Clinical Trials Register

Summary
EudraCT Number:	2010-023183-40
Sponsor's Protocol Code Number:	CSOM230I2201
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:	2011-05-20
Trial results	View 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

2010-023183-40

A.3

Full title of the trial

A randomized, open-label phase II multicenter study evaluating the efficacy of oral Everolimus alone or in combination with Pasireotide LAR i.m. in advanced progressive pancreatic neuroendocrine tumors (PNET)

A.3.2

Name or abbreviated title of the trial where available

The COOPERATE-2 study

A.4.1

Sponsor's protocol code number

CSOM230I2201

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	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma
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	Novartis Pharma GmbH
B.5.2	Functional name of contact point	Medical Competence Center
B.5.3	Address:
B.5.3.1	Street Address	Roonstr. 25
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90429
B.5.3.4	Country	Germany
B.5.4	Telephone number	00491802 23 23 00
B.5.5	Fax number	004991127312160
B.5.6	E-mail	infoservice.novartis@novartis.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/04/200
D.3 Description of the IMP
D.3.1	Product name	pasireotide LAR 20 mg
D.3.2	Product code	SOM230
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	Pasireotide
D.3.9.2	Current sponsor code	SOM230
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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.2.1.1.1	Trade name	Afinitor
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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/3/07/488
D.3 Description of the IMP
D.3.1	Product name	Everolimus
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Everolimus
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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: 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	No
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/3/04/200
D.3 Description of the IMP
D.3.1	Product name	pasireotide LAR 40 mg
D.3.2	Product code	SOM230
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	Pasireotide
D.3.9.2	Current sponsor code	SOM230
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
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

advanced progressive pancreatic neuroendocrine tumors (PNET)

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	15.0
E.1.2	Level	PT
E.1.2	Classification code	10067517
E.1.2	Term	Pancreatic neuroendocrine tumour
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 estimate the treatment effect of everolimus in combination with pasireotide LAR relative to everolimus alone on progression-free survival (PFS) in patients with advanced PNET and to assess the predictive probability of success in a possible subsequent phase III study once 80 PFS events have been observed.

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability profile of everolimus alone or in combination with pasireotide LAR
• To evaluate the Objective Response Rate (ORR) and Disease Control Rate (DCR)
• To evaluate the duration of response (DoR)
• To evaluate overall survival (OS)
• To estimate the treatment effect on PFS and to assess the predictive probability of success
in a possible subsequent phase III study once 105 PFS events have been observed
• To assess pharmacokinetic (PK) exposures of everolimus and pasireotide LAR
• To assess potential PK drug-drug interactions between everolimus and pasireotide LAR

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Advanced (unresectable or metastatic), histologically confirmed well differentiated (low to intermediate grade) pancreatic neuroendocrine tumor (PNET).
2. Radiological documentation of progressive disease within the last 12 months prior to randomization.
3. Measurable disease per RECIST Version 1.0 determined by multiphase MRI or triphasic CT.
4. Adult patients (male or female) ≥ 18 years of age.
5. WHO performance status ≤ 2
6. Adequate bone marrow function:
• WBC ≥ 2.5 x 109/L,
• ANC ≥ 1.5 x 109/L,
• Platelets ≥ 100 x 109/L,
• Hb ≥ 9 g/dL
7. No evidence of significant liver/pancreas disease:
• Serum bilirubin ≤ 1.5 x ULN,
• INR < 1.3,
• ALT and AST ≤ 3 x ULN
• Serum lipase ≤ 2 x ULN
8. Serum creatinine ≤ 2.0 mg/dl and estimated glomerular filtration rate (eGFR) > 30
ml/min/m2 (calculated with MDRD formula).
9. Written informed consent is to be obtained prior to any screening procedures.

E.4

Principal exclusion criteria

1. Patients currently requiring SSA treatment. 2. Patients who received prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, everolimus), or pasireotide.
3. Patients who received any cytotoxic chemotherapy, targeted therapy, SSAs, or biotherapy within the last 4 weeks. 4. Patients with more than 2 prior systemic treatment regimens
5. Patients with a known hypersensitivity to SSAs. 6. Patients with a known hypersensitivity to any component of the pasireotide LAR or s.c. formulations, everolimus or other rapamycin analogs (sirolimus, temsirolimus) or to their excipients. 7. Prior treatment with radiolabeled SSAs within the last 12 months. 8. Patients with hepatic artery embolization, cryoablation or radiofrequency ablation of hepatic metastasis within the last 3 months prior to randomization.
9. Patients who have received radiotherapy of target lesions. Patients who have received local radiotherapy of non-target lesions for local symptom control within the last 4 weeks must have recovered from any adverse effects of radiotherapy prior to randomization.
10. Patients who have undergone major surgery/surgical therapy for any cause within 1 month or surgical therapy of loco-regional metastases within the last 3 months prior to randomization. Patients should have recovered from the treatment and have a good clinical condition before entering this study.
11. Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent.
12. Patients with symptomatic cholelithiasis.
13.Patients who are not clinically euthyroid.Patients with history hypothyroidism are eligible if they are on adequate and stable replacement thyroid hormone therapy for at least 3 months
14.Patients with abnormal coagulation (PT [INR] or aPTT elevated by 30% above normal limits)
15.QT-related exclusion criteria:
•Patients with a QTcF > 470 ms
• History of syncope or family history of idiopathic sudden death, Long QT syndrome,
• Sustained or clinically significant cardiac arrhythmias,
• Patients with risk factors for torsades de pointes: Potassium < 3.0 mmol/L,
magnesium < 0.4 mmol/L or, calcium < 1.75 mmol/L at baseline. If the electrolyte
abnormalities are corrected prior to start of study drug, the patient may become
eligible for the trial. Cardiac failure, clinically significant/symptomatic bradycardia or
high-grade AV block,
• Concomitant medications known to prolong the QT interval (see Appendix 2).
• Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes mellitus or Parkinson’s disease), HIV, liver cirrhosis, uncontrolled
hypothyroidism or cardiac failure.
16. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
• Uncontrolled diabetes as defined by HbA1c ≥ 8% despite adequate therapy,
• Fasting serum cholesterol > 300 mg/dL (7.75 mmol/L) OR fasting triglycerides > 2.5
x ULN despite appropriate lipid lowering medication.
• Severely impaired lung function defined as spirometry and DLCO that is 50% of the
normal predicted value and/or O2 saturation that is 88% or less at rest on room air.
DLCO should be adjusted to hemoglobin value and patient lung volumes.
• Patients with the presence of active or suspected acute or chronic uncontrolled
infection or with a history of immunodeficiency, including a positive HIV test result
(ELISA and Western blot). A HIV test will not be required; however, previous
medical history will be reviewed.
• Non-malignant medical illnesses that are uncontrolled or whose control may be
jeopardized by the treatment with this study treatment.
• History or active liver disease such as cirrhosis, decompensated liver disease, chronic active hepatitis or chronic persistent hepatitis.
• Quantifiable HBV-DNA or positive hepatitis B surface antigen (HbsAg).
• Quantifiable HCV-RNA.
• History of, or current alcohol misuse/abuse within the past 12 months.
• Known gallbladder or bile duct disease, acute or chronic pancreatitis.
• Life-threatening autoimmune and ischemic disorders.
• Patients who have a history of another primary malignancy within the last 3 years,
with the exception of locally excised non-melanoma skin cancer and carcinoma in situ
of uterine cervix.
• Symptomatic CNS metastases requiring corticosteroid therapy.
• Patients who have any current or prior medical condition that may interfere with the conduct of the study or the evaluation of its results in the opinion of the Investigator or the Sponsor’s Medical Monitor.
17. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study.

E.5 End points

E.5.1

Primary end point(s)

PFS per RECIST 1.0. (defined as the time from randomization to the date of the first documented tumor progression or death from any cause,whichever comes first)

E.5.1.1

Timepoint(s) of evaluation of this end point

Once 80 PFS events have occurred (expected after approximately 24
months)

E.5.2

Secondary end point(s)

1. Safety and tolerability profile of Everolimus alone or in combination
with Pasireotide LAR
2. Objective Response Rate (ORR) and Disease Control Rate (DCR)
3. Duration of response (DoR)
4. Overall Survival (OS)
5. The treatment effect on PFS and to assess the predictive probability of
success in a possible subsequent phase III study once 105 PFS events
have been observed.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. to 4. : Once 80 PFS events have occurred (expected after
approximately 24 months)
5.: Once 105 PFS events have occurred (expected after approximately 63
months)

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

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

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

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)

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

Australia

Brazil

Japan

Thailand

Turkey

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

LPLV

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

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.1.3

Elderly (>=65 years)

Yes

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

F.4.2.2

In the whole clinical trial

150

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)

Please refer to 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

2011-06-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-06-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-02-19

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