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

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.

• Authors: Talia Golan, Elina Zorde Khvalevsky, Ayala Hubert, Rachel Malka Gabai, Naama Hen, Amiel Segal, Abraham Domb, Gil Harari, Eliel Ben David, Stephen Raskin, Yuri Goldes, Eran Goldin, Rami Eliakim, Maor Lahav, Yael Kopleman, Alain Dancour, Amotz Shemi, Eithan Galun
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 27 Pg. 24560-70 (Sep 15 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26009994 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study)

Chemical References

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

Topics

• Absorbable Implants
• Aged
• Aged, 80 and over
• Antigens, Neoplasm (blood)
• Antineoplastic Agents (therapeutic use)
• Camptothecin (analogs & derivatives, therapeutic use)
• Carcinoma, Pancreatic Ductal (drug therapy, therapy)
• Combined Modality Therapy
• Deoxycytidine (analogs & derivatives, 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, therapy)
• Proto-Oncogene Proteins p21(ras) (antagonists & inhibitors, genetics)
• RNA, Small Interfering
• RNAi Therapeutics (methods)
• Gemcitabine