Study of MM-398 With or Without 5-FU/LV, Versus 5-FU/LV in Patients With Metastatic Pancreatic Cancer (NAPOLI-1)

A Randomized, Open Label Phase 3 Study of MM-398, With or Without 5-Fluorouracil and Leucovorin, Versus 5 Fluorouracil and Leucovorin in Patients With Metastatic Pancreatic Cancer Who Have Failed Prior Gemcitabine-based Therapy

The study is an open label, randomized phase 3 study of MM-398 with or without 5-Fluorouracil (5-FU) and Leucovorin (also known as folinic acid), versus 5-FU and leucovorin in metastatic pancreatic cancer patients who have progressed on prior gemcitabine based therapy.

Study Overview

• Status: Completed
• Conditions: Metastatic Pancreatic Cancer
• Intervention / Treatment: Drug: MM-398; Drug: 5 Fluorouracil; Drug: Leucovorin

• Study Type: Interventional
• Enrollment (Actual): 417
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
  • Rosario, Argentina
  • Santa Fe, Argentina
• Australia
  • New South Wales
    • Westmead, New South Wales, Australia
  • South Australia
    • Kurralta Park, South Australia, Australia
  • Victoria
    • Boxhill, Victoria, Australia
    • Heidelberg, Victoria, Australia
    • Melbourne, Victoria, Australia
  • Western Australia
    • Nedlands, Western Australia, Australia
• Brazil
  • Belo Horizonte, Brazil
  • Ijui, Brazil
  • Passo Fundo, Brazil
  • Porto Alegre, Brazil
  • Sao Paulo, Brazil
• Canada
  • Quebec
    • Montreal, Quebec, Canada
• Czech Republic
  • Horovice, Czech Republic
  • Olomouc, Czech Republic
  • Prague, Czech Republic
  • Pribram, Czech Republic
• France
  • Bordeaux, France
  • Lille, France
  • Marseille, France
• Germany
  • Berlin, Germany
  • Jens, Germany
  • Munich, Germany
  • Ulm, Germany
• Hungary
  • Budapest, Hungary
  • Pecs, Hungary
  • Szeged, Hungary
  • Szolnok, Hungary
  • Szombathely, Hungary
• Italy
  • Castellana Grotte, Italy
  • Genova, Italy
  • Legnano, Italy
  • Naples, Italy
  • Roma, Italy
• Korea, Republic of
  • Hwasun-gun, Korea, Republic of
  • Seoul, Korea, Republic of
• South Africa
  • Port Elizabeth, South Africa
  • Pretoria, South Africa
  • Western Cape, South Africa
• Spain
  • Alicante, Spain
  • Barcelona, Spain
  • Madrid, Spain
  • Santander, Spain
  • Valencia, Spain
• Taiwan
  • Chiayi, Taiwan
  • Kaohsiung, Taiwan
  • Taiching, Taiwan
  • Tainan, Taiwan
  • Taipei, Taiwan
  • Taoyuan, Taiwan
• United Kingdom
  • Liverpool, United Kingdom
  • London, United Kingdom
  • Manchester, United Kingdom
  • Sutton, United Kingdom
• United States
  • Arizona
    • Gilbert, Arizona, United States
    • Glendale, Arizona, United States
    • Scottsdale, Arizona, United States
  • California
    • Burbank, California, United States
    • Duarte, California, United States
    • Fresno, California, United States
    • LaVerne, California, United States
    • San Luis Obispo, California, United States
  • Florida
    • Boyton Beach, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
  • Missouri
    • Kansas City, Missouri, United States
    • St Louis, Missouri, United States
  • Nevada
    • Henderson, Nevada, United States
  • New Mexico
    • Albuquerque, New Mexico, United States
  • New York
    • Buffalo, New York, United States
  • Ohio
    • Columbus, Ohio, United States
  • Oklahoma
    • Norman, Oklahoma, United States
  • South Carolina
    • Greenville, South Carolina, United States
  • Texas
    • Bedford, Texas, United States
    • Dallas, Texas, United States
    • Tyler, Texas, United States
  • Virginia
    • Fairfax, Virginia, United States
    • Norfolk, Virginia, United States

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 or cytologically confirmed adenocarcinoma of the exocrine pancreas
• Metastatic disease
• Documented disease progression after prior gemcitabine based therapy
• KPS >/= 70
• Adequate bone marrow function
• Adequate hepatic function
• Adequate renal function

Exclusion Criteria:

• Active CNS metastasis
• Clinically significant GI disorders
• Severe arterial thromboembolic events less than 6 months before inclusion
• NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure
• Active infection or uncontrolled fever
• Pregnant or breast feeding patients

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MM-398; MM-398 120 mg/m2 Q3W IV. Note: The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 120 mg/m2 dose of irinotecan hydrochloride trihydrate is equivalent to 100 mg/ m2 of irinotecan free base.	Drug: MM-398; Arm A: MM-398 120 mg/m2 IV Q3W Arm C: MM-398 80mg/m2 IV Q2W; Other Names: PEP02
Active Comparator: 5 Fluorouracil and Leucovorin IV	Drug: 5 Fluorouracil; Arm B: 5 Fluorouracil 2000 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: 5 Fluorouracil 2400 mg/m2 IV every 2 weeks; Other Names: 5-FU; Drug: Leucovorin; Arm B: Leucovorin 200 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: Leucovorin 400 mg/m2 IV every 2 weeks; Other Names: Folinic Acid
Experimental: MM-398, 5-FU and Leucovorin; MM-398 80 mg/m2, 5-FU and Leucovorin Q2W IV. Note: The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m2 dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base.	Drug: MM-398; Arm A: MM-398 120 mg/m2 IV Q3W Arm C: MM-398 80mg/m2 IV Q2W; Other Names: PEP02; Drug: 5 Fluorouracil; Arm B: 5 Fluorouracil 2000 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: 5 Fluorouracil 2400 mg/m2 IV every 2 weeks; Other Names: 5-FU; Drug: Leucovorin; Arm B: Leucovorin 200 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks Arm C: Leucovorin 400 mg/m2 IV every 2 weeks; Other Names: Folinic Acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival was the primary efficacy endpoint of the study and was defined as the time from the date of patient randomization to the date of death or the date the patient was last known to be alive. OS was summarized by Kaplan-Meier methodology for each treatment group. Pairwise treatment group comparisons were carried out using unstratified log rank analyses on the ITT population. Hazard ratio estimates are from Cox regression analysis. The comparison of Arm C is based only on patients who were randomized under the 3-arm version of the protocol. Consequently, the 5-FU+Leucovorin (Combo Therapy Comparison) group is a subset of all patients randomized to 5-FU+Leucovorin, which is the Mono Therapy Comparison control and contains patients randomized under both the 2-arm and 3-arm versions of the protocol.	From randomization to death; until the data cut off 14 Feb 2014. The maximum time in follow up was 25 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	Progression-free survival was defined as the time from the date of randomization to the date of disease progression, or death (any cause) on or prior to the clinical cutoff date, whichever occurred earlier. Participants who did not have disease progression or had not died were censored at the date of the last tumor assessment. Patients with two or more consecutive missing response assessments prior to a visit with documented progression (or death) were censored at the last date of tumor assessment when the patient was documented to be progression free. PFS was summarized using Kaplan-Meier methods. The comparison of Arm C is based only on patients who were randomized under the 3-arm version of the protocol. Consequently, the 5-FU+Leucovorin (Combo Therapy Comparison) group is a subset of all patients randomized to 5-FU+Leucovorin, which is the Mono Therapy Comparison control and contains patients randomized under both the 2-arm and 3-arm versions of the protocol.	Randomization until disease progression or death from any cause; Until the data cut off of 14 Feb 2014. The maximum time in follow up was 25 months.
Objective Response Rate	The objective response rate was a secondary efficacy endpoint of the study and was defined by the percentage of patients in the study population with a best overall response of Complete Response (CR) or Partial Response (PR) as assessed by the investigator. Best overall response was defined per RECIST (version 1.1) recorded from randomization until progression or end of study. RECIST (v 1.1) criteria does not require confirmation of response, but an additional, more stringent analysis was also conducted, with designation of CR (or PR) requiring confirmation of response at least 4 weeks following the initial assessment of CR (or PR). Stable disease (SD) required an assessment of SD at least 6 weeks after starting treatment. Subjects with insufficient data for response classification were classified as Not Evaluable for best overall response, and as a non-responder for objective response, in the ITT population. Treatment groups are as indicated for the primary outcome of OS.	Assessment every 6 weeks after initial response; Day 1 to data cut off of 14 Feb 2014; maximum time on study 25 months.
Time to Treatment Failure	Time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity or death.	Randomization to treatment discontinuation (any cause). The maximum time in follow up was 25 months
Percentage of Patients With Clinical Benefit Response	Composite measure based on patient-reported pain (per VAS), patient-reported pain medication, KPS, and weight. Clinical benefit is indicated by either: (a) improvement in pain (less pain intensity with stable or decreased pain medication; or less pain medication with stable or decreased pain intensity) with stable or improved KPS; or (b) improvement in KPS with stable or improved pain. With stable for KPS and pain, clinical benefit may be indicated with an observation of positive weight change. Clinical benefit response (CBR) was classified weekly and a patient was considered a clinical benefit responder if clinical benefit was observed and maintained over a 4 week period.	Randomization to treatment discontinuation.The maximum time in follow up was 25 months
Percentage of Patients With Tumor Marker (CA 19-9) Response	Tumor marker response (TMR) was evaluated by the change in CA19-9 serum levels. Response was defined as a decrease of 50% of CA19-9 in relation to the baseline level at least once during the treatment period.	Baseline to treatment discontinuation every 6 weeks; The maximum time in follow up was 25 months
EORTC-QLQ-C30	This patient recorded outcome consists of 15 subscales in 3 independent domains: global health-related quality of life (HRQoL), functional scales (cognitive, emotional, physical, role and social functioning), and symptom scales (appetite loss, constipation, diarrhea, dyspnea, fatigue, insomnia, nausea and vomiting, and pain). For each subscale, patients were classified as improved, worsened or stable. Improvement is indicated by achievement of subscale score at least 10% improved from baseline and maintained for at least 6 weeks. Worsened is indicated by subscale score at least 10% worse than baseline. Stable is indicated by neither improvement nor worsened. Achievement of improvement prior to worsening was classified as improvement.	Baseline to treatment discontinuation every 6 weeks; The maximum time in follow up was 25 months
Pharmacokinetic Measurements of Total Irinotecan	Plasma concentration-time data for MM-398 will be analyzed using population pharmacokinetic methods.	6 weeks after first study drug administration

Collaborators and Investigators

• Sponsor: Merrimack Pharmaceuticals
• Investigators: Study Director: Eliel Bayever, MD, Merrimack Pharmaceuticals

Publications and helpful links

General Publications

• Chen LT, Macarulla T, Blanc JF, Mirakhur B, de Jong FA, Belanger B, Bekaii-Saab T, Siveke JT. Early dose reduction/delay and the efficacy of liposomal irinotecan with fluorouracil and leucovorin in metastatic pancreatic ductal adenocarcinoma (mPDAC): A post hoc analysis of NAPOLI-1. Pancreatology. 2021 Jan;21(1):192-199. doi: 10.1016/j.pan.2020.10.029. Epub 2020 Oct 10.
• Macarulla Mercade T, Chen LT, Li CP, Siveke JT, Cunningham D, Bodoky G, Blanc JF, Lee KH, Dean A, Belanger B, Wang-Gillam A. Liposomal Irinotecan + 5-FU/LV in Metastatic Pancreatic Cancer: Subgroup Analyses of Patient, Tumor, and Previous Treatment Characteristics in the Pivotal NAPOLI-1 Trial. Pancreas. 2020 Jan;49(1):62-75. doi: 10.1097/MPA.0000000000001455. Erratum In: Pancreas. 2020 Mar;49(3):e27.
• Bang YJ, Li CP, Lee KH, Chiu CF, Park JO, Shan YS, Kim JS, Chen JS, Shim HJ, Rau KM, Choi HJ, Oh DY, Belanger B, Chen LT. Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI-1 study. Cancer Sci. 2020 Feb;111(2):513-527. doi: 10.1111/cas.14264. Epub 2019 Dec 20.
• Macarulla T, Blanc JF, Wang-Gillam A, Chen LT, Siveke JT, Mirakhur B, Chen J, de Jong FA. Liposomal irinotecan and 5-fluorouracil/leucovorin in older patients with metastatic pancreatic cancer - A subgroup analysis of the pivotal NAPOLI-1 trial. J Geriatr Oncol. 2019 May;10(3):427-435. doi: 10.1016/j.jgo.2019.02.011. Epub 2019 Mar 4.
• Wang-Gillam A, Hubner RA, Siveke JT, Von Hoff DD, Belanger B, de Jong FA, Mirakhur B, Chen LT. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors. Eur J Cancer. 2019 Feb;108:78-87. doi: 10.1016/j.ejca.2018.12.007. Epub 2019 Jan 14.
• Chen LT, Siveke JT, Wang-Gillam A, Li CP, Bodoky G, Dean AP, Shan YS, Jameson GS, Macarulla T, Lee KH, Cunningham D, Blanc JF, Chiu CF, Schwartsmann G, Braiteh FS, Mamlouk K, Belanger B, de Jong FA, Hubner RA. Survival with nal-IRI (liposomal irinotecan) plus 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in per-protocol and non-per-protocol populations of NAPOLI-1: Expanded analysis of a global phase 3 trial. Eur J Cancer. 2018 Dec;105:71-78. doi: 10.1016/j.ejca.2018.09.010. Epub 2018 Nov 8.
• Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6;387(10018):545-557. doi: 10.1016/S0140-6736(15)00986-1. Epub 2015 Nov 29. Erratum In: Lancet. 2016 Feb 6;387(10018):536.

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: December 14, 2011
• First Submitted That Met QC Criteria: December 15, 2011
• First Posted (Estimate): December 19, 2011

Study Record Updates

• Last Update Posted (Estimate): June 17, 2016
• Last Update Submitted That Met QC Criteria: June 16, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: Pancreatic cancer; Metastatic pancreatic cancer; MM-398; PEP02; Gemcitabine refractory pancreatic cancer; Second line pancreatic cancer treatment; Pancreatic cancer post gemcitabine therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Fluorouracil; Leucovorin
• Other Study ID Numbers: MM-398-07-03-01