Metastatic Adenocarcinoma of the Pancreas
Conditions
Brief summary
The purpose of this study is to look at the efficacy and safety of Irinotecan liposome injection in combination with other approved drugs used for cancer therapy, namely 5 fluorouracil/leucovorin (5FU/LV) plus oxaliplatin compared to nab-paclitaxel + gemcitabine treatment in improving the overall survival of patients not previously treated for metastatic pancreatic cancer.
Interventions
Irinotecan liposome injection is irinotecan in the form of the sucrosofate salt, encapsulated in liposomes for i.v. infusion. It is supplied in sterile, single-use vials containing 10 mL of irinotecan liposome injection at a concentration of 4.3 mg/mL free base equivalent (FBE).
DRUGOxaliplatin
Oxaliplatin injection, USP is supplied in single-dose vials containing 50 mg, 100 mg or 200 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL.
DRUG5Fluorouracil
Fluorouracil injection, USP is a colorless to faint yellow, aqueous, sterile, nonpyrogenic injectable solution available in 50 mL and 100 mL pharmacy bulk package. Each mL contains 50 mg fluorouracil in water for injection, USP.
DRUGLeucovorin
Leucovorin Calcium for Injection is supplied in vials ranging from 50-500 mg and available as an injectable solution or lyophilized powder for reconstitution.
DRUGNab-paclitaxel
Nab-paclitaxel is a lyophilised powder containing 100 or 250 mg of paclitaxel formulated as albumin-bound particles in single-use vials for re-constitution. Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel.
DRUGGemcitabine
Gemcitabine for injection is a lyophilised powder for solution for infusion, with each single use vial containing 200 mg, 1 g or 2 g of gemcitabine.
Sponsors
Ipsen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histological or cytologically confirmed adenocarcinoma of the pancreas that has not been previously treated in the metastatic setting. * Initial diagnosis of metastatic disease must have occurred ≤6 weeks prior to screening. * Subject has one or more metastatic lesions measurable by computed tomography (CT) scan (or magnetic resonance imaging (MRI), if the subject is allergic to CT contrast media) according to RECIST Version 1.1 criteria. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Subject has adequate biological parameters as demonstrated by the following blood counts:(a) Absolute neutrophil count (ANC) ≥2000/mm3 without the use of hemopoietic growth factors within the last 7 days prior to randomisation (b) Platelet count ≥100,000/mm3 (c) Haemoglobin (Hgb) ≥9 g/dL obtained ≤14 days prior to randomisation. * Adequate hepatic function as evidenced by: (a) Serum total bilirubin ≤1.5x ULN (biliary drainage is allowed for biliary obstruction), and (b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x upper limit of normal (ULN) (≤5x ULN is acceptable if liver metastases are present). * Adequate renal function as evidenced by creatinine clearance ≥30 mL/min. * Adequate coagulation studies (obtained ≤14 days prior to randomisation) as demonstrated by prothrombin time and partial thromboplastin time within normal limits (≤1.5xULN ).
Exclusion criteria
* Prior treatment of pancreatic cancer in the metastatic setting with surgery, radiotherapy, chemotherapy or investigational therapy * Prior treatment of pancreatic adenocarcinoma with chemotherapy in the adjuvant setting, except those where at least 12 months have elapsed since completion of the last dose and no persistent treatment-related toxicities are present. * Subject has only localised advanced disease. * Documented serum albumin \<3 g/dL * Known history of central nervous system (CNS) metastases. * Clinically significant gastrointestinal disorder * History of any second malignancy in the last 2 years * Concurrent illnesses that would be a relative contraindication to trial participation * Use of strong inhibitors or inducers of CYP3A, CYP2C8 and UGT1A1 * Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma * Known low or absent dihydropyrimidine dehydrogenase (DPD) activity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, end of treatment (EoT) visit, then every 2 months thereafter up to primary completion date (PCD) of 23 July 2022 (maximum of 893 days) | The OS was defined as time from the date of randomization to the date of death due to any cause. Participants who did not have a date of death recorded at the time of the final analysis were censored at the last known time that the participant was alive. The median OS was measured using Kaplan-Meier technique. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose up to PCD of 23 July 2022 (maximum of 893 days) | PFS was defined as the time from the date of randomization to the first documented disease progression using response evaluation criteria in solid tumors (RECIST) Version 1.1 as per Investigator assessment or death due to any cause. The median PFS was measured using Kaplan-Meier technique. |
| Overall Response Rate (ORR) | Assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose up to PCD of 23 July 2022, (maximum of 893 days) | The ORR was defined as the percentage of participants with a best overall response (BOR) characterized as either a complete response (CR) or partial response (PR) per RECIST Version 1.1. BOR was defined as the best response as recorded from randomization until documented objective disease progression using RECIST Version 1.1. As per RECIST version 1.1, CR is disappearance of all target lesions; PR is \>=30% decrease in the sum of the longest diameter of target lesions; and overall response = CR + PR. The ORR was calculated using Clopper-Pearson method. |
Countries
Australia, Austria, Belgium, Brazil, Canada, Czechia, France, Germany, Greece, Hungary, Israel, Italy, Portugal, Russia, South Korea, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORIpsen Medical Director
Ipsen
Participant flow
Recruitment details
This Phase 3, open-label study was conducted in participants with metastatic adenocarcinoma of the pancreas at 187 investigational sites in 18 countries (Australia, Brazil, Canada, Israel, Republic of Korea, United States, Austria, Belgium, Czechia, France, Germany, Greece, Hungary, Italy, Portugal, Spain, United Kingdom, and Russia) between 11 February 2020 and 18 February 2025.
Pre-assignment details
This study consisted of a screening period (up to 28 days), treatment period (28-day cycles of treatment until radiologically determined disease progression per response evaluation criteria in solid tumors \[RECIST 1.1\]), unacceptable study medication related toxicity or withdrawal from study treatment followed by survival follow-up (until death or study closure, whichever occurred first). A total of 770 participants were randomized in 1:1 ratio using an interactive web response system (IWRS).
Participants by arm
| Arm | Count |
|---|---|
| NALIRIFOX Participants were treated with irinotecan liposome injection 50 mg/m\^2 followed by oxaliplatin 60 mg/m\^2, followed by LV 400 mg/m\^2 and then 5-FU 2400 mg/m\^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent. | 383 |
| Nab-paclitaxel+Gemcitabine Participants were treated with nab-paclitaxel 125 mg/m\^2 followed by gemcitabine 1000 mg/m\^2 IV on Days 1, 8 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent. | 387 |
| Total | 770 |
Baseline characteristics
| Characteristic | NALIRIFOX | Nab-paclitaxel+Gemcitabine | Total |
|---|---|---|---|
| Age, Continuous | 62.8 years STANDARD_DEVIATION 9.71 | 64.0 years STANDARD_DEVIATION 8.34 | 63.4 years STANDARD_DEVIATION 9.06 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 49 Participants | 30 Participants | 79 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 305 Participants | 328 Participants | 633 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 29 Participants | 29 Participants | 58 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 20 Participants | 18 Participants | 38 Participants |
| Race/Ethnicity, Customized Black or African American | 12 Participants | 7 Participants | 19 Participants |
| Race/Ethnicity, Customized Multiple | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 26 Participants | 29 Participants | 55 Participants |
| Race/Ethnicity, Customized Other | 7 Participants | 6 Participants | 13 Participants |
| Race/Ethnicity, Customized White | 315 Participants | 324 Participants | 639 Participants |
| Sex: Female, Male Female | 179 Participants | 157 Participants | 336 Participants |
| Sex: Female, Male Male | 204 Participants | 230 Participants | 434 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 345 / 370 | 359 / 379 |
| other Total, other adverse events | 364 / 370 | 371 / 379 |
| serious Total, serious adverse events | 207 / 370 | 198 / 379 |
Outcome results
Primary
Overall Survival (OS)
The OS was defined as time from the date of randomization to the date of death due to any cause. Participants who did not have a date of death recorded at the time of the final analysis were censored at the last known time that the participant was alive. The median OS was measured using Kaplan-Meier technique.
Time frame: Assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, end of treatment (EoT) visit, then every 2 months thereafter up to DCO date of 23 July 2022 (maximum of 893 days)
Population: The ITT population consisted of all randomized participants to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NALIRIFOX | Overall Survival (OS) | 11.1 months |
| Nab-paclitaxel+Gemcitabine | Overall Survival (OS) | 9.2 months |
p-value: 0.0495% CI: [0.7, 0.99]Stratified log-rank test
Secondary
Overall Response Rate (ORR)
The ORR was defined as the percentage of participants with a best overall response (BOR) characterized as either a complete response (CR) or partial response (PR) per RECIST Version 1.1. BOR was defined as the best response as recorded from randomization until documented objective disease progression using RECIST Version 1.1. As per RECIST version 1.1, CR is disappearance of all target lesions; PR is \>=30% decrease in the sum of the longest diameter of target lesions; and overall response = CR + PR. The ORR was calculated using Clopper-Pearson method.
Time frame: Assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose until EoT visit, (maximum of 893 days)
Population: The ITT population consisted of all randomized participants to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NALIRIFOX | Overall Response Rate (ORR) | 41.8 percentage of participants |
| Nab-paclitaxel+Gemcitabine | Overall Response Rate (ORR) | 36.2 percentage of participants |
p-value: 0.1195% CI: [0.95, 1.69]Cochran-Mantel-Haenszel
Secondary
Progression Free Survival (PFS)
PFS was defined as the time from the date of randomization to the first documented disease progression using response evaluation criteria in solid tumors (RECIST) Version 1.1 as per Investigator assessment or death due to any cause. The median PFS was measured using Kaplan-Meier technique.
Time frame: Assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose until EoT visit (maximum of 893 days)
Population: The ITT population consisted of all randomized participants to whom study treatment was assigned by randomization. Only participants with PFS event are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NALIRIFOX | Progression Free Survival (PFS) | 7.4 months |
| Nab-paclitaxel+Gemcitabine | Progression Free Survival (PFS) | 5.6 months |
p-value: <0.000195% CI: [0.58, 0.83]Stratified log-rank test