IRINOTECAN for Metastatic pancreatic ductal adenocarcinoma

Inclusion criteria

• {"criterion_text":"- Written informed consent obtained from the patient prior to performing any protocol-related procedures, including screening evaluations (only after interim analysis at Step 2 for patients who were not randomized in R1)\n- Registration in a National Health Care System (PUMa – Protection Universelle Maladie included\n- 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\n- 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)\n- Distinct inclusion criteria for STEP 1 and STEP 2 : STEP 2 : Metastatic disease\n- Distinct inclusion criteria for STEP 1 and STEP 2 : STEP 2 : •\tL2 therapy after progression under 5-FU-based chemotherapy for localized/locally advanced or metastatic stage\n- Age ≥18 years old. The patient over 75 years of age is eligible only if the patient’s G8 score (G8 questionnaire) is ≥14\n- Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1,\n- Histologically or cytologically proven PDAC,\n- ≥1 measurable lesion according to RECIST v 1.1 (Computed tomography thorax-abdomen-pelvis [TAP-CT] scan ≤ 4 weeks)\n- 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\n- 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]\n- 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.\n- 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"}

Exclusion criteria

• {"criterion_text":"- Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study\n- 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\n- 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\n- Known or suspected allergy or hypersensitivity to any of the study drugs or any of the study drug excipients\n- 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)\n- Live vaccine administration within 4 weeks (30 days) prior to the first dose of study treatment,\n- Pregnancy/breast-feeding/lactation\n- Under a legal protection measure (guardianship, curatorship, or judicial safeguard), administrative decision, and/or incapable of giving his/her consent\n- 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\n- Distinct exclusion criteria for STEP 1 and STEP 2 : STEP1 : Any previous chemotherapy for advanced disease\n- Distinct exclusion criteria for STEP 1 and STEP 2 : STEP1 : Previous adjuvant chemotherapy (by gemcitabine based or FOLFIRINOX) is NOT authorized\n- History of allogenic organ transplantation or active autoimmune, connective tissue disorder, or inflammatory disease requiring systemic treatment\n- Distinct exclusion criteria for STEP 1 and STEP 2 : STEP1 : Uncontrolled central nervous system metastases and/or carcinomatous meningitis\n- 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\n- Distinct exclusion criteria for STEP 1 and STEP 2 : STEP1 : Patients with known homozygous UGT1A1*28 (Gilbert’s disease)\n- 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)\n- Prolongation of QTc interval >470 milliseconds, previous ventricular arrhythmia, known or suspected long-QT syndrome\n- 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\n- Distinct exclusion criteria for STEP 1 and STEP 2 : STEP 2 : Previous gemcitabine-based chemotherapy\n- Distinct exclusion criteria for STEP 1 and STEP 2 : STEP 2 : Known previous colonization or infection with K. pneumoniae resistant to quinolones\n- 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\n- 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\n- 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\n- Distinct exclusion criteria for STEP 1 and STEP 2 : STEP 2 : Inability to take oral treatment\n- 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\n- Distinct exclusion criteria for STEP 1 and STEP 2 : STEP 2 : Known glucose-6-phosphate dehydrogenase deficiency\n- 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\n- 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)\n- Uncontrolled central nervous system metastases and/or carcinomatous meningitis,\n- Uncontrolled massive pleural effusion or massive ascites"}

Primary endpoints

• {"endpoint_text":"- STEP 1 The 6-month PFS post R1 in patients with L1 NALIRIFOX followed by LV5FU2 (5-FU/LV) in Arm 1A defined by the number of patients free of radiological progression or death at 6 post R1 divided by the total number of patients assessable for the PFS status at 6 months.","definition_or_measurement_approach":"Defined by the number of patients free of radiological progression or death at 6 months post R1 divided by the total number of patients assessable for the PFS status at 6 months."}
• {"endpoint_text":"- STEP 2: The 6-month OS of L2 in Arm 2A (gemcitabine-based chemotherapy combination with ciprofloxacin) post R2, defined by the number of patients alive at 6 months divided by the total number of patients assessable for the OS status at 6 months.","definition_or_measurement_approach":"Defined by the number of patients alive at 6 months post R2 divided by the total number of patients assessable for the OS status at 6 months."}

Secondary endpoints

• {"endpoint_text":"- STEP 1: The 6-month PFS rate of standard NALIRIFOX in Arm 1B, defined by the number of patients free of radiological progression or death at 6 months post R1 divided by the total number of patients assessable for the PFS status at 6 months","definition_or_measurement_approach":"Defined by the number of patients free of radiological progression or death at 6 months post R1 divided by the total number of patients assessable for the PFS status at 6 months."}
• {"endpoint_text":"- STEP 1 : PFS-L1 in Arm 1A and in Arm 1B, defined as the time between the date of R1 and the date of the first documented disease progression (PD; per RECIST 1.1) determined by the Investigator or death due to any cause, whichever occurs first","definition_or_measurement_approach":"Time from R1 to first documented PD per RECIST 1.1 or death from any cause."}
• {"endpoint_text":"- STEP 1 : OS-R1 in Arm 1A and in Arm 1B, defined as the time between the date of R1 and the date of death from any cause","definition_or_measurement_approach":"Time from R1 to death from any cause."}
• {"endpoint_text":"- STEP 1 :ORR-L1 at 4 months of L1 in Arm 1A and in Arm 1B, defined as the number of patients with a response of complete response (CR) or partial response (PR) divided by the number of patients with measurable target lesion at baseline","definition_or_measurement_approach":"Proportion of patients with CR or PR at 4 months divided by number of patients with measurable target lesions at baseline (per RECIST 1.1)."}
• {"endpoint_text":"- STEP 1 : ORR-RI in Arm 1A, defined as the number of patients with CR or PR divided by the number of patients with measurable target lesions at baseline","definition_or_measurement_approach":"Proportion of patients with CR or PR after NALIRIFOX reintroduction divided by number of patients with measurable target lesions at baseline."}
• {"endpoint_text":"- STEP 1 : BRR-L1 in Arm 1A and in Arm 1B, defined as the best response designation, recorded between the date of R1 and the date of objectively documented PD (per RECIST 1.1) or the date of subsequent anti-cancer therapy, whichever occurs first","definition_or_measurement_approach":"Best response recorded between R1 and objective PD (RECIST 1.1) or start of subsequent anticancer therapy."}
• {"endpoint_text":"- STEP 1 : BRR-L1R in Arm 1A, defined as the best response designation, recorded between the date of reintroduction of NALIRIFOX and the date of objectively documented PD post NALIRIFOX reintroduction (per RECIST 1.1)","definition_or_measurement_approach":"Best response between NALIRIFOX reintroduction and subsequent PD (RECIST 1.1)."}
• {"endpoint_text":"- STEP 1 : DDC in Arm 1A and in Arm 1B","definition_or_measurement_approach":"Duration of disease control (specific definition not further detailed in CTIS record)."}
• {"endpoint_text":"- STEP 1 : Only grade 3-4 AEs/SAEs related to treatment according to the NCI CTCAE v 5.0","definition_or_measurement_approach":"Incidence of grade 3-4 adverse events/serious adverse events related to treatment as per NCI CTCAE v5.0."}
• {"endpoint_text":"- STEP 1: The rate of peripheral neuropathy","definition_or_measurement_approach":"Rate/incidence of peripheral neuropathy (measurement per NCI CTCAE v5.0)."}
• {"endpoint_text":"- STEP 1 : HRQoL (EORTC QLQ-C30 [Appendix 25.2] and EORTC QLQ-PAN26 in Arm 1A and in Arm 1B","definition_or_measurement_approach":"Health-related quality of life assessed by EORTC QLQ-C30 and EORTC QLQ-PAN26 questionnaires."}
• {"endpoint_text":"- Step 2 : OS-R2 in in Arm 2A and Arm 2B, defined as the time between the date of R2 and the date of death from any cause","definition_or_measurement_approach":"Time from R2 to death from any cause."}
• {"endpoint_text":"- Step 2 : PFS-L2 according to RECIST 1.1 in Arm 2A and Arm 2B, defined as the time from R2 to the date of the first documented PD (per RECIST 1.1) determined by the Investigator or death due to any cause, whichever occurs first","definition_or_measurement_approach":"Time from R2 to first documented PD per RECIST 1.1 or death from any cause."}
• {"endpoint_text":"- STEP 2 : ORR-L2 in Arm 2A and Arm 2B, defined as the number of patients with CR/PR divided by the number of patients with measurable target lesions at baseline.","definition_or_measurement_approach":"Proportion of patients with CR/PR in L2 divided by number with measurable target lesions at baseline."}
• {"endpoint_text":"- STEP 2 : BRR-L2 of L2 in Arm 2A and Arm 2B, defined as the best response designation (CR/PR/SD), recorded between the date of R2 and the date of objectively documented PD (per RECIST 1.1) or the date of subsequent anti-cancer therapy, whichever occurs first","definition_or_measurement_approach":"Best response (CR/PR/SD) between R2 and PD or subsequent anticancer therapy."}
• {"endpoint_text":"- STEP 2 : All grade AEs and severe (grade 3-5) AEs in Arm 2A and Arm 2B, according to the NCI CTCAE v 5.0","definition_or_measurement_approach":"Incidence of all-grade and grade 3-5 adverse events per NCI CTCAE v5.0."}
• {"endpoint_text":"- STEP2 : The rate (percentage) of occurrence of MRB","definition_or_measurement_approach":"Rate (percentage) of occurrence of multi-resistant bacteria (MRB) in the gut microbiome."}
• {"endpoint_text":"- STEP 2 : The pharmacokinetics of gemcitabine clearance and gemcitabine’s metabolite, dFdU, between Arm 2A and Arm 2B","definition_or_measurement_approach":"Pharmacokinetic comparison of gemcitabine clearance and metabolite dFdU between arms."}

France

Earliest CTIS Part Ii Submission Date

24-03-2025

Latest Decision Or Authorization Date

27-05-2025

Processing Time Days

64

Number Of Sites

12

Number Of Participants

142

Primary sponsor

Full Name

Association Gercor

Organisation Type

Laboratory/Research/Testing facility

Country Of Registered Address

France