Second Line Treatment With Nal-IRI and S1 in Pancreatic Cancer

Study Overview
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Brief Summary
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To determine the optimal second line treatment strategy in patients with metastatic pancreatic cancer who underwent a therapy with gemcitabine.

Detailed Description
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The 5-year survival of patients with pancreatic cancer is less than 5%. Despite improvements over the past years with the introduction of FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin and leucovorin) and gemcitabine and nab-paclitaxel, the vast majority will have disease recurrence or progression within 6 months. Single-arm phase II studies have been conducted after gemcitabine-based therapy. Randomized clinical trial data are limited in this setting, but the conclusion up to recently was that there is no superior chemotherapeutic regimen after gemcitabine failure. However, the NAPOLI trial altered the treatment landscape. In this trial, patients with metastatic pancreatic cancer that progressed after treatment with gemcitabine-based chemotherapy received liposomal irinotecan (nal-IRI) either as single agent or in combination with 5-fluorouracil/ leucovorin (5-FU/LV), or 5-FU/LV alone. Patients treated with the combination of nal-IRI plus 5-FU/LV experienced a median survival of 6.1 months versus 4.2 months for the 5-FU/LV group. Recently, two studies on the clinical use of S-1 for pancreatic cancer have been reported from Japan. In the first study, S-1 demonstrated non-inferiority to gemcitabine in overall survival (OS) for advanced pancreatic cancer. In the second study, S-1 showed superiority to adjuvant chemotherapy with gemcitabine in OS. In addition to gemcitabine, S-1 is now regarded as the key drug in the management of pancreatic cancer in Japan. Phase II studies of S-1 in patients with gemcitabine-resistant pancreatic cancer have demonstrated moderate activity with acceptable toxicity. Although there has been no confirmed evidence based on phase III trials, S-1 would be a feasible treatment option in this patient population. Objective: To determine the optimal second line treatment strategy in patients with metastatic pancreatic cancer, whereby the hypothesis is, based on studies conducted in the Asian population, that the combination of S-1 and nal-IRI will be superior compared to 5-FU/ LV and nal-IRI, in terms of progression free survival. Therefore, patients will be randomized, after the optimal dose of S-1 and nal-IRI has been determined in the run in phase, between S-1 in combination with nal-IRI and 5-FU/LV in combination with nal-IRI during the phase II part of the study.

Official Title
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A Randomized Phase II Study of Second Line Treatment With Liposomal Irinotecan and S1 Versus Liposomal Irinotecan and 5-fluorouracil in Patients With Metastatic Pancreatic Cancer Who Failed on First Line Gemcitabine-based Chemotherapy

Conditions
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Metastatic Pancreatic Cancer

Intervention / Treatment
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* Drug: S1 + Nal-IRI
* Drug: Nal-IRI+Leucovorin+5-FU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must satisfy all of the following inclusion criteria to be enrolled in the study. Able to understand and provide written informed consent ≥ 18 years of age Histologically or cytologically confirmed adenocarcinoma of pancreas Documented metastatic disease, according to RECIST 1.1. Previously treated with gemcitabine or gemcitabine containing therapy, or progression within 6 months of adjuvant gemcitabine based treatment Adequate hepatic, renal and hematological function Exclusion Criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: Serum total bilirubin ≥1.5 x ULN (biliary drainage is allowed for biliary obstruction) Severe renal impairment (CLcr ≤ 30 ml/min) Inadequate bone marrow reserves as evidenced by: ANC ≤ 1,5 x 10 9 /L; or Platelet count ≤ 100 x 10 9 /L; WHO/PS 0-1 Any clinically significant disorder impacting the risk-benefit balance negatively per physician's judgment Any clinically significant gastrointestinal disorder, including hepatic disorders, bleeding, inflammation, occlusion, or diarrhea > grade 1 Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) in last 6 months NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure. Or known abnormal ECG with clinically significant abnormal findings Active infection or an unexplained fever >38.5°C (excluding tumor fever), which in the physician's opinion might compromise the patient's health Current use or any use in last two weeks of strong CYP3A-enzyme inducers/inhibitors and/or strong UGT1A inhibitors Known hypersensitivity to any of the components of liposomal irinotecan (Nal-IRI) other liposomal irinotecan formulations, irinotecan, fluoropyrimidines, or leucovorin. Hypersensitivity to any of the active substances (tegafur, gimeracil, and oteracil) Previous treatment with fluoropyrimidine therapy Known dihydropyrimidine dehydrogenase (DPD) deficiency Breast feeding, known pregnancy, positive serum pregnancy test or unwillingness to use a reliable method of birth control, during therapy and for 3 months following the last dose of liposomal irinotecan (Nal-IRI). Treatment within 4 weeks with DPD inhibitors, including sorivudine or its chemically related analogues such as brivudine.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: S1 and liposomal irinotecan<br>S-1 will be given for 14 consecutive days, twice daily, followed by 2 weeks rest. Nal-IRI will be administered as an iv infusion on day 1 and 15. Treatment will be repeated every 4 wks. | Drug: S1 + Nal-IRI<br>* S-1 will be given for 14 consecutive days, twice daily, followed by 2 weeks rest. Nal-IRI will be administered as an intravenous infusion on day 1 and 15. Courses of treatment will be repeated every 4 weeks.<br>Drug: Nal-IRI+Leucovorin+5-FU<br>* Nal-IRI 80 mg/m2 will be administered first, followed by LV 400 mg/m2, followed by 5-FU 2400 mg/m2 as an IV infusion over 46-hours on days 1-3. Each cycle consists of 14 days. Courses of treatment will be repeated every 2 weeks.<br>|
| Experimental: Liposomal irinotecan, Leucovorin and 5-fluoracil<br>Nal-IRI 80 mg/m2 administered first, followed by LV 400 mg/m2, followed by 5-FU 2400 mg/m2 as an IV infusion over 46-hrs on days 1-3. Each cycle consists of 14 days. Treatment will be repeated every 2 wks. | Drug: Nal-IRI+Leucovorin+5-FU<br>* Nal-IRI 80 mg/m2 will be administered first, followed by LV 400 mg/m2, followed by 5-FU 2400 mg/m2 as an IV infusion over 46-hours on days 1-3. Each cycle consists of 14 days. Courses of treatment will be repeated every 2 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT of Nal-IRI with S1 | Dose limiting toxicity (DLT) of nal-IRI when co-administered with fixed dose S1 in patients with metastatic pancreatic cancer | 36 months | 
| MTD of Nal-IRI with S1 | Maximum tolerated dose (MTD) of nal-IRI when co-administered with fixed dose S1 in patients with metastatic pancreatic cancer | 36 months | 
| Progression free survival of NaI-IRI with S1 | Determination of the efficacy between the treatment arms in terms of progression free survival. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | To determine the overall survival (OS) benefit of nal-IRI combined with S-1, compared with nal-IRI combined with 5-FU/LV, in subjects pre-treated with gemcitabine based chemotherapy for metastatic pancreatic ductal adenocarcinoma. | 36 months | 
| Response rate according to RECIST 1.1 | To determine the response rate according to RECIST 1.1 of nal-IRI combined with S-1, compared with nal-IRI combined with 5-FU/LV, in subjects pre-treated with gemcitabine based chemotherapy for metastatic pancreatic ductal adenocarcinoma. | 36 months | 
| Adverse events according NCI CTC version 4.0 | To determine the adverse events according to NCI CTC version 4.0 of nal-IRI combined with S-1, compared with nal-IRI combined with 5-FU/LV, in subjects pre-treated with gemcitabine based chemotherapy for metastatic pancreatic ductal adenocarcinoma. | 36 months | 
| Quality of life QoL (QLQ-C30) | To determine Quality of life (QoL) benefit of nal-IRI combined with S-1, compared with nal-IRI combined with 5-FU/LV, in subjects pre-treated with gemcitabine based chemotherapy for metastatic pancreatic ductal adenocarcinoma using a questionnaire QLQ-C30.Scale ranges 1-4, 1 is very good, 4 is very bad. Higher values represent a worse outcome. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Second line, Liposomal irinotecan, S1, Pancreatic cancer