title: RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients.
abstract: OBJECTIVE
  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-LODERTM 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.
authors.affiliation: The Sackler School of Medicine, The Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Talia
authors.initials: T
authors.lastname: Golan
authors.affiliation: Silenseed Ltd., Jerusalem, Israel.
authors.forename: Elina Zorde
authors.initials: EZ
authors.lastname: Khvalevsky
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ayala
authors.initials: A
authors.lastname: Hubert
authors.affiliation: Silenseed Ltd., Jerusalem, Israel.
authors.forename: Rachel Malka
authors.initials: RM
authors.lastname: Gabai
authors.affiliation: Silenseed Ltd., Jerusalem, Israel.
authors.forename: Naama
authors.initials: N
authors.lastname: Hen
authors.affiliation: The Gastroenterology Institute, Shaare Zedek Medical Centre, Jerusalem, Israel.
authors.forename: Amiel
authors.initials: A
authors.lastname: Segal
authors.affiliation: 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.
authors.forename: Abraham
authors.initials: A
authors.lastname: Domb
authors.affiliation: MediStat Ltd., Jerusalem, Israel.
authors.forename: Gil
authors.initials: G
authors.lastname: Harari
authors.affiliation: Hadassah-Hebrew University Medical Centre, Jerusalem, Israel.
authors.forename: Eliel Ben
authors.initials: EB
authors.lastname: David
authors.affiliation: The Sackler School of Medicine, The Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Stephen
authors.initials: S
authors.lastname: Raskin
authors.affiliation: The Sackler School of Medicine, The Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Goldes
authors.affiliation: The Gastroenterology Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Goldin
authors.affiliation: The Sackler School of Medicine, The Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Rami
authors.initials: R
authors.lastname: Eliakim
authors.affiliation: The Sackler School of Medicine, The Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Maor
authors.initials: M
authors.lastname: Lahav
authors.affiliation: Gastroenterology Institute, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Kopleman
authors.affiliation: The Gastroenterology Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Alain
authors.initials: A
authors.lastname: Dancour
authors.affiliation: Silenseed Ltd., Jerusalem, Israel.
authors.forename: Amotz
authors.initials: A
authors.lastname: Shemi
authors.affiliation: The Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
mesh_terms: D020341:Absorbable Implants; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000097:blood; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000628:therapy*; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D004343:Drug Implants; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000628:therapy*; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics; D034741:RNA, Small Interfering; D000067492:RNAi Therapeutics / Q000379:methods*; D000093542:Gemcitabine
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004343:Drug Implants; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin; D000093542:Gemcitabine
keywords: KRAS; overall survival; pancreatic cancer; polymer implant; siRNA