RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients

Abstract

// Talia Golan 1 , Elina Zorde Khvalevsky 2 , Ayala Hubert 3 , Rachel Malka Gabai 2 , Naama Hen 2 , Amiel Segal 4 , Abraham Domb 5 , Gil Harari 6 , Eliel Ben David 7 , Stephen Raskin 1 , Yuri Goldes 1 , Eran Goldin 8 , Rami Eliakim 1 , Maor Lahav 1 , Yael Kopleman 9 , Alain Dancour 8 , Amotz Shemi 2 and Eithan Galun 10 1 The Sackler School of Medicine, The Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel 2 Silenseed Ltd., Jerusalem, Israel 3 Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 4 The Gastroenterology Institute, Shaare Zedek Medical Centre, Jerusalem, Israel 5 Institute of Drug Research, School of Pharmacy-Faculty of Medicine, Center for Nanoscience and Nanotechnology and The Alex Grass Centre for Drug Design and Synthesis, The Hebrew University of Jerusalem, Jerusalem, Israel 6 MediStat Ltd., Jerusalem, Israel 7 Hadassah-Hebrew University Medical Centre, Jerusalem, Israel 8 The Gastroenterology Institute, Shaare Zedek Medical Center, Jerusalem, Israel 9 Gastroenterology Institute, Hadassah Hebrew University Medical Center, Jerusalem, Israel 10 The Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel Correspondence to: Talia Golan, email: // Keywords : Pancreatic cancer, KRAS, overall survival, siRNA, polymer implant Received : March 04, 2015 Accepted : May 02, 2015 Published : May 19, 2015 Abstract Purpose: The miniature biodegradable implant siG12D-LODER™ was inserted into a tumor and released a siRNA drug against KRAS(G12D) along four months. This novel siRNA based drug was studied, in combination with chemotherapy, as targeted therapy for Locally Advanced Pancreatic Cancer (LAPC). Methods: An open-label Phase 1/2a study in the first-line setting of patients with non-operable LAPC was initiated. In this study patients were assigned to receive a single dose of siG12D-LODERs , in three escalating dose cohorts (0.025mg, 0.75mg and 3.0mg). Gemcitabine was given on a weekly basis, following the siG12D-LODER TM insertion, until disease progression. The recommended dose was further examined with modified FOLFIRINOX. The follow up period was eight weeks and survival until death. Results: Fifteen patients with LAPC were enrolled. Among the 15 treated patients, the most frequent adverse events observed were grade 1or 2 in severity (89%); five patients experienced serious adverse events (SAEs). In 12 patients analyzed by CT scans, none showed tumor progression, the majority (10/12) demonstrated stable disease and two showed partial response. Decrease in tumor marker CA19-9 was observed in 70% (7/10) of patients. Median overall survival was 15.12 months; 18 month survival was 38.5%. Conclusions: The combination of siG12D-LODER™ and chemotherapy is well tolerated, safe and demonstrated a potential efficacy in patients with LAPC. NCT01188785