further clinical benefit rate = 100% (PFS) in the first 6-8 months in all patients available for analysis. Tumor response was observed in some of the patients. Median TTM was 8.25 months with 95% CI of 7.20 to 11.40 months. The 9 patients which were treated with single-time LODER dosing and Gemcitabine showed a median overall survival of 12.0 months, and the 3 patients treated with LODER+ modified FOLFIRINOX showed a median overall survival of 28.3 months (NCT01188785) (Golan et al 2015).
Phase II (Now recruiting): On March 2018 Silenseed opened a multinational study- “A Phase 2 Study of KRAS-LODER in Combination With Chemotherapy in Patients With Locally Advanced Pancreatic Cancer (PROTACT)” (NCT01676259). Principle Investigator of the study: Eileen M. O’Reilly, MD, medical oncologist in Memorial Sloan Kettering Cancer Center (MSKCC).
The Study is now recruiting patients. Study patients are administered siG12D-LODER in combination with standard of care (SOC) chemotherapy (nab-paclitaxel and gemcitabine or FOLFIRINOX or modified FOLFIRINOX).
Efficacy evaluations will include measurements of (CT- based) tumor response, survival status including overall survival and progression-free survival, CA 19-9 serum levels and CEA levels, and quality of life measures. For more information see here.
Eileen M. O’Reilly, M.D. Associate Member, GI Medical Oncology Service Memorial Sloan-Kettering Cancer Center Associate Professor, Weill Medical College of Cornell University