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Oncotarget. 2015 Sep 15;6(27):24560-70.

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

Author information

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.

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

PMID:
26009994
PMCID:
PMC4695206
DOI:
10.18632/oncotarget.4183
[Indexed for MEDLINE]
Free PMC Article

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