A Study Evaluating the Efficacy of 5-FU + NALIRI and 5-FU + NALIRINOX for PDAC (NALPAC) (NALPAC)

A Non-comparative Randomized Phase 2 Study, Evaluating the Efficacy of 5-FU + NALIRI and 5-FU + NALIRINOX for Metastatic Pancreatic Ductal Adenocarcinoma (PDAC), Progressive After Gemcitabine-Abraxane or Gemcitabine Monotherapy

A non-comparative randomized phase 2 study, evaluating the efficacy of 5-FU + NALIRI and 5-FU + NALIRINOX for metastatic pancreatic ductal adenocarcinoma (PDAC), progressive after Gemcitabine-Abraxane or Gemcitabine monotherapy

Study Overview

• Status: Recruiting
• Conditions: Metastatic Pancreatic Ductal Adenocarcinoma
• Intervention / Treatment: Drug: Nanoliposomal irinotecan; Drug: 5 FU; Drug: Leucovorin; Drug: Oxaliplatin

Detailed Description

Based on the results of previous studies, the sponsor aims to assess efficacy and safety of this triplet (irinotecan, 5FU/LV and oxaliplatin) in second-line treatment in fit patients (ECOG 0-1) metastatic PDAC.

The primary objective is to assess the efficacy of NALIRINOX (= investigational arm) and NALIRI (= standard care arm) in terms of Progression-Free Survival Rate (PFSR).

As secondary objectives, the following will be evaluated in both arms:

• Safety/toxicity and tolerability profile according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.
• Progression free survival (PFS)
• Overall response rate and duration of response as assessed by imaging (RECIST 1.1) and tumor markers
• Overall survival (OS)

• Study Type: Interventional
• Enrollment (Anticipated): 134
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lina Dewever; Phone Number: +32 (0) 479 36 63 82; Email: lina.dewever@bgdo.org
• Study Contact Backup: Name: Ine De Bruyne; Phone Number: +32 (0) 478 81 04 27; Email: i.debruyne@bgdo.org

Study Locations

• Belgium
  • Antwerp, Belgium, 2650
    • Not yet recruiting
    • UZ Antwerpen
    • Contact: Sanne Wouters
    • Principal Investigator: Timon Vandamme, Prof
  • Bonheiden, Belgium
    • Recruiting
    • AZ Imelda
    • Contact: Doreen Iwens
    • Principal Investigator: Pieter-Jan Cuyle, Dr.
  • Brussels, Belgium, 1070
    • Not yet recruiting
    • ULB Erasme
    • Contact: Axelle Ghilain
    • Principal Investigator: Jean-Luc Van Laethem, Dr
  • Brussels, Belgium, 1200
    • Not yet recruiting
    • Cliniques Universitaires Saint-Luc UCL
    • Contact: Tuan Le
    • Principal Investigator: Ivan Borbath, Prof
  • Charleroi, Belgium
    • Not yet recruiting
    • Grand Hopital de Charleroi
    • Contact: Matthias Papier
    • Principal Investigator: Javier Carrasco, Dr.
  • Ghent, Belgium
    • Not yet recruiting
    • AZ Maria Middelares
    • Contact: Margaux Vansteelant
    • Principal Investigator: Els Monsaert, Dr.
  • Ghent, Belgium
    • Not yet recruiting
    • University Hospital Ghent
    • Contact: Tine Derre
    • Principal Investigator: Karen Geboes, Prof.
  • Liège, Belgium, 4000
    • Not yet recruiting
    • CHC MontLegia
    • Contact: Jocelyne Gilson
    • Principal Investigator: Ghislain Houbiers, Dr
  • Mechelen, Belgium
    • Not yet recruiting
    • Az Sint-Maarten
    • Contact: Katrien Beullens
    • Principal Investigator: Leen Mortier, Dr.
  • Mons, Belgium
    • Not yet recruiting
    • CHU Ambroise Pare
    • Contact: Mariane Blockmans
    • Principal Investigator: Marie Diaz, Dr.
  • Namur, Belgium
    • Not yet recruiting
    • CHR Namur
    • Contact: Christine Leon
    • Principal Investigator: Yeter Gokburun, Dr.
  • West-Vlaanderen
    • Brugge, West-Vlaanderen, Belgium
      • Not yet recruiting
      • AZ St-Lucas
      • Contact: Tania Maerten
      • Principal Investigator: Liesbeth Holvoet, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically proven metastatic adenocarcinoma of the pancreas
• Progression documented after gemcitabine-Abraxane, or gemcitabine monotherapy
• Signed written informed consent
• Age ≥ 18
• ECOG PS 0/1 at study entry
• Measurable disease
• Adequate renal (serum creatinine ≤ 1.5x upper reference range), liver (total bilirubin ≤ 1.5x upper reference range) and hematopoietic functions (PMN ≥ 1,5x109/L, platelets ≥ 100x109/L, hemoglobin ≥ 9g/dl)
• INR/PTT ≤ 1.5x ULN
• Life expectancy of at least 12 weeks
• Effective contraception for both male and female patients if the risk of conception exists during treatment and for one month after the last administration
• Peripheral Neuropathy < grade 2

Exclusion Criteria:

• Uncontrolled concurrent CNS, cardiac, infectious diseases, hypertension
• History of myocardial infarction, deep venous or arterial thrombosis, CVA during the last 6 months
• Known hypersensitivity to any of the components, including excipients, of study treatments
• Previous malignancy in the last past 3 years except basal cell cancer of the skin or preinvasive cancer of the cervix or carcinoma in situ of any type
• Pregnancy or breast feeding
• Medical or psychological conditions that would not permit the patient to complete the study or sign inform consent
• Unstable angina, congestive heart failure ≥NYHA class II
• Uncontrolled hypertension despite optimal management (systolic blood pressure >150 mmHg or diastolic pressure > 90mmHg)
• HIV infection
• Complete DPD deficiency
• Liver failure, cirrhosis Child Pugh B or C
• Active chronic hepatitis B or C with a need for antiviral treatment
• Brain metastasis
• Major surgery, open biopsy or significant traumatic injury within 4 weeks prior to the first dose of treatment
• History of organ allograft
• Ongoing uncontrolled, serious infection
• Renal failure requiring dialysis
• Patients receiving or having received any investigational treatment within 4 weeks prior to study entry, or participating to another clinical study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A NALIRI; Cycle length: 14 days Day 1: Leucovorin: 400 mg/m² IV - Dilute in 250 mL DSW and administer over two hours; Liposomal irinotecan (FBE): 70 mg/m² IV* - Dilute in 500 mL DSW and administer over 90 min; 5 FU: 2400 mg/m² IV - Dilute in 500 to 1000 mL 0,9% NS of DSW and administer as a continuous IV infusion over 46 hours. To accommodate an ambulatory pump for outpatient treatment can be administered undiluted (50 mg/mL) or the total dose diluted in 100 to 150 mL NS.Patients who are known to be homozygous for UGT1A1*28 should start treatment with 50 mg/m2 ONIVYDE. If they do not encounter drug related toxicities during the first cycle of therapy (started at a reduced dose of 50 mg/m2), they may have the dose of ONIVYDE increased to a dose of 70 mg/m2 in subsequent cycles based on individual patient tolerance.	Drug: Nanoliposomal irinotecan; In the control arm (Naliri) a dose of 70mg/m² is administered in combination with 5FU and leucovorin In the investigational arm (Nalirinox) a dose of 50mg/m² is administered in combination with 5FU, leucovorin and oxaliplatin; Other Names: Onyvide; Drug: 5 FU; In the control arm (Naliri) a dose of 2400 mg/m² is administered in combination with nanoliposomal irinotecan and leucovorin In the investigational arm (Nalirinox) a dose of 2400 mg/m² is administered in combination with nanoliposomal irinotecan, leucovorin and oxaliplatin; Other Names: Fluorouracil; Drug: Leucovorin; In the control arm (Naliri) a dose of 400 mg/m² is administered in combination with nanoliposomal irinotecan and 5FU In the investigational arm (Nalirinox) a dose of 400 mg/m² is administered in combination with nanoliposomal irinotecan, 5FU and oxaliplatin; Other Names: Folinate; Elvorine
Experimental: Arm B NALIRINOX; Cycle length: 14 days Day 1: Oxaliplatin 60 mg IV - Dilute in 500 mL D5W and administer over two hours (prior to leucovorin). Shorter oxaliplatin administration schedules (eg. 1mg/m2 per minute) appear to be safe.; Leucovorin: 400 mg/m² IV - Dilute in 250 mL DSW and administer over two hours (after oxaliplatin); Nanoliposomal irinotecan (FBE): 50 mg/m² IV - Dilute in 500 mL D5W and administer over 90 min; 5 FU: 2400 mg/m² IV - Dilute in 500 to 1000 mL 0,9% NS of DSW and administer as a continuous IV infusion over 46 hours. To accommodate an ambulatory pump for outpatient treatment can be administered undiluted (50 mg/mL) or the total dose diluted in 100 to 150 mL NS.	Drug: Nanoliposomal irinotecan; In the control arm (Naliri) a dose of 70mg/m² is administered in combination with 5FU and leucovorin In the investigational arm (Nalirinox) a dose of 50mg/m² is administered in combination with 5FU, leucovorin and oxaliplatin; Other Names: Onyvide; Drug: 5 FU; In the control arm (Naliri) a dose of 2400 mg/m² is administered in combination with nanoliposomal irinotecan and leucovorin In the investigational arm (Nalirinox) a dose of 2400 mg/m² is administered in combination with nanoliposomal irinotecan, leucovorin and oxaliplatin; Other Names: Fluorouracil; Drug: Leucovorin; In the control arm (Naliri) a dose of 400 mg/m² is administered in combination with nanoliposomal irinotecan and 5FU In the investigational arm (Nalirinox) a dose of 400 mg/m² is administered in combination with nanoliposomal irinotecan, 5FU and oxaliplatin; Other Names: Folinate; Elvorine; Drug: Oxaliplatin; Only administered in the investigational arm (Nalirinox): a dose of 60 mg/m² is administered in combination with nanoliposomal irinotecan, 5FU and Leucovorin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of NALIRINOX and NALIRI through Progression-Free Survival at D85	NALIRINOX is the investigational arm and NALIRI is the standard care arm. The efficacy will be assessed in terms of the Progression-Free Survival Rate (PFSR). This is defined as the proportion of patients alive and free of progression at day 85.	at day 85 from randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety/toxicity and tolerability profil: Severety of adverse events	Adverse events and Serious Adverse events will be assessed during the study treatment and until 14 days later. Severety will be graded according to the NCI-CTCAE version 5.0 and relationship to the study medication will be defined.	until 14 days after End of Treatment
Safety/toxicity and tolerability profil: Laboratory assessments	Standard laboratory safety assessments: They are mandatory prior to each administration of study medication and at the 15 days follow-up visit. Clinically significant vs not clinically significant.	until 14 days after End of Treatment
Safety/toxicity and tolerability profil: ECOG	WHO ECOG performance status (PS) will be defined prior to each administration of study medication and at the 15 days follow-up visit following the ECOG Performance Status Scale.	until 14 days after End of Treatment
Safety/toxicity and tolerability profil: review of body systems	A full review of body systems will be performed: heart rate, blood pressure, respiratory rate, body temperature, height, weight and ECG (screening visit only, unless clinically indicated). Clinically significant versus not clinically significant	until 14 days after End of Treatment
Progression Free Survival and sensitivity analysis: Effect of Center on prognostic factors	The effect of potential prognostic factors will be assessed through sensitivity analyses, including: Investigational Center	From date of first study treatment administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years after End of Treatment.
Progression Free Survival and sensitivity analysis: Effect of tumor location on prognostic factors	The effect of potential prognostic factors will be assessed through sensitivity analyses, including: Location of tumor (head of the pancreas versus other location)	From date of first study treatment administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years after End of Treatment
Progression Free Survival and sensitivity analysis: Effect of previous chemotherapy on prognostic factors	The effect of potential prognostic factors will be assessed through sensitivity analyses, including: Previous chemotherapy: gemcitabine alone vs gem-abx	From date of first study treatment administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years after End of Treatment
Progression Free Survival and sensitivity analysis: effect of ECOG on prognostic factors	The effect of potential prognostic factors will be assessed through sensitivity analyses, including: WHO ECOG performance status (0 versus 1)	From date of first study treatment administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years after End of Treatment
Objective tumor response: Rate of complete response and partial response	Tumor (response) evaluation will be performed according to RECIST criteria v. 1.1 (CT scan thorax, abdomen and pelvis or MRI abdomen and pelvis + CT chest) based upon the investigator's assessment. Overall response is defined as a best response of either CR or PR (CR+PR).	performed within 28 days before start therapy, 3 times every 6 weeks and afterwards every 8 weeks
Duration of overall survival	For patients who are still alive at the time of study analysis or who are lost to follow up, survival will be censored at the last recorded date that the patient is known to be alive or at the date of data cut-off, whatever occurs earlier.	Time from Day 1 of therapy to death until maximum 5 years after End of Treatment
Duration of disease control	Disease control is defined as a best response of either CR, PR, or SD (CR+PR+SD).	From date of first study treatment administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years after End of Treatment
Duration of response	The duration of response will be censored on the date of last known tumor assessment for not progressed patients lost to follow up or deceased prior to the next planned tumor assessment (within 60 days). Not evaluable patients at one time point assessment will be censored at the date of last known assessment.	Time from measurement criteria are first met for CR/PR to either the first time disease progression is documented or death (for not progressed patients who deceased within 60 days from last tumor assessment) until maximum 5 years after EOT

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory lab investigation for potential prognostic and predictive biomarkers on blood and tumor samples	Translational research will be performed for potential prognostic and predictive biomarkers. For that purpose, plasma samples will be kept in the selected centres' biobanks. The translational research will be carried out on tumor samples collected before the start of treatment and on blood samples collected as per below. Tumor tissue: 10 slices of the paraffin embedded tissue collected during the diagnosis of the disease will be collected. Blood samples: Two 10 ml blood samples from each patient who consents to participate in the biological study will be collected before the start of the treatment, and before each cycle till the discontinuation of the treatment. The exact measurements that will be done, have not been defined yet.	Sapmples will be collected throughout the study and shipped to the sponsor maximum 1 year after last 15 day follow-up visit

Collaborators and Investigators

• Sponsor: Belgian Group of Digestive Oncology
• Collaborators: University Hospital St Luc, Brussels
• Investigators: Principal Investigator: Ivan Borbath, University hospital St-luc, Brussel

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2022
• Primary Completion (Anticipated): June 30, 2025
• Study Completion (Anticipated): December 31, 2027

Study Registration Dates

• First Submitted: December 9, 2021
• First Submitted That Met QC Criteria: July 22, 2022
• First Posted (Actual): July 25, 2022

Study Record Updates

• Last Update Posted (Actual): July 27, 2022
• Last Update Submitted That Met QC Criteria: July 25, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin; Irinotecan
• Other Study ID Numbers: NALPAC

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