PANORAMIX : Optimizing 1st-line NALIRIFOX and Exploring Microbiota's Role in 2nd Line Pancreatic Cancer Treatment (PANORAMIX)

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.

The main objective of PANORAMIX phase II trial is to optimize first-lie (L1) NALIRIFOX treatment for pancreatic cancer through the implementation of 5-fluorouracil (5-FU) maintenance therapy. Additionally, it aims to investigate the role of antibiotics and microbiota in second-line (L2) treatment.

Study Overview

• Status: Not yet recruiting
• Conditions: PDAC - Pancreatic Ductal Adenocarcinoma
• Intervention / Treatment: Drug: Nal-IRI; Drug: Oxaliplatin; Drug: Leucovorin; Drug: 5-Fluorouracil; Drug: Ciprofloxacin; Drug: Paclitaxel; Drug: Gemcitabine; Other: Placebo

Detailed Description

This randomized non-comparative phase II study consists of two sequential steps.

Step 1 (main objective), the primary goal is to assess the efficacy of a maintenance strategy with LV5FU2 alone after disease control with first-line NALIRIFOX-based chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

Step 2 of the study (exploratory objective), aim is to assess the efficacy and safety of the addition of fluoroquinolone (ciprofloxacin) to gemcitabine-based chemotherapy in second-line setting.

• Study Type: Interventional
• Enrollment (Estimated): 206
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Cindy NEUZILLET, MD; Phone Number: 7129 +33 (0) 1 47 11 15 15; Email: cindy.neuzillet@curie.fr
• Study Contact Backup: Name: Marie-Line GARCIA LARNICOL, MD; Phone Number: +33 (0) 1 40 29 85 04; Email: marie-line.garcia-larnicol@gercor.com.fr

Study Locations

• France
  • Besançon, France
    • CHU de Besancon
  • La Tronche, France
    • CHU de Grenoble
  • Lille, France
    • CHU de Lille
    • Contact: Anthony TURPIN, MD
  • Paris, France
    • Institut Curie
    • Contact: Pauline VAFLARD, MD
  • Paris, France
    • Pitié Salpêtrière hospital
    • Contact: Jean Baptiste BACHET, MD
  • Paris, France
    • Saint-Antoine Hospital
  • Poitiers, France
    • CHU de Poitiers
    • Contact: David TOUGERON, MD
  • Reims, France
    • CHU de Reims
    • Contact: Olivier Bouche
  • Saint-Cloud, France
    • Institute Curie
    • Contact: Cindy NEUZILLET, MD
  • Saint-Mandé, France
    • Hopital d'Instruction des Armees BEGIN
    • Contact: Julie LAVOLE, MD
  • Saint-Étienne, France
    • CHU de Saint Etienne
    • Contact: Nicole WILLIET, MD
  • Villejuif, France
    • Paul Brousse Hospital
    • Contact: Elise COLLE, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Overlapping inclusion criteria for STEP 1 AND STEP 2

1. 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 first randomization [R1]),
2. Age ≥18 years old. STEP 1: The patient over 75 years of age is eligible only if the patient's G8 score (G8 questionnaire) is > 14,
3. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1,
4. Histologically or cytologically proven PDAC,
5. ≥1 measurable lesion according to RECIST v 1.1 (Computed tomography thorax-abdomen-pelvis [TAP-CT] scan ≤ 4 weeks), Note: abdominal magnetic resonance imaging (MRI) is allowed (e.g., in case of contra-indication to CT scan contrast injection) provided that this imaging modality is used consistently throughout the tumor evaluations,
6. 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,

7. Adequate organ function, obtained within 21 days prior to randomization of study treatment, as defined by the following:

   • Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN; ≤ 5 x ULN in case of liver metastases) - STEP 2, if paclitaxel administration,
   • Total serum bilirubin < 1.5 x ULN (STEP 2, if paclitaxel administration),
   • Serum albumin ≥ 28 g/L,
   • Hemoglobin ≥ 9.0 g/dl,
   • Absolute neutrophil count (ANC) ≥ 2 x 10^9L,
   • Platelets - STEP 1: ≥ 150 x 10^9L; STEP 2: ≥ 100 x 10^9L,
   • Creatinine clearance ≥ 50 mL/min (Modification of the Diet in Renal Disease [MDRD]),
8. 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.
9. 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,

10. Registration in a National Health Care System (PUMa - Protection Universelle Maladie included).

    Distinct inclusion criteria for STEP 1 and STEP 2 STEP 1

11. No prior first-line chemotherapy (5-FU or gemcitabine based, or FOLFIRINOX) 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, Note: relapse after FOLFIRINOX adjuvant chemotherapy in case of resectable disease is NOT allowed,
12. No dihydropyrimidine dehydrogenase (DPD) deficiency (Uracilemia dosage >16 ng/ml), Uracilemia dosing results must be available before inclusion).

STEP 2 11. Metastatic disease, 12. L2 therapy after progression under 5-FU-based chemotherapy for localized/locally advanced or metastatic stage, Note: relapse <4 months after the end of adjuvant chemotherapy in case of resectable disease is allowed.

Exclusion Criteria:

Overlapping exclusion criteria for STEP 1 AND STEP 2

1. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study,
2. History of allogenic organ transplantation or active autoimmune, connective tissue disorder, or inflammatory disease requiring systemic treatment,
3. 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,
4. History of idiopathic pulmonary fibrosis, interstitial lung disease (ILD), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening (TAP-CT-scan),
5. Current systemic steroid therapy (>10 mg daily dose of prednisone or equivalent; minimal wash-out of 1 week [7 days]) or immunosuppressive therapy,
6. 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,
7. 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), Note: Local surgery of isolated lesions for palliative intent is acceptable,
8. Uncontrolled central nervous system metastases and/or carcinomatous meningitis,
9. Uncontrolled massive pleural effusion or massive ascites,
10. 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,
11. 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,
12. QT/QTc interval >470 ms (for women) and > 450 ms (for men), previous ventricular arrhythmia, known or suspected long-QT syndrome, Note: Caution is required when using medicinal products with human thymidine kinase substrates, e.g. zidovudine and other drugs known to prolong the QTc interval (exhaustive list on https: //www.crediblemeds.org.")
13. Known or suspected allergy or hypersensitivity to any of the study drugs or any of the study drug excipients,
14. 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), Note: Patients with past HBV infection or resolved HBV infection (defined as having a negative HbsAg test and a positive hepatitis B core antigen [HBc] antibody test) are eligible; patients with previously treated and cured HCV infection (negative RNA) are also eligible,
15. Live vaccine administration within 4 weeks (30 days) prior to the first dose of study treatment,
16. Pregnancy/breast-feeding/lactation,
17. 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 18. Any unresolved NCI CTCAE toxicity of grade ≥ 2 from previous anticancer therapy (including peripheral neuropathy of grade ≥ 1) except for alopecia or vitiligo, 19. Any previous chemotherapy for advanced disease, 20. Uncontrolled central nervous system metastases and/or carcinomatous meningitis, 21. Peripheral neuropathy with functional discomfort > grade 2, 22. Clinically significant active heart disease or myocardial infarction within 6 months given the cardiotoxicity of 5-FU, 23. Abnormal values of potassium, magnesium, and calcium levels at inclusion, 24. Patients with known homozygous UGT1A1*28 (Gilbert's disease), 25. 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), 26. Brivudine-based treatment within 4 weeks preceding treatment initiation. STEP 2 18. Antibiotics use in the month before the day of treatment initiation or for > 5 days within 3 months before the day of treatment initiation, 19. Previous gemcitabine-based chemotherapy, 20. Known previous colonization or infection with K. pneumoniae resistant to quinolones, 21. Prophylactic phenytoin within 1 week (7 days) prior to the first dose of study treatment, 22. Any contra-indication to ciprofloxacin: history of fluoroquinolone-related severe side effects (muscle, tendons, joint…), severe aortic disease (aneurysm, dissection), myasthenia, epilepsy, 23. Inability to take oral treatment, 24. Concomitant medication with CYP1A2 substrates (e.g., theophylline, clozapine, duloxetine, tizanidine, olanzapine, propranolol, amitryptilin, and methotrexate, 25. Known glucose-6-phosphate dehydrogenase deficiency.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: STEP 1 - Experimental Arm 1A : First-line NALIRIFOX with LV5FU2 [5-FU/leucovorin] maintenance); NALIRIFOX (NAL-IRI + 5FU/LV + oxaliplatin; 8 cycles) followed by LV5FU2 maintenance administered every 14 days (2 weeks) followed by NALIRIFOX reintroduction (for maximum 8 cycles) followed by LV5FU2 maintenance	Drug: Nal-IRI; NAL-IRI 50 mg/m2, administered over 80-100 minutes, on day 1 of a 14-days cycle; Other Names: iposomal irinotecan; Drug: Oxaliplatin; 60 mg/m2 (starting 2 hours later, administered over 110-130 minutes) on day 1; Drug: Leucovorin; As part of NALIRIFOX -for 8 cycle treatment: (L + D racemic form) 400 mg/m2 on day 1 (equivalent to 200 mg/m2 levoleucovorin) (starting 30 minutes after oxaliplatin, administered over 25-35 minutes) As part of LV5FU2 maintenance treatment: 400 mg/m2 IV infusion over 30 min on day 1 (equivalent to 200 mg/m2 levoleucovorin). LV could be administered over 2 hours to oxaliplatin according to The National Thesaurus of Digestive Oncology (TNCD) https://www.snfge.org/sites/www.snfge.org/files/tncd/2024-05/tncd_chap-09-cancer-pancre%CC%81as_2024-05-17_1.pdf, at investigator's discretion; Drug: 5-Fluorouracil; As part of NALIRIFOX -for 8 cycle treatment: 2400 mg/m² IV initiated on day 1, with continuous infusion over 46 hours (no bolus infusion with 5-FU) As part of LV5FU2 maintenance treatment: 400 mg/m2 bolus over 10 min then 2,400 mg/m2 IV infusion over 46h
Active Comparator: STEP 1 - Arm 1B: NALIRIFOX; NALIRIFOX until disease progression or unacceptable toxicity	Drug: Nal-IRI; NAL-IRI 50 mg/m2, administered over 80-100 minutes, on day 1 of a 14-days cycle; Other Names: iposomal irinotecan; Drug: Oxaliplatin; 60 mg/m2 (starting 2 hours later, administered over 110-130 minutes) on day 1; Drug: Leucovorin; As part of NALIRIFOX -for 8 cycle treatment: (L + D racemic form) 400 mg/m2 on day 1 (equivalent to 200 mg/m2 levoleucovorin) (starting 30 minutes after oxaliplatin, administered over 25-35 minutes) As part of LV5FU2 maintenance treatment: 400 mg/m2 IV infusion over 30 min on day 1 (equivalent to 200 mg/m2 levoleucovorin). LV could be administered over 2 hours to oxaliplatin according to The National Thesaurus of Digestive Oncology (TNCD) https://www.snfge.org/sites/www.snfge.org/files/tncd/2024-05/tncd_chap-09-cancer-pancre%CC%81as_2024-05-17_1.pdf, at investigator's discretion; Drug: 5-Fluorouracil; As part of NALIRIFOX -for 8 cycle treatment: 2400 mg/m² IV initiated on day 1, with continuous infusion over 46 hours (no bolus infusion with 5-FU) As part of LV5FU2 maintenance treatment: 400 mg/m2 bolus over 10 min then 2,400 mg/m2 IV infusion over 46h
Experimental: STEP 2 - Arm 2A: Gemcitabine +/- paclitaxel + ciprofloxacin; Gemcitabine: 1,000 mg/m2 intravenously (IV) over 30 minutes weekly on days 1, 8, 15 of each 28-days cycle. +/- Paclitaxel 80 mg/m2 weekly on days 1, 8, 15 of each 28-days cycle (at the discretion of investigator). Ciprofloxacin (6 capsules/cycle, withhold if gemcitabine is not administered): 500 mg twice daily (morning and evening; 12 hours should elapse between two doses) on days 1, 8, 15 (on day of gemcitabine infusion) for a maximum of 6 months.	Drug: Ciprofloxacin; 6 capsules/cycle : 500 mg twice daily on days 1, 8, 15 (on day of gemcitabine infusion) for a maximum of 6 months; Drug: Paclitaxel; 80 mg/m2 weekly on days 1, 8, 15 of each 28-days cycle (at the discretion of investigator); Drug: Gemcitabine; 1,000 mg/m2 intravenously (IV) over 30 minutes weekly on days 1, 8, 15 of each 28-days cycle
Active Comparator: STEP 2 - Arm 2B: Gemcitabine +/- paclitaxel + placebo; Gemcitabine: 1,000 mg/m2 intravenously (IV) over 30 minutes weekly on days 1, 8, 15 of each 28-days cycle. +/- Paclitaxel 80 mg/m2 weekly on days 1, 8, 15 of each 28-days cycle (at the discretion of investigator). Placebo (6 capsules/cycle, withhold if gemcitabine is not administered): 500 mg twice daily (morning and evening; 12 hours should elapse between two doses) on days 1, 8, 15 (on day of gemcitabine infusion) for a maximum of 6 months.	Drug: Paclitaxel; 80 mg/m2 weekly on days 1, 8, 15 of each 28-days cycle (at the discretion of investigator); Drug: Gemcitabine; 1,000 mg/m2 intravenously (IV) over 30 minutes weekly on days 1, 8, 15 of each 28-days cycle; Other: Placebo; 6 capsules/cycle : 500 mg twice daily (morning and evening; 12 hours should elapse between two doses) on days 1, 8, 15 (on day of gemcitabine infusion) for a maximum of 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-month progression-free survival (PFS) rate post randomization Step 1 (R1) in Arm 1A	To assess the efficacy of a 6-month PFS rate post R1 in patients with metastatic PDAC who received first-line (L1) NALIRIFOX with LV5FU2 (5-FU/leucovorin) maintenance strategy during Step 1 (Arm 1A).	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival first-line (PFS-L1) post randomization Step 1 (R1) in Arm 1A and in Arm 1B	To assess PFS-L1 post R1 in Arm 1A and Arm 1B	up to 5 years
Progression-free survival (PFS) post NALIRIFOX reintroduction (PFS-reintro) in Arm 1A	To assess PFS-reintro in Arm 1A	up to 5 years
Overall survival post randomization Step 1 (OS-R1) in Arm 1A and in Arm 1B	To assess OS-R1 in Arm 1A and Arm 1B	up to 5 years
Overall response rate of first-line (ORR-L1) at 4 months in Arm 1A and in Arm 1B	To assess ORR-L1 at 4 months in Arm 1A and Arm 1B, according to RECIST 1.1	4 months
Overall response rate post NALIRIFOX reintroduction (ORR-RI) in Arm 1A	To assess ORR-RI in Arm 1A	up to 5 years
Best response rate of first-line (BRR-L1) in Arm 1A and in Arm 1B	To assess BRR-L1 in Arm 1A and Arm 1B	up to 5 years
Best response rate of first-line after reintroduction of NALIRIFOX (BRR-L1R) in Arm 1A	To assess BRR-L1R in Arm 1A	up to 5 years
Duration of disease control (DDC) in Arm 1A and in Arm 1B	To assess DDC in Arm 1A and in Arm 1B	up to 5 years
Grade 3-4 adverse events (AEs)/serious AEs (SAEs) related to treatment	To assess safety (only grade 3-4 AEs/SAEs related to treatment in Arm 1A and Arm 1B, according to the NCI CTCAE v5.0	until 28 days after end of treatment visit
Rate of peripheral neuropathy in Arm 1A and Arm 1B	To assess the rate of peripheral neuropathy (all grade and severe [grade 3-5] adverse events [AEs] in Arm 1A and Arm 1B, according to NCI CTCAE v5.0	up to 5 years
6-month progression-free survival (PFS) post randomization (R1) of standard NALIRIFOX in Arm 1B	To assess a 6-month PFS post R1 of standard NALIRIFOX in Arm 1B	6 months
Health-related quality of life (HRQoL) by EORTC QLQ-C3 in Arm 1A and in Arm 1B	To assess HRQoL in Arm 1A and Arm 1B using EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is a 30-item, tumor-specific, patient-based questionnaire designed for self-administration. The form scores range from 0 to 100. Higher scores indicated worse symptomatic problems.	up to 5 years
Health-related quality of life (HRQoL) by EORTC QLQ-PAN26 in Arm 1A and in Arm 1B	To assess HRQoL in Arm 1A and Arm 1B using EORTC QLQ-PAN26 questionnaire. The EORTC QLQ-PAN26 is a module specific to pancreatic cancer, to be used in conjunction to the EORTC QLQ-C30. It contains 26 items. As for the EORTC QLQ-C30, one score is generated for each item, in order that a high score represents a high functional level and a high symptomatic level. Estimated duration: 10 min.	up to 5 years

Collaborators and Investigators

• Sponsor: GERCOR - Multidisciplinary Oncology Cooperative Group
• Collaborators: Servier
• Investigators: Principal Investigator: Cindy NEUZILLET, MD, Institute Curie, Versailles Saint-Quentin University, Saint-Cloud,

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2025
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: June 11, 2025
• First Submitted That Met QC Criteria: June 11, 2025
• First Posted (Actual): June 19, 2025

Study Record Updates

• Last Update Posted (Estimated): July 1, 2025
• Last Update Submitted That Met QC Criteria: June 26, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Anti-Bacterial Agents; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Micronutrients; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Cytochrome P-450 Enzyme Inhibitors; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Protective Agents; Antidotes; Vitamin B Complex; Vitamins; Cytochrome P-450 CYP1A2 Inhibitors; Oxaliplatin; Irinotecan; Gemcitabine; Fluorouracil; Leucovorin; Paclitaxel; Ciprofloxacin
• Other Study ID Numbers: PANORAMIX G-116 PRODIGE 105

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No