Repurposing of Decitabine in Kras-Dependent Refractory Pancreatic Cancer
A proof-of-concept, biomarker-driven, phase-II clinical trial to explore the repurposing of decitabine against advanced, refractory, KRAS-dependent pancreatic ductal adenocarcinoma (PDAC): The ORIENTATE (tailOred dRug repurposIng of dEcitabine in KRAS-dependeNt refracTory pAncreaTic cancEr) trial.
- Digestive cancer
Why this trial?
Pancreatic cancer is currently the 4th leading cause of death by cancer in Europe. Surgical resection with (neo)adjuvant therapy is the only potentially curative treatment. Unfortunately, because of the late presentation of the disease, only 15 to 20 percent of patients are candidates for surgery. Current standard treatment options for patients that are not eligible for surgery, consist of chemotherapy (mFOLFIRINOX or gemcitabine plus albumin-bound paclitaxel). Nevertheless, prognosis remains very poor and the need for more effective treatment options is high.
KRAS gene mutations occur in 95% of pancreatic ductal adenocarcinoma (PDAC) and play a role in cancer development and progression. Based on preclinical PDAC cancer models, it is possible to identify so-called KRAS-dependent tumours.
Preclinical research showed that targeting KRAS dependency reduced tumour growth. In PDAC patient samples, KRAS-dependent tumours seem to be prevalent in 30% to 50%. If it can be confirmed that targeting KRAS dependency in patients is effective, this might be a novel treatment strategy for a considerable group of patients.
Why this intervention?
Decitabine (DEC) has been approved by the FDA for the treatment of myelodysplastic syndromes and acute myeloid leukaemia.
Preclinical studies show that DEC has cytotoxic activity and suppresses the growth of KRAS-dependent PDAC, which is not the case in KRAS-independent PDAC. Based on their own studies and those of other research groups, the investigators of this trial hypothesise that DEC may be a potent anticancer drug in KRAS-dependent PDAC, and that the KRAS dependency of tumours can be determined by calculated scores based on the analysis of gene expression of the tumour biopsy. Based on these hypotheses, the investigators propose a proof-of-concept, biomarker-driven clinical trial to explore the activity of DEC against advanced, refractory KRAS-dependent PDAC.
The ORIENTATE study is an open-label single-arm phase II clinical trial that will explore the activity of DEC against advanced, refractory KRAS-dependent PDAC.
A tumour biopsy will be performed at baseline to determine the KRAS mutational status and dependency and determine the patients’ eligibility for the trial. Patients with a score of KRAS-dependency above the cut-off are eligible, and will receive DACOGEN (decitabine) at the dose of 10 mg/m2/d in a 4-week treatment cycle. Initially, nine patients will be included in the trial. Patients will continue to receive study treatment until objective radiological disease progression.
If none of 9 recruited patients show a response, the study will be stopped, as the treatment will be deemed ineffective. In case of 1 or more responses, another 8 patients will be enrolled. The study will be considered positive if at least three responders are identified, in terms of overall response rate. The trial also assesses treatment safety and tolerability, clinical benefit, impact on quality of life and survival outcomes.
Dr. Luca Cardone, Regina Elena National Cancer Institute – IRCCS, Rome, Italy (Scientific Principal Investigator)
Prof. Michele Milella, University of Verona - School of Medicine, Verona, Italy (Clinical Principal Investigator)
Regina Elena National Cancer Institute – IRCCS, Rome, Italy
More info: NCT05360264 – EudraCt 2021-002632-23
Mottini, C.; Tomihara, H.; Carrella, D.; et al, Predictive Signatures Inform the Effective Repurposing of Decitabine to Treat KRAS-Dependent Pancreatic Ductal Adenocarcinoma. Cancer Res 2019, 79, (21), 5612-5625.
Koundinya, M.; Sudhalter, J.; Courjaud, A.; et al, Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers. Cell Chem Biol 2018, 25, (6), 705-717 e11.
Santana-Codina, N.; Roeth, A. A.; Zhang, Y et al, Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nat Commun 2018, 9, (1), 4945.
Qian, J.; Niu, J.; Li, M.; et al, In vitro modeling of human pancreatic duct epithelial cell transformation defines gene expression changes induced by K-ras oncogenic activation in pancreatic carcinogenesis. Cancer Res 2005, 65, (12), 5045-53.
Loboda, A.; Nebozhyn, M.; Klinghoffer, R.; et al, A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors. BMC Med Genomics 2010, 3, 26.
Author: Kristine Beckers (Trial Manager)
Last updated: May 2022