PDAC - Pancreatic Ductal Adenocarcinoma
Conditions
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.
Interventions
DRUGNal-IRI
NAL-IRI 50 mg/m2, administered over 80-100 minutes, on day 1 of a 14-days cycle
DRUGCiprofloxacin
6 capsules/cycle : 500 mg twice daily on days 1, 8, 15 (on day of gemcitabine infusion) for a maximum of 6 months
DRUGPaclitaxel
80 mg/m2 weekly on days 1, 8, 15 of each 28-days cycle (at the discretion of investigator)
DRUGGemcitabine
1,000 mg/m2 intravenously (IV) over 30 minutes weekly on days 1, 8, 15 of each 28-days cycle
DRUGOxaliplatin
60 mg/m2 (starting 2 hours later, administered over 110-130 minutes) on day 1
DRUGLeucovorin
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
DRUG5-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
OTHERPlacebo
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
Sponsors
Servier
GERCOR - Multidisciplinary Oncology Cooperative Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Only STEP 2 of the study is masked; a double-blinded.
Intervention model description
This is a randomized, non-comparative two-step study in patients with metastatic PDAC. STEP 1 (main objective) This is a two-arm, open-label, randomized (2:1), non-comparative single stage phase II study to assess the efficacy of 5-FU-based maintenance after NALIRIFOX initiation (Arm 1A) versus standard NALIRIFOX in patients with metastatic PDAC (Arm 1B). STEP 2 (secondary exploratory objective) This is a two-arm, double-blinded, randomized (1:1), non-comparative, two-stage phase II with ciprofloxacin + gemcitabine-based chemotherapy (gemcitabine +/- paclitaxel) regimen (Arm 2A) versus gemcitabine-based chemotherapy (gemcitabine +/- paclitaxel) regimen + placebo (Arm 2B)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6-month progression-free survival (PFS) rate post randomization Step 1 (R1) in Arm 1A | 6 months | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) post NALIRIFOX reintroduction (PFS-reintro) in Arm 1A | up to 5 years | To assess PFS-reintro in Arm 1A |
| Overall survival post randomization Step 1 (OS-R1) in Arm 1A and in Arm 1B | up to 5 years | To assess OS-R1 in Arm 1A and Arm 1B |
| Overall response rate of first-line (ORR-L1) at 4 months in Arm 1A and in Arm 1B | 4 months | To assess ORR-L1 at 4 months in Arm 1A and Arm 1B, according to RECIST 1.1 |
| Overall response rate post NALIRIFOX reintroduction (ORR-RI) in Arm 1A | up to 5 years | To assess ORR-RI in Arm 1A |
| Best response rate of first-line (BRR-L1) in Arm 1A and in Arm 1B | up to 5 years | To assess BRR-L1 in Arm 1A and Arm 1B |
| Best response rate of first-line after reintroduction of NALIRIFOX (BRR-L1R) in Arm 1A | up to 5 years | To assess BRR-L1R in Arm 1A |
| Progression-free survival first-line (PFS-L1) post randomization Step 1 (R1) in Arm 1A and in Arm 1B | up to 5 years | To assess PFS-L1 post R1 in Arm 1A and Arm 1B |
| Grade 3-4 adverse events (AEs)/serious AEs (SAEs) related to treatment | until 28 days after end of treatment visit | 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 |
| Rate of peripheral neuropathy in Arm 1A and Arm 1B | up to 5 years | 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 |
| Health-related quality of life (HRQoL) by EORTC QLQ-C3 in Arm 1A and in Arm 1B | up to 5 years | 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. |
| Health-related quality of life (HRQoL) by EORTC QLQ-PAN26 in Arm 1A and in Arm 1B | up to 5 years | 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. |
| 6-month progression-free survival (PFS) post randomization (R1) of standard NALIRIFOX in Arm 1B | 6 months | To assess a 6-month PFS post R1 of standard NALIRIFOX in Arm 1B |
| Duration of disease control (DDC) in Arm 1A and in Arm 1B | up to 5 years | To assess DDC in Arm 1A and in Arm 1B |
Countries
France
Contacts
Primary ContactCindy NEUZILLET, MD
Backup ContactMarie-Line GARCIA LARNICOL, MD
Outcome results
None listed