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.

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

Figure 1

A. Study design. B. siG12D-LODER^TM is placed with Endoscopic US biopsy needle.

Figure 2. siG12D drug covers the entire tumor tissue within one week

Subcutaneous tumors of pancreatic PancO2 origin were treated with empty-LODER^TM or LODER^TM containing 5μg siG12D. Seven days post-implantation mice were sacrificed, tumor tissue was formalin-fixed, paraffin embedded and cut to slices of 5μm. A. The graph depicts relative amounts of antisense siG12D strand, measured by Relative Quantitative Real-Time PCR, at certain distances from the LODER^TM border. The results were normalized to RNU6 and calibrated to untreated control. B. Representative tumor tissue, H&E stained, seven days post implantation.

Figure 3

A. Overall survival: Kaplan-Meier curves depict OS of siG12D-LODER^TM-treated patients. The two open circles mark patients who were still alive at the time of analysis. B. Time To Metastasis: Kaplan-Meier curves depict TTM of siG12D-LODER^TM-treated patients.

Figure 4. Anti-tumor effect of combination treatment with siG12D-LODER^TM in locally advanced non-operable PAC in a patient

A. left panel: a CT scan was performed prior to the implantation of siG12D-LODER^TM using EUS; tumor measures 35.42mm in longest diameter; right panel: nine months later a significant tumor mass reduction is shown on a follow-up CT scan, tumor measures 26.16mm in the longest diameter. B. The level of CA19-9 in blood, showing 23% decrease immediately after LODER^TM insertion, prior SOC treatment.

Figure 5. CT changes from base-line: The difference in the CT measurements shown as a waterfall plot

A. Change in longest diameter (LD) 2, 4 and 6-8 months after siG12D­-LODER^TM implantation. (*) marks the cases for which data after 4 months or later were not available. B. Change in tumor volume 2, 4 and 6-8 months after siG12D-LODER^TM implantation. (*) marks the cases for which data after 4 months or later were not available. C. Percentage of patients who showed progression of disease (PD); stable disease (SD); partial response (PR) or complete response (CR), based on the changes in LD according to the RECIST 1.1 guidelines. D. CA19-9 changes after 8 weeks: The graph shows waterfall plot of changes from baseline in the levels of the CA19-9 tumor marker.