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

Pancreatic Adenocarcinoma Metastatic Clinical Trial

— ORIENTATE  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05360264
• Other study ID #: IFO21_02
• Secondary ID: 2021-002632-23
• Status: Recruiting
• Phase: Phase 2
• Start date: January 15, 2022
• Est. completion date: February 2025

Study information

• Verified date: March 2023
• Source: Regina Elena Cancer Institute
• Contact: LUCA CARDONE, PhD
• Phone: +390652662577
• Email: luca.cardone[@]ifo.it
• Is FDA regulated: No
• Study type: Interventional

Clinical 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 18
• Est. completion date: February 2025
• Est. primary completion date: February 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age = 18 years;

2. Histologically or cytologically proven, advanced, inoperable (metastatic or locally advanced), PDAC;

3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2;

4. Life expectancy of at least 12 weeks;

5. At least one and no more than two lines of systemic treatment for advanced disease;

6. At least one metastatic lesion(s) and/or primary tumor amenable to pre-treatment biopsy;

7. KRAS dependency, as assessed by molecular analysis of RNA isolated from a fresh tumor biopsy;

8. Imaging-documented progressive disease (PD), according to modified RECIST 1.1 criteria;

9. Imaging-documented measurable disease, according to modified RECIST 1.1 criteria;

10. Adequate organ and marrow function;

11. Postmenopausal status or evidence of non-childbearing status (negative urine or serum pregnancy test) for women of childbearing potential;

12. 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

Exclusion Criteria:

1. Uncontrolled intercurrent illness(es);

2. Pregnancy or lactation;

3. Active and uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy;

4. Major surgical intervention within 4 weeks prior to enrollment;

5. Radiotherapy, surgery, chemotherapy, or an investigational therapy within 2 weeks prior to signing the treatment ICF;

6. Any previous treatment with DEC;

7. 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;

8. Persistent toxicities (=CTCAE grade 2) caused by previous cancer therapy, excluding alopecia;

9. 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;

10. Serious psychiatric or medical conditions that could interfere with a valid informed consent.

Related Conditions & MeSH terms

• Adenocarcinoma
• Pancreatic Adenocarcinoma Metastatic

Intervention

Drug:
• Decitabine 50 MG [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.

Locations

Country	Name	City	State
Italy	Irccs S. Raffaele - Milano	Milano
Italy	Istituto Nazionale Tumori Di Napoli Irccs Pascale	Napoli
Italy	Azienda Ospedaliero-Universitaria Pisana	Pisa
Italy	Istituti Fisioterapici Ospitalieri- Ifo - Istituto Regina Elena	Rome
Italy	Policlinico A. Gemelli E C.I.C.- Policlinico Universitario A. Gemelli	Rome
Italy	Az.Osp.Universitaria Integrata Verona- Borgo Roma	Verona

Sponsors (7)

Lead Sponsor	Collaborator
Luca Cardone	Anticancer Fund, Belgium, Azienda Ospedaliera Universitaria Integrata Verona, Catholic University of the Sacred Heart, Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale, San Raffaele University Hospital, Italy, University of Pisa

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	From registration to date of documented best response, assessed up to 24 months
Secondary	Disease Control Rate (DCR)	The percentage of patients who have achieved complete response, partial response and stable disease according to modified RECIST 1.1	Every 8 weeks (±1 week) from enrolment for the first 40 weeks, then every 12 weeks (±1 week) up to discontinuation the treatment
Secondary	Clinical Benefit Rate (CBR)	CBR is a multidimensional endpoint encompassing performance status, pain, and weight loss/gain	Every 8 weeks (±1 week) from enrolment for the first 40 weeks, then every 12 weeks (±1 week) up to discontinuation the treatment
Secondary	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.	On day 1 of every cycle and at the treatment discontinuation
Secondary	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)	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.
Secondary	PFS (progression free survival)	PFS will be calculated form treatment start until progression or death.	Every 8 weeks (±1 week) from enrolment for the first 40 weeks, then every 12 weeks (±1 week) and at the treatment discontinuation
Secondary	OS (overall survival)	OS will be calculated from treatment start until progression or death.	Every 8 weeks (±1 week) from enrolment for the first 40 weeks, then every 12 weeks (±1 week) and at the treatment discontinuation