Clinical Trials Register

Summary
EudraCT Number:	2019-001562-15
Sponsor's Protocol Code Number:	CAAA601A22301
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-06-14
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

2019-001562-15

A.3

Full title of the trial

A phase III multi-center, randomized, open-label study to evaluate the efficacy and safety of Lutathera in patients with Grade 2 and Grade 3 advanced GEP-NET.

A.3.1

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

A phase III multi-center, randomized, open-label study to evaluate the efficacy and safety of Lutathera in combination with best supportive care octreotide long-acting (30 mg), when given as a 1st line treatment in GEP-NET patients with high proliferation rate tumors (G2 and G3), in comparison to treatment with high dose (60 mg) octreotide long-acting.

A.3.2

Name or abbreviated title of the trial where available

NETTER-2

A.4.1

Sponsor's protocol code number

CAAA601A22301

A.5.4

Other Identifiers

Name:

IND No.

Number:

77219

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	Advanced Accelerator Applications
B.1.3.4	Country	France
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	Advanced Accelerator Applications
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Advanced Accelerator Applications International
B.5.2	Functional name of contact point	Regulatory Affairs Team
B.5.3	Address:
B.5.3.1	Street Address	Rue de la Tour-de-l'Ile 4
B.5.3.2	Town/ city	Geneva
B.5.3.3	Post code	1204
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+4122519 0700
B.5.5	Fax number	+4122519 0586
B.5.6	E-mail	Regulatory_Affairs@adacap.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	Yes
D.2.1.1.1	Trade name	Lutathera 370 MBq/mL solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Advanced Accelerator Applications
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/3/07/523
D.3 Description of the IMP
D.3.1	Product name	Lutathera 370 MBq/mL solution for infusion
D.3.4	Pharmaceutical form	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	LUTETIUM (177LU) OXODOTREOTIDE
D.3.9.1	CAS number	437608-50-9
D.3.9.3	Other descriptive name	177Lu-DOTA0-Tyr3-Octreotate, lutetium Lu 177 dotatate
D.3.9.4	EV Substance Code	SUB180110
D.3.10	Strength
D.3.10.1	Concentration unit	MBq/ml megabecquerel(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	370
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	Yes
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.2.1.1.1	Trade name	Sandostatin® LAR® 10 mg powder and solvent for suspension for injection Sandostatin® LAR® 20 mg powder and solvent for suspension for injection Sandostatin® LAR® 30 mg powder and solvent for suspension for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Ireland Limited
D.2.1.2	Country which granted the Marketing Authorisation	Malta
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	Sandostatin® LAR® powder and solvent for suspension for injection
D.3.4	Pharmaceutical form	Powder and solvent for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Octreotide
D.3.9.1	CAS number	79517-01-4
D.3.9.3	Other descriptive name	OCTREOTIDE ACETATE
D.3.9.4	EV Substance Code	SUB03490MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 30
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	Yes
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

Patients with somatostatin receptor positive, well-differentiated G2 and G3, advanced GEP NETs

E.1.1.1

Medical condition in easily understood language

Patients with tumors that have a specific target (GEP NET) for treatment with Lutathera

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	PT
E.1.2	Classification code	10052399
E.1.2	Term	Neuroendocrine tumour
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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10077559
E.1.2	Term	Gastroenteropancreatic neuroendocrine tumour disease
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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10077560
E.1.2	Term	Gastroenteropancreatic neuroendocrine tumor disease
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 demonstrate that Lutathera is superior to active comparator in delaying the time-to-first occurrence of progression or death (PFS) as first line treatment.

E.2.2

Secondary objectives of the trial

Key secondary objectives:
-To demonstrate the superiority of Lutathera, compared to active comparator, in terms of objective response
-To demonstrate the superiority of Lutathera, compared to active comparator, in terms of time to deterioration in selected QoL items/scales.

Other Secondary Objectives:
-To evaluate the efficacy of Lutathera, compared to active comparator, in keeping the disease under control
-To evaluate the efficacy of Lutathera, compared to active comparator, in terms of duration of response
-To evaluate the safety and tolerability of Lutathera
-To evaluate the effect of Lutathera on survival

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Presence of metastasized or locally advanced, inoperable (curative intent) histologically proven, well differentiated Grade 2 or Grade 3 gastroenteropancreatic neuroendocrine (GEP-NET) tumor diagnosed within 6 months prior to screening.
2. Ki67 index ≥10 and ≤ 55%.
3. Patients ≥15 years of age and a body weight of >40 kg at screening.
4. Expression of somatostatin receptors on all target lesions documented by CT/MRI scans, assessed by any of the following somatostatin receptor imaging (SRI) modalities within 3 months prior to randomization: [68Ga]-DOTA-TOC (e.g. Somakit-TOC®) PET/CT (or MRI when applicable based on target lesions) imaging or [68Ga]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging (e.g. NETSPOT®) or Somatostatin Receptor scintigraphy (SRS) with 111In-pentetreotide (Octreoscan® SPECT/CT), SRS with [99mTc]-Tektrotyd, [64Cu]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions).
5. The tumor uptake observed in the target lesions must be > normal liver uptake observed on planar imaging.
6. Karnofsky Performance Score (KPS) ≥60.
7. Presence of at least 1 measurable site of disease.
8. Patients who have provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities.

E.4

Principal exclusion criteria

1. Creatinine clearance <40 mL/min calculated by the Cockroft Gault method.
2. Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L (2000/mm3); platelets <75x109/L (75x103/mm3).
3. Total bilirubin >3 x ULN.
4. Serum albumin <3.0 g/dL unless prothrombin time is within the normal range.
5. Pregnancy or lactation.
6. A) Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study treatment period (including crossover
and re-treatment, if applicable) and for 7 months after study drug discontinuation.
B) Sexually active male patients, unless they agree to remain abstinent (refrain from heterosexual intercourse) or be willing to use condoms and highly effective methods of contraception with female partners of childbearing potential or pregnant female partners during the treatment period (including
cross-over and re-treatment, if applicable) and for 4 months after study drug discontinuation. In addition, male patients must refrain from donating sperm during this same period.
7. Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
8. Documented RECIST progression to previous treatments for the current GEP-NET at any time prior to randomization.
9. Patients for whom in the opinion of the investigator other therapeutic options (eg chemo-, targeted therapy) are considered more appropriate than the therapy offered in the study, based on patient and disease characteristics.
10. Any previous therapy with Interferons, Everolimus (mTOR-inhibitors), chemotherapy or other systemic therapies of GEP-NET administered for more than 1 month or within 12 weeks prior to randomization in the study.
11. Any previous radioembolization, chemoembolization and radiofrequency ablation for GEP-NET.
12. Any surgery within 12 weeks prior to randomization in the study.
13. Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to screening in the study. Patients with a history of brain metastases must have a head CT or MRI with contrast to document stable disease prior to randomization in the study.
14. Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with history of congestive heart failure who do not violate this exclusion criterion will undergo an evaluation of their cardiac ejection fraction prior to randomization via echocardiography. The results from an earlier assessment (not exceeding 30 days prior to randomization) may substitute the evaluation at the discretion of the Investigator, if no clinical worsening is noted. The patient’s measured cardiac ejection fraction in these patients must be >40% before randomization.
15. QTcF > 470 msec for females and QTcF > 450 msec for males or congenital long QT syndrome.
16. Uncontrolled diabetes mellitus as defined by hemoglobin A1c value > 7.5%.
17. Hyperkaleamia >6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to study enrolment.
18. Any patient receiving treatment with short-acting octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of Lutathera, or any patient receiving treatment with SSAs (eg octreotide long-acting), which cannot be interrupted for at least 6 weeks before the administration of Lutathera, unless the tumor uptake on target lesions observed by study-permitted somatostatin receptor imaging (SRI) modalities during continued long-acting SSA treatment is greater than the liver uptake observed by planar imaging.
19. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
20. Prior external beam radiation therapy to more than 25% of the bone marrow.
21. Current spontaneous urinary incontinence.
22. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
23. Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.
24. Hypersensitivity to any somatostatin analogues, the IMPs active substance or to any of the excipients.
25. Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 days.

E.5 End points

E.5.1

Primary end point(s)

Progression Free Survival (PFS): Time from randomization to the first line progression (centrally assessed according to RECIST 1.1) or death due to any cause.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 99 PFS events

E.5.2

Secondary end point(s)

-ORR: Rate of patients with best overall response of partial response (PR) or complete response (CR) (centrally assessed according to RECIST 1.1)

-Time to decline (TTD) by 10 points from baseline in the following scores measured by the
EORTC QLQ-G.I.NET21 questionnaire, EORTC QLQC30 questionnaire: global health status, diarrhea, fatigue and pain.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of treatment phase or after discontinuation

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

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

Yes

E.8.1.6

Cross over

Yes

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Optional Re-treatment phase

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

Yes

E.8.2.3.1

Comparator description

Sandostatin LAR Depot

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

Canada

Korea, Republic of

United Kingdom

United States

France

Germany

Italy

Netherlands

Spain

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

The End of Study is after 4 years have elapsed from the randomization of the last patient or 6 months after the last cross-over or re-treatment
dose in the study, whichever occurs last. The time window to start cross-over or retreatment with Lutathera in this study is within 4 years
after the last patient has been randomized. For patients in the Lutathera arm who progress beyond this window, access to retreatment
with Lutathera may be granted via Post Study Drug Supply (PSDS) programs.

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

112

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

101

F.4.2.2

In the whole clinical trial

222

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)

At the end of treatment, all patients will be continued to be treated according to local best care practice.

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

2019-11-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Ongoing

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Orphan Designation Number:
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