Neoplasms

Digestive System Diseases

Gland and Hormone Related Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Pancreatic Neoplasms

Adenocarcinoma

Recurrence

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Pancreatic Cancer

Antineoplastic Agents

All Drugs and Chemicals

Decitabine

Antimetabolites

Enzyme Inhibitors

A fresh, mandatory, tumor biopsy will be performed at baseline to assess KRAS mutational status and functional dependency and determine the patient's eligibility for the trial. KRAS dependency will be assessed based on computational score and inferred by a transcriptional signature of tumor cells. Transcriptomic data will be generated by using RNAseq data. Sample RNA processing and generation of the gene expression profile will be guaranteed within a maximum of 10 working days from the biopsy.

Patients with high L-, S- or both L/S- scores of KRAS-dependency will receive DACOGEN.

DACOGEN will be administered i.v. over 1 hour, at the dose of 10 mg/m2/d, daily on days 1-5 and 8-12 of each 4-wk cycle.

Patients will continue to receive study treatment until objective radiological disease progression per modified RECIST 1.1, as assessed by the investigator, unacceptable toxicity, physician's decision, patient's refusal, or until they meet any other discontinuation criteria.

DACOGEN will be administered i.v. over 1 hour, at the dose of 10 mg/m2/d, daily on days 1-5 and 8-12 of each 4-wk cycle.

Decitabine 50 MG [Dacogen]

LUCA CARDONE, PhD

Michele Milella, Prof.

MICHELE RENI, MD

ANTONIO AVALLONE, MD

ENRICO VASILE, MD

ERISELD KRASNIQI, MD

GIAMPAOLO TORTORA, Prof.

MICHELE MILELLA, Prof.

The study is designed to assess the therapeutic efficacy of decitabine repurposing against advanced, refractory, ductal adenocarcinoma (PDAC) with molecular transcriptional signatures indicating dependency on the KRAS oncogene

TYPE OF STUDY: Phase II study, open label, multicentre, single arm, interventional, Non-randomized ￼ TARGET POPULATION: Advanced (locally advanced or metastatic), pre-treated PDAC patients, progressing after at least one and no more than two lines of systemic therapy, whose tumors express a KRAS-dependency signature.

￼ RATIONALE. BACKGROUND: KRAS gene mutations occur in 95% of PDAC. Inhibitors targeting the prevalent KRASG12V and KRASG12D mutations in PDAC have yet to reach the clinical setting. Oncogenic KRAS-driven signatures have been derived from PDAC cancer models. Based on these, it is possible to identify a subset of PDACs that are highly addicted to oncogenic KRAS, and referred to as KRAS-dependent tumors (dKRAS), in which the direct targeting of KRAS or KRAS-dependent phenotypes reduced tumor growth. Notably, KRAS dependency was associated with a rewiring of nucleotide metabolism and the inhibition of pyrimidine biosynthesis was sufficient to inhibit the growth of dKRAS PDAC cells. In contrast, tumors that, though harboring KRAS mutations, do not display KRAS dependency are resistant to anti-KRAS targeting.

Decitabine (DEC) is FDA-approved for the treatment of myelodysplastic syndromes and acute myeloid leukaemia. Importantly, phase-I and -II clinical trials of DEC have defined a recommended phase II dose (RP2D) for DEC monotherapy in solid tumors.

HYPOTHESES AND RATIONALE: Preclinical studies show that DEC has cytotoxic activity and inhibits the growth of dKRAS PDAC, whereas KRAS-independent PDACs are not responsive. Based on solid preclinical studies and the scientific literature, the investigators' hypotheses are that: i) DEC is a potent anticancer drug inhibiting pyrimidine homeostasis and eliciting DNA damage in PDAC with a KRAS dependency; ii) The KRAS dependency of tumors can be analytically defined by computational scores based on the analysis of the gene expression signature on tumor biopsy; iii) These genetic scores might have a prognostic value. Based on these hypotheses, the investigators propose a proof-of-concept, biomarker-driven, phase-II clinical trial to explore the activity of DEC repurposing against advanced, refractory KRAS-dependent PDAC.

OBJECTIVES: The primary objective of the trial is to provide proof-of-concept of DEC antitumor activity in dKRAS metastatic PDAC.

Secondary objectives of the trial are to assess the feasibility of a molecularly tailored approach in advanced, pre-treated PDAC, as well as to assess treatment safety and tolerability, clinical benefit, impact on quality of life, and survival outcomes.

tailOred dRug repurposIng of dEcitabine in KRAS-dependeNt refracTory pAncreaTic cancEr

A Proof-of-concept, Biomarker-driven, Phase-II Clinical Trial to Explore the Activity of Decitabine Repurposing Against Advanced, Refractory, KRAS-dependent Pancreatic Ductal Adenocarcinoma (PDAC):The ORIENTATE Trial

Best response is recorded from the start of the treatment until disease progression. Tumor assessments according to modified RECIST 1.1 criteria will be performed at baseline and every 8 weeks (±1week) up to 40 weeks and then every 12 weeks (±1 week) until objective radiological disease progression according to modified RECIST criteria (evised RECIST guideline (version 1.1). Eur J Cancer 2009. DOI:10.1016/j.ejca.2008.10.026).

The percentage of patients who have achieved complete response, partial response and stable disease according to modified RECIST 1.1

CBR is a multidimensional endpoint encompassing performance status, pain, and weight loss/gain

Tumor marker response is defined as percent reduction of CA19.9 at nadir, as compared to baseline levels and will be evaluated only in patients with elevated CA19.9 levels at baseline.

Monitored throughout the study and will be assessed and graded according to CTCAE (version 5.0)

Spots Global Cancer Trial Database for pancreatic adenocarcinoma recurrent