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

NCT ID: NCT07028424

Last Updated: 2025-07-01

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 206 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-07-31
• Study Completion Date: 2030-12-31

Brief Summary

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.

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.

Conditions

PDAC - Pancreatic Ductal Adenocarcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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

Group Type: EXPERIMENTAL

Nal-IRI

Intervention Type: DRUG

NAL-IRI 50 mg/m2, administered over 80-100 minutes, on day 1 of a 14-days cycle

Oxaliplatin

Intervention Type: DRUG

60 mg/m2 (starting 2 hours later, administered over 110-130 minutes) on day 1

Leucovorin

Intervention Type: DRUG

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

5-Fluorouracil

Intervention Type: DRUG

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

STEP 1 - Arm 1B: NALIRIFOX

NALIRIFOX until disease progression or unacceptable toxicity

Group Type: ACTIVE_COMPARATOR

Nal-IRI

Intervention Type: DRUG

NAL-IRI 50 mg/m2, administered over 80-100 minutes, on day 1 of a 14-days cycle

Oxaliplatin

Intervention Type: DRUG

60 mg/m2 (starting 2 hours later, administered over 110-130 minutes) on day 1

Leucovorin

Intervention Type: DRUG

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

5-Fluorouracil

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Ciprofloxacin

Intervention Type: DRUG

6 capsules/cycle : 500 mg twice daily on days 1, 8, 15 (on day of gemcitabine infusion) for a maximum of 6 months

Paclitaxel

Intervention Type: DRUG

80 mg/m2 weekly on days 1, 8, 15 of each 28-days cycle (at the discretion of investigator)

Gemcitabine

Intervention Type: DRUG

1,000 mg/m2 intravenously (IV) over 30 minutes weekly on days 1, 8, 15 of each 28-days cycle

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.

Group Type: ACTIVE_COMPARATOR

Paclitaxel

Intervention Type: DRUG

80 mg/m2 weekly on days 1, 8, 15 of each 28-days cycle (at the discretion of investigator)

Gemcitabine

Intervention Type: DRUG

1,000 mg/m2 intravenously (IV) over 30 minutes weekly on days 1, 8, 15 of each 28-days cycle

Placebo

Intervention Type: OTHER

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

Interventions

Nal-IRI

NAL-IRI 50 mg/m2, administered over 80-100 minutes, on day 1 of a 14-days cycle

Intervention Type: 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

Intervention Type: DRUG

Paclitaxel

80 mg/m2 weekly on days 1, 8, 15 of each 28-days cycle (at the discretion of investigator)

Intervention Type: DRUG

Gemcitabine

1,000 mg/m2 intravenously (IV) over 30 minutes weekly on days 1, 8, 15 of each 28-days cycle

Intervention Type: DRUG

Oxaliplatin

60 mg/m2 (starting 2 hours later, administered over 110-130 minutes) on day 1

Intervention Type: 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

Intervention Type: 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

Intervention Type: DRUG

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

Intervention Type: OTHER

Other Intervention Names

iposomal irinotecan

Eligibility Criteria

Inclusion Criteria

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).

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

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Servier

INDUSTRY

Sponsor Role: collaborator

GERCOR - Multidisciplinary Oncology Cooperative Group

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Cindy NEUZILLET, MD

Role: PRINCIPAL_INVESTIGATOR

Institute Curie, Versailles Saint-Quentin University, Saint-Cloud,

Locations

CHU de Besançon

Besançon, , France

CHU de Grenoble

La Tronche, , France

CHU de Lille

Lille, , France

Institut Curie

Paris, , France

Pitié Salpêtrière Hospital

Paris, , France

Saint-Antoine Hospital

Paris, , France

CHU de Poitiers

Poitiers, , France

CHU de Reims

Reims, , France

Institute Curie

Saint-Cloud, , France

CHU de Saint Etienne

Saint-Etienne, , France

Hôpital d'Instruction des Armées Bégin

Saint-Mandé, , France

Paul Brousse Hospital

Villejuif, , France

Countries

France

Central Contacts

Cindy NEUZILLET, MD

Role: CONTACT

cindy.neuzillet@curie.fr

+33 (0) 1 47 11 15 15 ext. 7129

Marie-Line GARCIA LARNICOL, MD

Role: CONTACT

marie-line.garcia-larnicol@gercor.com.fr

+33 (0) 1 40 29 85 04

Facility Contacts

Anthony TURPIN, MD

Role: primary

Pauline VAFLARD, MD

Role: primary

Jean Baptiste BACHET, MD

Role: primary

David TOUGERON, MD

Role: primary

Olivier BOUCHE

Role: primary

Cindy NEUZILLET, MD

Role: primary

Nicole WILLIET, MD

Role: primary

Julie LAVOLE, MD

Role: primary

Elise COLLE, MD

Role: primary

Other Identifiers

PANORAMIX G-116 PRODIGE 105

Identifier Type: -

Identifier Source: org_study_id