Clinical Trials Register

Summary
EudraCT Number:	2016-005147-17
Sponsor's Protocol Code Number:	AIO-PAK-0216
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-10-09
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

Germany - BfArM

A.2

EudraCT number

2016-005147-17

A.3

Full title of the trial

Second-line therapy with Nal-IRI/5-FU/FA after failure of gemcitabine/nab-paclitaxel in advanced pancreatic cancer - predictive role of 1st-line therapy

Zweitlinientherapie mit Nal-IRI/5-FU/FA nach Versagen von Gemcitabin/Nab-Paclitaxel bei fortgeschrittenem Bauchspeicheldrüsenkrebs – Prädiktive Rolle der Erstlinientherapie

A.3.1

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

A study to investigate the effects of the course of first-line therapy with gemcitabine on the success of second-line therapy with NAL-IRI combination therapy

Eine Studie zur Untersuchung der Auswirkungen des Verlaufs der Erstlinientherapie mit Gemcitabin auf den Erfolg der Zweitlinientherapie mit NAL-IRI-Kombinationstherapie

A.3.2

Name or abbreviated title of the trial where available

PREDICT

A.4.1

Sponsor's protocol code number

AIO-PAK-0216

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	AIO-Studien-gGmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Baxalta GmbH
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AIO-Studien-gGmbH
B.5.2	Functional name of contact point	AIO-Studien-gGmbH
B.5.3	Address:
B.5.3.1	Street Address	Kuno-Fischer-Straße 8
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	14057
B.5.3.4	Country	Germany
B.5.4	Telephone number	004930814534432
B.5.5	Fax number	004930322932926
B.5.6	E-mail	aio.regulatory@aio-studien-ggmbh.de

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	Yes
D.2.1.1.1	Trade name	ONIVYDE®
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxalta Innovations GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/933
D.3 Description of the IMP
D.3.1	Product name	nanoliposomal irinotecan
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 trihydrate (salt in a pegylated liposomal formulation)
D.3.9.3	Other descriptive name	IRINOTECAN HYDROCHLORIDE TRIHYDRATE
D.3.9.4	EV Substance Code	SUB45873
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	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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	5-fluorouracil
D.3.4	Pharmaceutical form	Solution for injection
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	5-fluorouracil
D.3.9.3	Other descriptive name	FLUOROURACIL
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	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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Leucovorin
D.3.4	Pharmaceutical form	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	Ca-Folinic acid
D.3.9.3	Other descriptive name	CALCIUM FOLINATE
D.3.9.4	EV Substance Code	SUB06052MIG
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	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

locally advanced or metastatic pancreatic cancer after failure of a gemcitabine/nab-paclitaxel 1st-line treatment

Lokal fortgeschrittenes oder metastasiertes Pankreaskarzinom nach Versagen einer Gemcitabin / Nab-Paclitaxel Erstlinienbehandlung

E.1.1.1

Medical condition in easily understood language

advanced or metastatic pancreatic cancer after failure of a gemcitabine/nab-paclitaxel 1st-line treatment

fortgeschrittener oder metastasierter Bauchspeicheldrüsenkrebs nach Versagen einer Gemcitabin / Nab-Paclitaxel Erstlinienbehandlung

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10033604
E.1.2	Term	Pancreatic cancer
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10033605
E.1.2	Term	Pancreatic cancer metastatic
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10033606
E.1.2	Term	Pancreatic cancer non-resectable
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10033607
E.1.2	Term	Pancreatic cancer recurrent
E.1.2	System Organ Class	100000004864

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

Confirmation that longer Time-To-Treatment-Failure (TTF) during first-line treatment is predictive for the benefit of 2nd- line treatment with Nal-IRI combination chemotherapy.

E.2.2

Secondary objectives of the trial

Secondary objectives of this study are:
• to generate additional efficacy and safety data for the 2nd-line treatment
• to assess the Quality of Life and Patient Reported Outcomes during 2nd-line treatment
• to asses the impact of the course of the 1st-line treatment on the outcome of the 2nd-line therapy
• to explore the impact of physiological and molecular markers on the efficacy of the 2nd-line
• to validate a prognostic second-line score accord. to Sinn et al., 2016

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent including participation in translational research and any locally-required authorization (EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
2. Clinical indication for a 2nd-line systemic therapy according to current standard-of-care.
3. Age ≥ 18 years at time of study entry
4. Patients with histologically or cytologically confirmed pancreatic ductal adenocarcinoma
5. Imaging of evaluable lesions (either sonography, X-ray, CT scans, MRI): only in case of treatment failure because of progress
6. ECOG performance status 0-2
7. One line of systemic gemcitabine/Nab-paclitaxel -based therapy for advanced disease (irrespective of prior adjuvant therapy)
OR
Previous adjuvant gemcitabine/Nab-paclitaxel-based chemotherapy with documented progression less than 6 months after termination
8. Documentation of prior therapy (duration, maximum toxicity, reason for discontinuation)
9. Adequate blood count, liver-enzymes, and renal function:
• neutrophil count > 1.5 x 10^6/mL
• Platelet count ≥ 100 x 10^9/L (≥100,000 per mm^3)
• AST (SGOT)/ALT (SGPT) ≤ 5 x institutional upper limit of normal
• bilirubin ≤1.5 ULN (<3 x ULN in patients with confirmed mechanical cholestasis)
• Creatinine Clearance CLcr ≥ 30 mL/min
10. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

E.4

Principal exclusion criteria

Medical criteria:
1. Any condition or comorbidity that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results, including but not limited to:
a) Active uncontrolled infection, chronic infectious diseases, immune deficiency syndromes
b) Premalignant hematologic disorders, e.g. myelodysplastic syndrome
c) Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 6 months before enrollment
d) Prior (<3 years) or concurrent malignancy (other than biliary-tract cancer) which either progresses or requires active treatment. Exceptions are: basal cell cancer of the skin, pre-invasive cancer of the cervix, T1a or T1b prostate carcinoma, or superficial urinary bladder tumor [Ta, Tis and T1].
e) Pre-existing lung disease of clinical significance or with impact on performance status
f) History or clinical evidence of CNS metastases
Exceptions are: Subjects who have completed local therapy and who meet both of the following criteria:
I. are asymptomatic and
II. have no requirement for steroids 6 weeks prior to start of study treament. Screening with CNS imaging (CT or MRI) is required only if clinically indicated or if the subject has a history of CNS metastases
g) Allogeneic transplantation requiring immunosuppressive therapy or other major immunosuppressive therapy
h) Severe non-healing wounds, ulcers or bone fractions
i) Evidence of bleeding diathesis or coagulopathy
j) Major surgical procedures, except open biopsy, or significant traumatic injury within 28 days prior to star of study treatment, or anticipation of the need for major surgical procedure during the course of the study except for surgery of central intravenous line placement for chemotherapy administration.
k) Known Gilbert-Meulengracht syndrome
l) Known chronic hypoacusis, tinnitus or vertigo
m) Bone marrow depression (e.g., after radiation therapy)
n) Pernicious anemia and other megaloblastic anemias secondary to vitamin B12 deficiency
o) Severe impairment of hepatic function
p) Diarrhea
Drug related criteria:
2. Medication that is known to interfere with any of the agents applied in the trial.
3. Known dihydropyrimidine dehydrogenase (DPD) deficiency with acitivity score of 0.5 or less
4. History of hypersensitivity to any of the study drugs or any of the constituents of the products.
5. Any other efficacious cancer treatment except protocol specified treatment at study start.
Safety criteria:
6. Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year). [Acceptable methods of contraception are: implants, injectable contraceptives, combined oral contraceptives, intrauterine pessars (only hormonal devices), sexual abstinence or vasectomy of the partner]. Women of childbearing potential must have a negative pregnancy test (urine or serum β-HCG acc. to SOC) at Screening.
Methodological criteria:
7. Any experimental pretreatment for advanced disease
8. Participation in another clinical study with an investigational product during the last 30 days before inclusion or 7 half-lifes of previously used trial medication, whichever is longer, with the following exception: Any clinical study with the IMPs Nab-paclitaxel + gemcitabine and under the condition that the potential study subject was only exposed to Nab-paclitaxel + gemcitabine doublet chemotherapy during the course of the previous study is exempt. The previous Nab-paclitaxel + gemcitabine treatment must be consistent with current treatment approaches for first-line therapy with regard to dosing and scheduling. The following non-comprehensive list of clinical trials may serve as a guidance: ALPACA (EudraCT number: 2014-004086-24); GrantPax (EudraCT Number: 2015-002890-40), NEONAX (EudraCT number: 2013-005559-34), NEOLAP (EudraCT number: 2013-004796-12).
9. Previous enrollment in the present study (does not include screening failure).
Regulatory and ethical criteria:
10. Patient who might be dependent on the sponsor, site or the investigator
11. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

E.5 End points

E.5.1

Primary end point(s)

Time to Treatment Failure of second-line treatment (TTF2)
Expected increase of the TTF2 by 50% in the cohort of patients with favorable TTF1 (TTF1 high: upper third of the patient population) as compared to patients with short TTF1 (TTF low: lowest third of the patient population)

E.5.1.1

Timepoint(s) of evaluation of this end point

End of Study (EoS)

E.5.2

Secondary end point(s)

- Overall survival
- AEs / SAEs
- QoL [EORTC QLQ-PAN26, QLQ-C30; EQ-5D-5L]
- Evaluation of time to definitive deterioration of QoL (TDD)
- Growth modulation index (GMI)
- Second-line score accord. to Sinn et al., 2016

E.5.2.1

Timepoint(s) of evaluation of this end point

End of Study (EoS)

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

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Quality of life

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

E.8.1.1

Randomised

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)

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

End of Study (EoS)
End of Study (EoS) is defined as the time point when the last patient has completed a 10 month treatment and follow-up period

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

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:

135

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

135

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

270

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)

Patients will be treated according to standard-of-care at the discretion of the investigator.

Patienten werden nach Studienende entsprechend dem medizinischen Standard nach dem Ermessen des Arztes behandelt.

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

2017-12-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-01-30

P. End of Trial
P.	End of Trial Status	Completed

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