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

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, 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

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.

Conflict of interest statement

CONFLICTS OF INTEREST

There is no conflict of interest

Figures

Figure 1
Figure 1
A. Study design. B.siG12D-LODERTM is placed with Endoscopic US biopsy needle.
Figure 2. siG12D drug covers the entire…
Figure 2. siG12D drug covers the entire tumor tissue within one week
Subcutaneous tumors of pancreatic PancO2 origin were treated with empty-LODERTM or LODERTM 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 LODERTM 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
Figure 3
A. Overall survival: Kaplan-Meier curves depict OS of siG12D-LODERTM-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-LODERTM-treated patients.
Figure 4. Anti-tumor effect of combination treatment…
Figure 4. Anti-tumor effect of combination treatment with siG12D-LODERTM in locally advanced non-operable PAC in a patient
A. left panel: a CT scan was performed prior to the implantation of siG12D-LODERTM 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 LODERTM insertion, prior SOC treatment.
Figure 5. CT changes from base-line: The…
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-LODERTM 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-LODERTM 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.

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Source: PubMed

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