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Metastatic Pancreatic CancerPhase 3NAPOLI-1NCT01494506

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

A Phase 3 study testing MM-398, 5 Fluorouracil and Leucovorin in people with Metastatic Pancreatic Cancer, run by Merrimack Pharmaceuticals at 79 sites in 15 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Metastatic Pancreatic Cancer
What is being tested?
MM-398, 5 Fluorouracil and Leucovorin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
417 participants
Where
79 sitesin 15 countries
Study dates
Nov 2011to Oct 2015
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

79 sites in 15 countries.

79 sites in 15 countries

United States23 sites

  • Study site

    Albuquerque, New Mexico

  • Study site

    Atlanta, Georgia

  • Study site

    Bedford, Texas

  • Study site

    Boyton Beach, Florida

  • Study site

    Buffalo, New York

  • Study site

    Burbank, California

  • Study site

    Columbus, Ohio

  • Study site

    Dallas, Texas

  • Study site

    Duarte, California

  • Study site

    Fairfax, Virginia

  • Study site

    Fresno, California

  • Study site

    Gilbert, Arizona

  • Study site

    Glendale, Arizona

  • Study site

    Greenville, South Carolina

  • Study site

    Henderson, Nevada

  • Study site

    Kansas City, Missouri

  • Study site

    LaVerne, California

  • Study site

    Norfolk, Virginia

  • Study site

    Norman, Oklahoma

  • Study site

    San Luis Obispo, California

  • Study site

    Scottsdale, Arizona

  • Study site

    St Louis, Missouri

  • Study site

    Tyler, Texas

Other trials in United States

Australia6 sites

  • Study site

    Boxhill, Victoria

  • Study site

    Heidelberg, Victoria

  • Study site

    Kurralta Park, South Australia

  • Study site

    Melbourne, Victoria

  • Study site

    Nedlands, Western Australia

  • Study site

    Westmead, New South Wales

Other trials in Australia

Taiwan6 sites

  • Study site

    Chiayi City

  • Study site

    Kaohsiung City

  • Study site

    Taiching

  • Study site

    Tainan

  • Study site

    Taipei

  • Study site

    Taoyuan

Other trials in Taiwan

Brazil5 sites

  • Study site

    Belo Horizonte

  • Study site

    Ijuí

  • Study site

    Passo Fundo

  • Study site

    Porto Alegre

  • Study site

    São Paulo

Other trials in Brazil

Hungary5 sites

  • Study site

    Budapest

  • Study site

    Pécs

  • Study site

    Szeged

  • Study site

    Szolnok

  • Study site

    Szombathely

Other trials in Hungary

Italy5 sites

  • Study site

    Castellana Grotte

  • Study site

    Genova

  • Study site

    Legnano

  • Study site

    Naples

  • Study site

    Roma

Other trials in Italy

Spain5 sites

  • Study site

    Alicante

  • Study site

    Barcelona

  • Study site

    Madrid

  • Study site

    Santander

  • Study site

    Valencia

Other trials in Spain

Czechia4 sites

  • Study site

    Hořovice

  • Study site

    Olomouc

  • Study site

    Prague

  • Study site

    Příbram

Other trials in Czechia

Germany4 sites

  • Study site

    Berlin

  • Study site

    Jens

  • Study site

    Munich

  • Study site

    Ulm

Other trials in Germany

United Kingdom4 sites

  • Study site

    Liverpool

  • Study site

    London

  • Study site

    Manchester

  • Study site

    Sutton

Other trials in United Kingdom

Argentina3 sites

  • Study site

    Buenos Aires

  • Study site

    Rosario

  • Study site

    Santa Fe

Other trials in Argentina

France3 sites

  • Study site

    Bordeaux

  • Study site

    Lille

  • Study site

    Marseille

Other trials in France

South Africa3 sites

  • Study site

    Port Elizabeth

  • Study site

    Pretoria

  • Study site

    Western Cape

Other trials in South Africa

South Korea2 sites

  • Study site

    Hwasun-gun

  • Study site

    Seoul

Other trials in South Korea

Canada1 site

  • Study site

    Montreal, Quebec

Other trials in Canada

About this study

Official title: 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.

Being tested
MM-398, 5 Fluorouracil, Leucovorin
Keywords
Pancreatic cancer, MM-398, PEP02, Metastatic pancreatic cancer, Gemcitabine refractory pancreatic cancer, Second line pancreatic cancer treatment, Pancreatic cancer post gemcitabine therapy
Medical subject headings
Pancreatic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MM-398Drug

    Also called PEP02

    Arm A: MM-398 120 mg/m2 IV Q3W

    Arm C: MM-398 80mg/m2 IV Q2W

  • 5 FluorouracilDrug

    Also called 5-FU

    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

  • LeucovorinDrug

    Also called Folinic Acid

    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

Study groups in NCT01494506
Study groupRoleWhat they receive
MM-398ExperimentalMM-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.
Receives: Drug: MM-398
5 Fluorouracil and Leucovorin IVActive comparator5 Fluorouracil and Leucovorin IV
Receives: Drug: 5 Fluorouracil; Drug: Leucovorin
MM-398, 5-FU and LeucovorinExperimentalMM-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.
Receives: Drug: MM-398; Drug: 5 Fluorouracil; Drug: Leucovorin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: From randomization to death; until the data cut off 14 Feb 2014. The maximum time in follow up was 25 months.

Secondary outcomes (7)

  1. 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.

    Measured: 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.

  2. 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.

    Measured: Assessment every 6 weeks after initial response; Day 1 to data cut off of 14 Feb 2014; maximum time on study 25 months.

  3. Time to Treatment Failure

    Time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity or death.

    Measured: Randomization to treatment discontinuation (any cause). The maximum time in follow up was 25 months

  4. 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.

    Measured: Randomization to treatment discontinuation.The maximum time in follow up was 25 months

  5. 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.

    Measured: Baseline to treatment discontinuation every 6 weeks; The maximum time in follow up was 25 months

  6. 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.

    Measured: Baseline to treatment discontinuation every 6 weeks; The maximum time in follow up was 25 months

  7. Pharmacokinetic Measurements of Total Irinotecan

    Plasma concentration-time data for MM-398 will be analyzed using population pharmacokinetic methods.

    Measured: 6 weeks after first study drug administration

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Dec 2011 (estimated)
  2. Study startNov 2011
  3. Primary completionFeb 2014
  4. Study completionOct 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
417 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01494506
Sponsor's protocol ID
MM-398-07-03-01
Acronym
NAPOLI-1
Status last verified
Jun 2016
First submitted
14 Dec 2011
Last updated
17 Jun 2016
Data monitoring committee
Yes

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.

    PubMed 33214082

  • 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.

    PubMed 31856081

  • 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.

    PubMed 31789476

  • 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.

    PubMed 30842038

  • 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.

    PubMed 30654298

  • 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.

    PubMed 30414528

  • 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.

    PubMed 26615328

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing MM-398, 5 Fluorouracil and Leucovorin in people with Metastatic Pancreatic Cancer, run by Merrimack Pharmaceuticals at 79 sites in 15 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 17 Jun 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 79 sites in United States, Australia, Taiwan, Brazil, Hungary and 10 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 12 Feb 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Survival (time frame: From randomization to death; until the data cut off 14 Feb 2014. The maximum time in follow up was 25 months.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01494506, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jun 2016.

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