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Pancreatic Adenocarcinoma MetastaticPhase 2ORIENTATENCT05360264

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

A Phase 2 study testing Decitabine 50 MG [Dacogen] in people with Pancreatic Adenocarcinoma Metastatic and Pancreatic Adenocarcinoma Recurrent, run by Luca Cardone at 6 sites in Italy.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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 Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Decitabine 50 MG [Dacogen]
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
7 participants
Where
6 sitesItaly
Study dates
15 Jan 2022to 10 Oct 2024
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age ≥ 18 years;
  • Histologically or cytologically proven, advanced, inoperable (metastatic or locally advanced), PDAC;
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2;
  • Life expectancy of at least 12 weeks;
  • At least one and no more than two lines of systemic treatment for advanced disease;
  • At least one metastatic lesion(s) and/or primary tumor amenable to pre-treatment biopsy;
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  • KRAS dependency, as assessed by molecular analysis of RNA isolated from a fresh tumor biopsy;
  • Imaging-documented progressive disease (PD), according to modified RECIST 1.1 criteria;
  • Imaging-documented measurable disease, according to modified RECIST 1.1 criteria;
  • Adequate organ and marrow function;
  • Postmenopausal status or evidence of non-childbearing status (negative urine or serum pregnancy test) for women of childbearing potential;
  • Women of childbearing potential (defined as not post- menopausal for 12 months or no previous surgical sterilization) and fertile men must agree to use two highly effective forms of contraception while they are receiving

Who cannot join

  • Uncontrolled intercurrent illness(es);
  • Pregnancy or lactation;
  • Active and uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy;
  • Major surgical intervention within 4 weeks prior to enrollment;
  • Radiotherapy, surgery, chemotherapy, or an investigational therapy within 2 weeks prior to signing the treatment ICF;
  • Any previous treatment with DEC;
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  • Patients with second primary cancers, except for adequately treated non- melanoma skin cancer, curatively treated in-situ cancer of the cervix, stage 1 grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) treated with curative intent and with no evidence of active disease at >1 year from the completion of curative treatment prior to study entry;
  • Persistent toxicities (≥CTCAE grade 2) caused by previous cancer therapy, excluding alopecia;
  • Serious medical risk factors involving any of the major organ systems such that the investigator considers it unsafe for the patient to receive an experimental research drug;
  • Serious psychiatric or medical conditions that could interfere with a valid informed consent.

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

Italy6 sites

  • Irccs S. Raffaele - Milano

    Milan

  • Istituto Nazionale Tumori Di Napoli Irccs Pascale

    Naples

  • Azienda Ospedaliero-Universitaria Pisana

    Pisa

  • Istituti Fisioterapici Ospitalieri- Ifo - Istituto Regina Elena

    Rome, 00015

  • Policlinico A. Gemelli E C.I.C.- Policlinico Universitario A. Gemelli

    Rome

  • Az.Osp.Universitaria Integrata Verona- Borgo Roma

    Verona

Other trials in Italy

About this study

Official title: 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

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

Read the detailed description

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.

Being tested
Decitabine 50 MG [Dacogen]

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Decitabine 50 MG [Dacogen]Drug

    Also called 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.

Study groups in NCT05360264
Study groupRoleWhat they receive
Experimental groupExperimentalA 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.
Receives: Drug: Decitabine 50 MG [Dacogen]

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Best Overall Respone (BOR) according to RECIST1.1

    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).

    Measured: From registration to date of documented best response, assessed up to 24 months

Secondary outcomes (6)

  1. Disease Control Rate (DCR)

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

    Measured: Every 8 weeks (±1 week) from enrolment for the first 40 weeks, then every 12 weeks (±1 week) up to discontinuation the treatment

  2. Clinical Benefit Rate (CBR)

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

    Measured: Every 8 weeks (±1 week) from enrolment for the first 40 weeks, then every 12 weeks (±1 week) up to discontinuation the treatment

  3. tumor marker (Ca19.9) response

    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.

    Measured: On day 1 of every cycle and at the treatment discontinuation

  4. Number of participants with treatment-related adverse events as assessed by CTCAE version 5.0

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

    Measured: Adverse Events will be collected from time of signature of informed consent throughout the treatment period up to and including the 30-day follow-up period.

  5. PFS (progression free survival)

    PFS will be calculated form treatment start until progression or death.

    Measured: Every 8 weeks (±1 week) from enrolment for the first 40 weeks, then every 12 weeks (±1 week) and at the treatment discontinuation

  6. OS (overall survival)

    OS will be calculated from treatment start until progression or death.

    Measured: Every 8 weeks (±1 week) from enrolment for the first 40 weeks, then every 12 weeks (±1 week) and at the treatment discontinuation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 May 2022
  2. Study start15 Jan 2022
  3. Primary completion10 Oct 2024
  4. Study completion10 Oct 2024

Why it stopped: Unexpected toxicity events were documented during interim safety evaluations of the investigational drug.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
Single Group Assignment
Masking
None (open label)
Enrolment
7 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05360264
Sponsor's protocol ID
IFO21_02
Other IDs
2021-002632-23
Acronym
ORIENTATE
Status last verified
Mar 2025
First submitted
6 Apr 2022
Last updated
24 Mar 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Tost J, Ak-Aksoy S, Campa D, Corradi C, Farinella R, Ibanez-Costa A, Dubrot J, Earl J, Melian EB, Kataki A, Kolnikova G, Madjarov G, Chaushevska M, Strnadel J, Tanic M, Tomas M, Dubovan P, Urbanova M, Buocikova V, Smolkova B. Leveraging epigenetic alterations in pancreatic ductal adenocarcinoma for clinical applications. Semin Cancer Biol. 2025 Feb;109:101-124. doi: 10.1016/j.semcancer.2025.01.003. Epub 2025 Jan 23.

    PubMed 39863139

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Decitabine 50 MG [Dacogen] in people with Pancreatic Adenocarcinoma Metastatic and Pancreatic Adenocarcinoma Recurrent, run by Luca Cardone at 6 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 24 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Unexpected toxicity events were documented during interim safety evaluations of the investigational drug.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Best Overall Respone (BOR) according to RECIST1.1 (time frame: From registration to date of documented best response, assessed up to 24 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05360264, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Mar 2025.

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