Clinical Trials Register

Summary
EudraCT Number:	2011-004687-30
Sponsor's Protocol Code Number:	MM-398-07-03-01
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-12-27
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2011-004687-30

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study of MM-398 with or without 5-Fluorouracil and Leucovorin
compared with 5- Fluorouracil and Leucovorin in Patients with advanced
pancreatic cancer who were previously treated unsuccessfully with a
gemcitabine-based therapy.

A.3.2

Name or abbreviated title of the trial where available

NAPOLI 1

A.4.1

Sponsor's protocol code number

MM-398-07-03-01

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Merrimack Pharmaceuticals Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Merrimack Pharmaceuticals
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merrimack Pharmaceuticals Inc
B.5.2	Functional name of contact point	Merrimack 398 clinical trial Mger
B.5.3	Address:
B.5.3.1	Street Address	One Kendall Square, Suite B7201
B.5.3.2	Town/ city	Cambridge,
B.5.3.3	Post code	MA 02139
B.5.3.4	Country	United States
B.5.4	Telephone number	001617441-1000
B.5.5	Fax number	001617491-1386
B.5.6	E-mail	clinical@merrimackpharma.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Nanoliposomal Irinotecan
D.3.2	Product code	MM-398
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Irinotecan Hydrochloride
D.3.9.1	CAS number	136572-09-3
D.3.9.3	Other descriptive name	Nanoliposomal Irinotecan
D.3.9.4	EV Substance Code	SUB02772MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Concentrate for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FLUOROURACIL
D.3.9.1	CAS number	51-21-8
D.3.9.4	EV Substance Code	SUB07721MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Concentrate for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Calcium Folinate
D.3.9.1	CAS number	58-05-9
D.3.9.3	Other descriptive name	Folinic acid
D.3.9.4	EV Substance Code	SUB13910MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/l milligram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Metastatic Pancreatic Cancer

E.1.1.1

Medical condition in easily understood language

cancer of the pancreas that has spread to other areas

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10033610
E.1.2	Term	Pancreatic carcinoma metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10033599
E.1.2	Term	Pancreatic adenocarcinoma metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10033605
E.1.2	Term	Pancreatic cancer metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare overall survival following treatment with MM-398, with
orwithout 5-fluorouracil and leucovorin,versus 5-fluorouracil and
leucovorin in patients with metastatic pancreatic cancer that have
progressed on gemcitabine based therapy.

E.2.2

Secondary objectives of the trial

• To compare the following time-to-event efficacy
endpoints between the two treatment arms:
Progression-free survival (PFS)
Time to treatment failure (TTF)
• To compare the Objective Response Rate (ORR) between the two
treatment arms
• To compare the tumor marker response of CA 19-9 between the
two treatment arms
• To compare the Clinical Benefit Response (CBR) rate between
the two treatment arms
• To assess patient-reported outcomes (PROs) between the two
treatment arms using the European Organization for Research and
Treatment of Cancer (EORTC) quality-of-life core questionnaire
(EORTC-QLQ-C30)
• To compare the safety and adverse event profile between
the two treatment arms
•To determine the pharmacokinetic properties of MM-398, as a single agent and in combination with 5-FU and leucovorin, in this
population

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Translational Research Companion Protocol for 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

E.3

Principal inclusion criteria

• Histologically or cytologically confirmed adenocarcinoma of
exocrine pancreas
• Documented metastatic disease; disease status may be measurable or non-measurable as defined by RECIST v1.1 guidelines
• Documented disease progression after prior gemcitabine or
gemcitabine containing therapy, in locally advanced or metastatic
setting. Examples of permitted therapies include, but are not limited to:
o Single agent gemcitabine
o Any one gemcitabine-based regimen, with or without
maintenance gemcitabine
o Single agent gemcitabine to which a platinum agent, a
fluoropyrimidine, or erlotinib was subsequently added
o Gemcitabine administered in the adjuvant setting if disease
recurrence occurred within 6 months of completing the
adjuvant therapy
• KPS > 70
• Adequate bone marrow reserves as evidenced by:
o ANC > 1,500 cells/μl without the use of hematopoietic growth
factors; and
o Platelet count > 100,000 cells/μl; and
o Hemoglobin > 9 g/dL
• Adequate hepatic function as evidenced by:
o Serum total bilirubin within normal range for the institution
(biliary drainage is allowed for biliary obstruction)
o Albumin levels ≥ 3.0 g/dL
o Aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN is acceptable
if liver metastases are present)
• Adequate renal function as evidenced by a serum creatinine ≤1.5
x ULN
• Normal ECG or ECG without any clinically significant findings
• Recovered from the effects of any prior surgery, radiotherapy or
other anti-neoplastic therapy
• At least 18 years of age
• Able to understand and sign an informed consent (or have a legal
representative who is able to do so)

E.4

Principal exclusion criteria

• Active CNS metastases (indicated by clinical symptoms, cerebral
edema, steroid requirement, or progressive disease) patients should have been off steroids for at least 28 days prior to starting study therapy
• Clinically significant gastrointestinal disorder including hepatic
disorders, bleeding, inflammation, occlusion, or diarrhea > grade 1
• History of any second malignancy in the last 5 years; subjects with prior history of in-situ cancer or basal or squamous cell skin cancer are eligible. Subjects with other malignancies are eligible if they have been continuously disease free for at least 5 years.
• Severe arterial thromboembolic events (myocardial infarction,
unstable angina pectoris, stroke) less than 6 months before inclusion
• NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure
• Active infection or an unexplained fever > 38.5°C during screening visits or on the first scheduled day of dosing (at the discretion of the investigator, patients with tumor fever may be enrolled), which in the investigator's opinion might compromise the patient's participation in the trial or affect the study outcome
• Known hypersensitivity to any of the components of MM-398, other liposomal products, fluropyrimidines or leucovorin
• Investigational therapy administered within 4 weeks, or within a time interval less than at least 5 half lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study
• Any other medical or social condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results
• Pregnant or breast feeding; females of child-bearing potential must test negative for pregnancy at the time of enrollment based on a urine or serum pregnancy test. Both male and female patients of reproductive potential must agree to use a reliable method of birth control, during the study and for 3 months following the last dose of study drug.

E.5 End points

E.5.1

Primary end point(s)

Overall survival (OS)

E.5.1.1

Timepoint(s) of evaluation of this end point

The analysis for primary endpoint will take place once at least 305 death events have occurred.

E.5.2

Secondary end point(s)

Progression Free Survival
Time to treatment failure
Objective Response Rate
Clinical Benefit Response
Tumor Marker Response
Patient Reported Outcome

E.5.2.1

Timepoint(s) of evaluation of this end point

On-going

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Brazil

Canada

Czech Republic

France

Germany

Hungary

India

Italy

Korea, Republic of

Russian Federation

South Africa

Spain

Taiwan

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

As per protocol

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

150

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

255

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

150

F.4.2.2

In the whole clinical trial

405

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

As per protocol

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-03-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-11-06

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