According to the National Cancer Institute (NCI), the estimated new cases and deaths from pancreatic cancer in the United States in 2018 will be 55,440 and 44,330, respectively. Pancreatic ductal adenocarcinoma is the most common pancreatic neoplasm, responsible for the 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, specifically a mutation called G12D. For example, in a total of 68 genomic alterations were 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 reduce (“to silence”) this mutated KRAS (G12D) 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 programmed cell death (apoptosis), as well as halting of tumor growth.
Phase I: In years 2011-2015 Silenseed conducted an open label, multicenter, singe dose, 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 in three medical centers, Sheba, Hadassah and Shaare Zedek. 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. In evaluating the safety profile, we considered several factors including the following: (i) no DLT – no dose limiting toxicity (DLT) events were observed during the study, and the highest dose administered was well tolerated; (ii) G1/2 AEs – the most adverse events were grade 1 and 2, transient, and not related to the study drug or to the study procedure; and (iii) no drug-related SAEs – the more severe adverse events (SAEs) were few compared to the number of such events in normal treatments. Five of the 15 patients experienced SAEs, such as pancreatitis, cholangitis, pancytopenia abdominal pain, and colonic obstruction. However, none of the SAEs were considered to be related to KRAS-LODER, and were rather attributable to either the insertion procedure or chemotherapy (FOLFIRINOX) treatments given in conjunction with our KRAS-LODER (three SAEs identified in one of our patients eleven days after LODER administration and five days after administration of FOLFIRINOX and found not likely to be related to KRAS-LODER).
In all efficacy measures – tumor response, tumor marker decrease, time to metastases, 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 observed in some of the patients. The TTM (Time To Metastases) was 100% over 5.16 months in all patients. Median TTM was 8.25 months with 95% CI of 7.20 to 11.40 months. At 18 months TTM was 15.4%. Reduction in tumor marker CA 19-9 was observed in 70% of patients. Median overall survival (as of May 2014) was 15.12 months, compared to historical data showing median overall survival of 10-13 months in studies in patients with the same disease who received Gemcitabine (Chauffert et al, 2008; Loehrer et al, 2011; Herman et al 2013). We treated the last four patients with FOLFIRINOX and the average survival of this small group was extended, with two patients still alive almost two years after treatment. In this Phase I/IIa trial we administered only one time dosing at recruitment. The doses were escalated among three cohorts at 0.025 mg, 0.75 mg, and 3.0 mg of the study drug. To optimize the treatment, we intend to treat patients every four months. These encouraging results have been published in the general meeting of American Society of Clinical Oncology and in the 2014 Gastrointestinal Cancers Symposium titled “Novel KRAS-directed therapy in combination with chemotherapy for locally advanced pancreatic adenocarcinoma.” The conclusions from this study suggest that a combination of KRAS-LODER and chemotherapy is well tolerated. The combination has demonstrated promising efficacy in LAPC with durable responses (NCT01188785).
Phase II (Now recruiting): On March 2018 Silenseed opened a multinational controlled study “A Phase 2 Study of KRAS-LODER in Combination With Chemotherapy in Patients With Unresectable Locally Advanced Pancreatic Cancer” (NCT01676259). Principle Investigator of the study: Eileen M. O’Reilly, MD, Medical oncologist in Memorial Sloan Kettering Cancer Center (MSKCC).
Study now is recruiting patients at MSKCC: Principle Investigators in MSKCC: Anna Varghese, MD, Medical Oncologist and (Gastroenterology PI): Mark A. Schattner, MD, FASGE, AGAF, Gastroenterologist. 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, Pain and Performance status. In addition, exploratory analyses and biomarkers in blood, urine and tissue samples will be studied, including circulating tumor cells, (CTC), circulating free DNA (cfDNA) and exosomes. Mutation analysis (including pancreatic cancer related mutations, including KRAS mutations) will be studied in biopsy samples, blood and urine samples and in cfDNA. 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