Pancreatic cancer first-line NALIRIFOX optimization with 5-FU maintenance and role of antibiotics and microbiota exploration in second-line treatment – A non-comparative, randomized phase II PANORAMIX GERCOR G-116 PRODIGE 105 study

Prior treatment

• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study
• Live vaccine administration within 4 weeks (30 days) prior to the first dose of study treatment,
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP1 : Any unresolved NCI CTCAE toxicity of grade ≥ 2 from previous anticancer therapy (including peripheral neuropathy of grade ≥ 1) except for alopecia or vitiligo
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP1 : Any previous chemotherapy for advanced disease
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP1 : Previous adjuvant chemotherapy (by gemcitabine based or FOLFIRINOX) is NOT authorized
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP1 : Any use of strong CYP3A4 inducers/inhibitors and/or strong UGT1A1 inhibitors (patients are ineligible if unable to discontinue the use of strong CYP3A4 or UGT1A1 inhibitors at least 1 week or strong CYP3A4 inducers at least 2 weeks prior to receiving first dose of NAL-IRI injection), or presence of any other contraindications for irinotecan)
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP 2 : Antibiotics use in the month before the day of treatment initiation or for > 5 days within 3 months before the day of treatment initiation
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP 2 : Previous gemcitabine-based chemotherapy
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP 2 : Known previous colonization or infection with K. pneumoniae resistant to quinolones
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP 2 : Prophylactic phenytoin within 1 week (7 days) prior to the first dose of study treatment
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP 2 : Concomitant medication with CYP1A2 substrates (e.g., theophylline, clozapine, duloxetine, tizanidine, olanzapine, propranolol, amitryptilin, and methotrexate
• Current systemic steroid therapy (> 10 mg daily dose of prednisone or equivalent; minimal wash-out of 1 week [7 days]) or immunosuppressive therapy
• Prior radiotherapy treatment to more than 30% of the bone marrow or a wide field of radiation within 4 weeks (30 days) prior to the first dose of study drug
• Major surgical procedure (as defined by the Investigator) within 4 weeks (30 days) prior to the first dose of trial treatment (Step 1 and Step 2)

Other illness

• 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 (e.g. bleeding, inflammation, occlusion, malabsorption syndrome, ulcerative colitis, gastrointestinal ulceration, infection or sepsis, inflammatory bowel disease or partial bowel obstruction) associated with diarrhea, or geographical/social/ psychiatric illness situations that would limit compliance with study requirement and study follow-up, substantially increase risk of incurring AEs, or compromise the ability of the patient to give written informed consent
• Known or suspected allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
• Active bacterial, viral, or fungal infection requiring systemic therapy, including tuberculosis, hepatitis B (HBV, known positive HBV surface antigen [HbsAg] result), hepatitis C (HBC, with positive RNA), or human immunodeficiency virus (HIV positive 1/2 antibodies)
• History of allogenic organ transplantation or active autoimmune, connective tissue disorder, or inflammatory disease requiring systemic treatment
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP1 : Clinically significant active heart disease or myocardial infarction within 6 months given the cardiotoxicity of 5-FU
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP1 : Patients with known homozygous UGT1A1*28 (Gilbert’s disease)
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP 2 : Any contra-indication to ciprofloxacin: history of fluoroquinolone-related severe side effects (muscle, tendons, joint…), severe aortic disease (aneurysm, dissection), myasthenia, epilepsy
• Diagnosis of any second malignancy that required any treatment within the last 3 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri
• History of idiopathic pulmonary fibrosis, interstitial lung disease (ILD), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening (TAP-CT-scan)

Lab values

• History or current evidence of any condition, therapy, 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
• Prolongation of QTc interval >470 milliseconds, previous ventricular arrhythmia, known or suspected long-QT syndrome
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP 2 : Known glucose-6-phosphate dehydrogenase deficiency

Other

• Pregnancy/breast-feeding/lactation
• Under a legal protection measure (guardianship, curatorship, or judicial safeguard), administrative decision, and/or incapable of giving his/her consent
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP1 : Uncontrolled central nervous system metastases and/or carcinomatous meningitis
• Distinct exclusion criteria for STEP 1 and STEP 2 : STEP 2 : Inability to take oral treatment
• Uncontrolled central nervous system metastases and/or carcinomatous meningitis,
• Uncontrolled massive pleural effusion or massive ascites

• Written informed consent obtained from the patient prior to performing any protocol-related procedures, including screening evaluations
• Registration in a National Health Care System (PUMa – Protection Universelle Maladie included
• Distinct inclusion criteria for STEP 1 and STEP 2 : STEP 1 : No prior first-line therapy for metastatic disease; if treatment with any investigational medicinal product (IMP) the delay before the last dose and inclusion more than or equal to 28 days
• Distinct inclusion criteria for STEP 1 and STEP 2 : STEP 1 : No dihydropyrimidine dehydrogenase (DPD) deficiency (uracilemia dosage >16 ng/ml), Uracilemia dosing results must be available before inclusion)
• Distinct inclusion criteria for STEP 1 and STEP 2 : STEP 2 : Metastatic disease
• Distinct inclusion criteria for STEP 1 and STEP 2 : STEP 2 : • L2 therapy after progression under 5-FU-based chemotherapy for localized/locally advanced or metastatic stage
• Age ≥18 years old. The patient over 75 years of age is eligible only if the patient’s G8 score (G8 questionnaire) is ≥14
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1,
• Histologically or cytologically proven PDAC,
• ≥1 measurable lesion according to RECIST v 1.1 (Computed tomography thorax-abdomen-pelvis [TAP-CT] scan ≤ 4 weeks)
• Availability of archival tissue samples for exploratory research. Step 2: can be the same as in Step 1 or it can be newly obtained sample
• Adequate organ function, obtained within 21 days prior to randomization of study treatment, as defined by the following: 1) Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN; (≤ 5 x ULN in case of liver metastases) ꟷ STEP 2: if paclitaxel administration, 2) Total serum bilirubin ≤ 1.5 x ULN (Step 2 if paclitaxel administration) 3) albumin ≥ 28 g/L 4) Hemoglobin ≥ 9.0 g/dl 5) Absolute neutrophil count (ANC) ≥ 1.5 x 109L 6) Platelets ꟷ STEP 1: ≥ 150 x 109L; STEP 2: ≥ 100 x 109L 7) Creatinine clearance ≥ 50 mL/min (Modification of the Diet in Renal Disease [MDRD]
• Evidence of post-menopausal status or negative serum pregnancy test within 7 days before starting study treatment for female pre-menopausal patients. Women of childbearing potential (WOCBP) should use effective contraception during study treatment and: 1 month (paclitaxel), 6 months (5FU, LV), 7 months (NAL-IRI), 15 months (oxaliplatin), and 6 months (gemcitabine+/-paclitaxel and ciprofloxacin/placebo) after the patient’s last dose of treatment. Males who are fertile should use effective contraception during study treatment and 4 months (NAL-IRI), 6 months (5-FU, LV), 12 months (oxaliplatin), and 6 months (gemcitabine+/-paclitaxel and ciprofloxacin/placebo) after the patient’s last dose of treatment.
• 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