Personalized First-line Chemotherapy Choice in Advanced Pancreatic Adenocarcinoma Using Transcriptomic Signatures

Study Overview
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Brief Summary
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The aim of this study is to assess the clinical value of 5 transcriptomic signatures prognostic of chemotherapeutic sensitivity to improve the Objective Response Rate (ORR) of first-line (L1). Chemotherapy regimen (FOLFIRINOX vs Gem-nabP) will be selected based on transcriptomic signatures applied to the pre-therapeutic liver biopsy of newly diagnosed PDAC patients.

Detailed Description
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Step 1: patients will sign a 1st informed consent prospectively for the molecular screening (RNAseq profile). 5 transcriptomic signatures will be applied for prediction of response to 5 Fluoro-Uracil (5FU), oxaliplatin, irinotecan, gemcitabine and taxane. Biomarker status will be obtained for all patients as part of good clinical practice. Patients will be eligible for prospective step 2 only if the transcriptomic analysis is informative and the treatment can be started within 28 days. Step 2: study treatment strategy: based on the results of transcriptomic signatures, patients will receive either FOLFIRINOX or Gem-nabP according to the following algorithm (2nd informed consent): Predicted to be FOLFIRINOX sensitive (regardless of sensitivity to Gem-nabP) = FOLFIRINOX Predicted to be FOLFIRINOX and Gem-nabP resistant = FOLFIRINOX Presence of a germline breast cancer (BRCA) mutation (regardless of transcriptomic signature) = FOLFIRINOX (tumors sensitive to platinum). Predicted to be Gem-nabP sensitive and FOLFIRINOX resistant = Gem-nabP Chemotherapy with FOLFIRINOX and Gemcitabine plus nab-paclitaxel will be administered as in routine practice, according to their approval. Dose adaptation will be allowed according to investigator's usual practice.

Official Title
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Pilot Study of Personalized First-line Chemotherapy Choice for Patients With Advanced Pancreatic Adenocarcinoma Using Transcriptomic Signatures (PACsign)

Conditions
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Carcinoma, Pancreatic Ductal, Prognosis

Intervention / Treatment
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* Other: Clinical value of 5 transcriptomic signatures to personalize the therapeutic decision for L1 in PDAC
* Other: Biomarkers of tumor signatures (translational studies)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained from the patient prior to performing any protocol-related procedures, including screening evaluations. Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Histologically or cytologically proven Pancreatic Ductal Adenocarcinoma (PDAC). Metastatic disease including liver metastases. Measurable or evaluable lesions according to RECIST v1.1 criteria. First-line therapy for metastatic disease (previous neoadjuvant/adjuvant chemotherapy not allowed). Age ≥ 18 years and ≤ 75 years at the time of study entry. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1. Have tumor liver tissue sample (chemo-naïve) that has been identified and confirmed as available for study. Adequate organ function, as defined by the following (blood test ≤ 7 days prior to inclusion): Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN) (≤ 5 ULN in case of liver metastases) Total serum bilirubin ≤ 1.5 ULN Serum albumin ≥ 28 g/L Hemoglobin ≥ 9.0 g/dl Absolute neutrophil count (ANC) ≥ 1,500/μL Platelets ≥ 100,000/μL Creatinine clearance ≥ 50 mL/min (MDRD). No Dihydropyrimidine dehydrogenase (DPD) deficiency (normal uracil level). Life expectancy ≥ 3 months. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Registration in a National Health Care System. Exclusion Criteria: Concurrent enrolment in another interventional clinical study. Previous treatment with chemotherapy for pancreatic cancer. Uncontrolled massive pleural effusion or massive ascites. Known deficiency in UGT1A1 (homozygous UGT1A1*28 allele). Active bacterial, viral, or fungal infection requiring systemic therapy, including tuberculosis, hepatitis B (known positive Hepatitis B Virus surface antigen (HBsAg) result), hepatitis C (with positive RNA), Sars-Cov-2 or human immunodeficiency virus (positive HIV 1/2 antibodies). Diagnosis of any second malignancy within the last 3 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri. Known active central nervous system metastases and/or carcinomatous meningitis; patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline). Uncontrolled intercurrent illness, including but not limited to, symptomatic congestive heart failure or coronary disease, peripheral artery disease, severe chronic obstructive pulmonary disease, decompensated cirrhosis, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent. Live vaccine administration within 30 days prior to the first dose of study treatment. Known or suspected allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with participation for the full duration of the trial, or is not in the best interest of the participant, in the opinion of the treating investigator. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug. Major surgical procedure (as defined by the Investigator) within 4 weeks prior to the first dose of trial treatment. Pregnancy/lactation. Person under legal protection or tutelage or guardianship.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Molecular screening for prediction of response<br>L1 chemotherapy regimen (FOLFIRINOX vs Gemcitabine plus nab-paclitaxel (GemnabP)) will be selected based on transcriptomic signatures applied to the pre-therapeutic biopsy of newly diagnosed PDAC patients. | Other: Clinical value of 5 transcriptomic signatures to personalize the therapeutic decision for L1 in PDAC<br>* Formalin-Fixed Paraffin-Embedded (FFPE) samples will be centralized in which nucleic acids extraction (DNA+RNA) and FFPE-compatible RNA-sequencing will be performed in real-time (≤28 days). RNAseq reads will be processed and all 5 transcriptomic signatures will be applied for prediction of response to 5FU, oxaliplatin, irinotecan, gemcitabine and taxane. In addition, biomarkers status will be obtained for all patients as part of good clinical practice.<br>Other: Biomarkers of tumor signatures (translational studies)<br>* Blood (serum and plasma) will be drawn at baseline, week 8, and tumor progression in order to look for surrogate biomarkers of tumor signatures in liquid biopsy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) at 4 months based on thorax-abdomen-pelvis (TAP) CT scan every 8 weeks according to RECIST v1.1. | ORR, defined as the percentage of patients whose disease decreased by at least 30% (partial response - PR) and/or disappeared (complete response - CR) under treatment among patients who start treatment. | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS, defined as the time from the date of treatment initiation to the date of progression or death whatever the cause. Progression will be assessed by the investigator based on TAP-CT scan every 8 weeks according to RECIST v1.1. | 18 months | 
| Overall Survival (OS) | OS, defined from the date of treatment initiation to the date of death whatever the cause. | 18 months | 
| Disease Control Rate (DCR) | DCR, defined as the percentage of patients who have achieved complete response, partial response or stable disease according to RECIST v1.1 among patients who start treatment. | 18 months | 
| Treatment-related severe (grade 3-5) toxicities | Toxicities will be graded, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (digestive, hematologic, neuropathy). | 18 months | 
| Feasibility of study procedure | Measured as the rate of usable samples | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transcriptomic signatures, Personalized first-line chemotherapy, Metastatic PDAC