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

Oncotarget. 2015 Sep 15;6(27):24560-70. doi: 10.18632/oncotarget.4183.

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-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.

Keywords: KRAS; overall survival; pancreatic cancer; polymer implant; siRNA.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Absorbable Implants
  • Aged
  • Aged, 80 and over
  • Antigens, Neoplasm / blood
  • Antineoplastic Agents / therapeutic use
  • Camptothecin / analogs & derivatives
  • Camptothecin / therapeutic use
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / therapy*
  • Combined Modality Therapy
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Disease-Free Survival
  • Drug Implants*
  • Female
  • Fluorouracil / therapeutic use
  • Humans
  • Irinotecan
  • Leucovorin / therapeutic use
  • Male
  • Middle Aged
  • Molecular Targeted Therapy*
  • Organoplatinum Compounds / therapeutic use
  • Oxaliplatin
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / therapy*
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • RNA, Small Interfering*
  • RNAi Therapeutics / methods*

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Drug Implants
  • KRAS protein, human
  • Organoplatinum Compounds
  • RNA, Small Interfering
  • Oxaliplatin
  • Deoxycytidine
  • Irinotecan
  • gemcitabine
  • Proto-Oncogene Proteins p21(ras)
  • Leucovorin
  • Fluorouracil
  • Camptothecin

Associated data

  • ClinicalTrials.gov/NCT01188785