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

• ClinicalTrials.gov Identifier: NCT05472259
• Recruitment Status: Recruiting
• First Posted: July 25, 2022
• Last Update Posted: July 27, 2022
• Sponsor: Belgian Group of Digestive Oncology
• Collaborator: University Hospital St Luc, Brussels
• Information provided by (Responsible Party): Belgian Group of Digestive Oncology

Tracking Information

• First Submitted Date: December 9, 2021
• First Posted Date: July 25, 2022
• Last Update Posted Date: July 27, 2022
• Actual Study Start Date: May 25, 2022
• Estimated Primary Completion Date: June 30, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 22, 2022)

Efficacy of NALIRINOX and NALIRI through Progression-Free Survival at D85 [ Time Frame: at day 85 from randomization ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 25, 2022)

• Safety/toxicity and tolerability profil: Severety of adverse events [ Time Frame: until 14 days after End of Treatment ]
  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.
• Safety/toxicity and tolerability profil: Laboratory assessments [ Time Frame: until 14 days after End of Treatment ]
  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.
• Safety/toxicity and tolerability profil: ECOG [ Time Frame: until 14 days after End of Treatment ]
  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.
• Safety/toxicity and tolerability profil: review of body systems [ Time Frame: until 14 days after End of Treatment ]
  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
• Progression Free Survival and sensitivity analysis: Effect of Center on prognostic factors [ Time Frame: 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. ]
  The effect of potential prognostic factors will be assessed through sensitivity analyses, including:

  • Investigational Center
• Progression Free Survival and sensitivity analysis: Effect of tumor location on prognostic factors [ Time Frame: 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 ]
  The effect of potential prognostic factors will be assessed through sensitivity analyses, including:

  • Location of tumor (head of the pancreas versus other location)
• Progression Free Survival and sensitivity analysis: Effect of previous chemotherapy on prognostic factors [ Time Frame: 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 ]
  The effect of potential prognostic factors will be assessed through sensitivity analyses, including:

  • Previous chemotherapy: gemcitabine alone vs gem-abx
• Progression Free Survival and sensitivity analysis: effect of ECOG on prognostic factors [ Time Frame: 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 ]
  The effect of potential prognostic factors will be assessed through sensitivity analyses, including:

  • WHO ECOG performance status (0 versus 1)
• Objective tumor response: Rate of complete response and partial response [ Time Frame: performed within 28 days before start therapy, 3 times every 6 weeks and afterwards every 8 weeks ]
  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).
• Duration of overall survival [ Time Frame: Time from Day 1 of therapy to death until maximum 5 years after End of Treatment ]
  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.
• Duration of disease control [ Time Frame: 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 ]
  Disease control is defined as a best response of either CR, PR, or SD (CR+PR+SD).
• Duration of response [ Time Frame: 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 ]
  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.

Original Secondary Outcome Measures (submitted: July 22, 2022)

• Safety/toxicity and tolerability profil: Adverse events [ Time Frame: until 14 days after End of Treatment ]
  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.
• Safety/toxicity and tolerability profil: Laboratory assessments [ Time Frame: until 14 days after End of Treatment ]
  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.
• Safety/toxicity and tolerability profil: ECOG [ Time Frame: until 14 days after End of Treatment ]
  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.
• Safety/toxicity and tolerability profil:review of body systems [ Time Frame: until 14 days after End of Treatment ]
  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
• Progression Free Survival and sensitivity analysis: Center [ Time Frame: 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. ]
  The effect of potential prognostic factors will be assessed through sensitivity analyses, including:

  • Investigational Center
• Progression Free Survival and sensitivity analysis: Tumor location [ Time Frame: 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 ]
  The effect of potential prognostic factors will be assessed through sensitivity analyses, including:

  • Location of tumor (head of the pancreas versus other location)
• Progression Free Survival and sensitivity analysis: Previous chemotherapy [ Time Frame: 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 ]
  The effect of potential prognostic factors will be assessed through sensitivity analyses, including:

  • Previous chemotherapy: gemcitabine alone vs gem-abx
• Progression Free Survival and sensitivity analysis: ECOG [ Time Frame: 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 ]
  The effect of potential prognostic factors will be assessed through sensitivity analyses, including:

  • WHO ECOG performance status (0 versus 1)
• Objective tumor response [ Time Frame: performed within 28 days before start therapy, 3 times every 6 weeks and afterwards every 8 weeks ]
  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).
• Overall survival [ Time Frame: Time from Day 1 of therapy to death until maximum 5 years after End of Treatment ]
  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.
• Disease control [ Time Frame: 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 ]
  Disease control is defined as a best response of either CR, PR, or SD (CR+PR+SD).
• Duration of response [ Time Frame: 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 ]
  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.

Current Other Pre-specified Outcome Measures (submitted: July 25, 2022)

Exploratory lab investigation for potential prognostic and predictive biomarkers on blood and tumor samples [ Time Frame: Sapmples will be collected throughout the study and shipped to the sponsor maximum 1 year after last 15 day follow-up visit ]

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.

Original Other Pre-specified Outcome Measures (submitted: July 22, 2022)

Exploratory investigation for potential prognostic and predictive biomarkers on blood and tumor samples [ Time Frame: Sapmples will be collected throughout the study and shipped to the sponsor maximum 1 year after last 15 day follow-up visit ]

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.

Descriptive Information

• Brief Title: A Study Evaluating the Efficacy of 5-FU + NALIRI and 5-FU + NALIRINOX for PDAC (NALPAC)
• Official Title: 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
• Brief Summary: 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

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
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Pancreatic Ductal Adenocarcinoma

Intervention

• 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 Name: 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 Name: 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

Study Arms

• 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.
  Interventions:

  • Drug: Nanoliposomal irinotecan
  • Drug: 5 FU
  • Drug: Leucovorin
• 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.
  Interventions:

  • Drug: Nanoliposomal irinotecan
  • Drug: 5 FU
  • Drug: Leucovorin
  • Drug: Oxaliplatin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 22, 2022): 134
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2027
• Estimated Primary Completion Date: June 30, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Lina Dewever; +32 (0) 479 36 63 82; lina.dewever@bgdo.org

Contact: Ine De Bruyne; +32 (0) 478 81 04 27; i.debruyne@bgdo.org

• Listed Location Countries: Belgium

Administrative Information

• NCT Number: NCT05472259
• Other Study ID Numbers: NALPAC
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Belgian Group of Digestive Oncology
• Original Responsible Party: Same as current
• Current Study Sponsor: Belgian Group of Digestive Oncology
• Original Study Sponsor: Same as current
• Collaborators: University Hospital St Luc, Brussels

Investigators

• Principal Investigator: Ivan Borbath; University hospital St-luc, Brussel

• PRS Account: Belgian Group of Digestive Oncology
• Verification Date: July 2022