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Efficacy of Everolimus Alone or in Combination With Pasireotide LAR in Advanced PNET (COOPERATE-2)

Primary Purpose

Islet Cell Tumor

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Everolimus
Pasireotide LAR
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Islet Cell Tumor focused on measuring Pancreatic, Neuroendocrine tumors, PNET, Pasireotide, Everolimus, Advanced progressive pancreatic neuroendocrine tumor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Advanced histologically confirmed well differentiated pancreatic neuroendocrine tumor
  • Progressive disease within the last 12 months
  • Measurable disease per RECIST Version 1.0 determined by multiphase MRI or triphasic CT

Exclusion Criteria:

  • Patients currently requiring somatostatin analog treatment
  • Prior therapy with mTOR inhibitors or pasireotide
  • Patients with more than 2 prior systemic treatment regimens
  • Previous cytotoxic chemotherapy, targeted therapy, somatostatin analogs, or biotherapy within the last 4 weeks

Other protocol-defined inclusion/exclusion criteria may apply

Sites / Locations

  • Dana Farber Cancer Institute SC-2
  • Montefiore Medical Center MMC
  • Oregon Health & Science University Knight Cancer Institute
  • University of Texas/MD Anderson Cancer Center UT MD Anderson Cancer Ctr
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Paseriotide LAR + Everolimus

Everolimus

Arm Description

everolimus 10 mg once daily po in combination with pasireotide LAR 60 mg every 28 days (q28d) im

everolimus 10 mg once daily po alone

Outcomes

Primary Outcome Measures

Progression-free Survival (PFS) Per Local Radiological Review
PFS per RECIST 1.0. (Response Evaluation Criteria in Solid Tumors). PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause.

Secondary Outcome Measures

Safety and Tolerability Profile of Everolimus Alone or in Combination With Pasireotide LAR
Consisted of monitoring and recording the rate, type, severity, and causal relationship of adverse events (AEs) and serious AEs (SAEs) to treatment. The safety analysis was based mainly on the frequency of AEs or SAEs and on the number of laboratory values that fell outside of pre-determined range.
Objective Response Rate (ORR) as Per Radiology Review
Objective response was determined by the local radiologist according to the RECIST Version 1.0. ORR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR). This is also referred to as Overall response rate. CR: Disappearance of all nontarget lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameter of all target lesions recorded at or after baseline.
Duration of Response (DoR)
80 PFS are expected after approximately 24 months. Kaplan Meier was initially planned to be used to depict duration of response by treatment group and by stratum. Later based on the mode of action of everolimus and pasireotide and based on study experience, only a low number of objective responses per RECIST were expected. Therefore, protocol was amended to only list duration of response, and confirmed responses were flagged in the listing. Hence, statistical analyses were not planned and such data are not available for the following table.
Overall Survival (OS) Using Kaplan Meier Method
Overall survival was defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival was to be censored at the date of last contact.
PFS and the Predictive Probability of Success in Phase III
105 PFS events expected after approximately 36 months
Disease Control Rate (DCR) as Per Radiology Review
Disease control rate is the percentage of patients with a best overall response of CR or PR or stable disease (SD) determined by the local radiologist according to the Response Evaluation Criteria In Solid Tumors Criteria (RECIST) Version 1.0. CR: Disappearance of all nontarget lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameter of all target lesions recorded at or after baseline. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD). PD: Any progression ≤ 18 weeks after randomization (and not qualifying for CR, PR or stable disease SD.
Summary of Pharmacokinetics (PK) for Everolimus for AUClast
Summary of Pharmacokinetics (PK) for Everolimus for CL/F
Summary of Pharmacokinetics (PK) for Everolimus for Cmax and Cmin
Summary of Pharmacokinetics (PK) for Everolimus for Tmax
Summary of Pasireotide Concentrations Following Intramuscular Injection of Pasireotide LAR 60mg

Full Information

First Posted
June 14, 2011
Last Updated
October 26, 2016
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01374451
Brief Title
Efficacy of Everolimus Alone or in Combination With Pasireotide LAR in Advanced PNET
Acronym
COOPERATE-2
Official Title
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) - The COOPERATE-2 Study
Study Type
Interventional

2. Study Status

Record Verification Date
October 2016
Overall Recruitment Status
Terminated
Why Stopped
The study was stopped for not meeting the primary endpoint for PFS.
Study Start Date
June 2011 (undefined)
Primary Completion Date
February 2015 (Actual)
Study Completion Date
February 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study will estimate the treatment effect of everolimus in combination with pasireotide LAR relative to everolimus alone on progression-free survival (PFS) in patients with advanced progressive PNET. A planned primary analysis was completed with data cut of 02-Apr-2014. The study did not meet its primary objective, which was based on progression-free survival (PFS) as per local radiology assessment and was prematurely terminated with the last patient last visit on 19-Feb-2015. However, it is important to note that the data did not reveal any new safety concerns. It was decided to stop the study and this decision was shared with the study sites on 31-Jul-2014.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Islet Cell Tumor
Keywords
Pancreatic, Neuroendocrine tumors, PNET, Pasireotide, Everolimus, Advanced progressive pancreatic neuroendocrine tumor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
160 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Paseriotide LAR + Everolimus
Arm Type
Experimental
Arm Description
everolimus 10 mg once daily po in combination with pasireotide LAR 60 mg every 28 days (q28d) im
Arm Title
Everolimus
Arm Type
Experimental
Arm Description
everolimus 10 mg once daily po alone
Intervention Type
Drug
Intervention Name(s)
Everolimus
Other Intervention Name(s)
RAD001
Intervention Description
Everolimus was supplied as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets
Intervention Type
Drug
Intervention Name(s)
Pasireotide LAR
Other Intervention Name(s)
SOM230 LAR
Intervention Description
Pasireotide LAR intra-muscular depot injections were supplied as a powder in vials containing 20 mg and 40 mg with ampoules containing 2 mL of vehicle (for reconstitution).
Primary Outcome Measure Information:
Title
Progression-free Survival (PFS) Per Local Radiological Review
Description
PFS per RECIST 1.0. (Response Evaluation Criteria in Solid Tumors). PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause.
Time Frame
Once 80 PFS events had occurred aproximately after 24 months
Secondary Outcome Measure Information:
Title
Safety and Tolerability Profile of Everolimus Alone or in Combination With Pasireotide LAR
Description
Consisted of monitoring and recording the rate, type, severity, and causal relationship of adverse events (AEs) and serious AEs (SAEs) to treatment. The safety analysis was based mainly on the frequency of AEs or SAEs and on the number of laboratory values that fell outside of pre-determined range.
Time Frame
Once 80 PFS events had occurred
Title
Objective Response Rate (ORR) as Per Radiology Review
Description
Objective response was determined by the local radiologist according to the RECIST Version 1.0. ORR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR). This is also referred to as Overall response rate. CR: Disappearance of all nontarget lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameter of all target lesions recorded at or after baseline.
Time Frame
Once 80 PFS events had occurred
Title
Duration of Response (DoR)
Description
80 PFS are expected after approximately 24 months. Kaplan Meier was initially planned to be used to depict duration of response by treatment group and by stratum. Later based on the mode of action of everolimus and pasireotide and based on study experience, only a low number of objective responses per RECIST were expected. Therefore, protocol was amended to only list duration of response, and confirmed responses were flagged in the listing. Hence, statistical analyses were not planned and such data are not available for the following table.
Time Frame
Once 80 PFS events had occurred
Title
Overall Survival (OS) Using Kaplan Meier Method
Description
Overall survival was defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival was to be censored at the date of last contact.
Time Frame
Once 80 PFS events had occurred
Title
PFS and the Predictive Probability of Success in Phase III
Description
105 PFS events expected after approximately 36 months
Time Frame
Once 105 PFS events had occurred occurred
Title
Disease Control Rate (DCR) as Per Radiology Review
Description
Disease control rate is the percentage of patients with a best overall response of CR or PR or stable disease (SD) determined by the local radiologist according to the Response Evaluation Criteria In Solid Tumors Criteria (RECIST) Version 1.0. CR: Disappearance of all nontarget lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameter of all target lesions recorded at or after baseline. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD). PD: Any progression ≤ 18 weeks after randomization (and not qualifying for CR, PR or stable disease SD.
Time Frame
Once 80 PFS events had occurred
Title
Summary of Pharmacokinetics (PK) for Everolimus for AUClast
Time Frame
Cycle 2 Day 1
Title
Summary of Pharmacokinetics (PK) for Everolimus for CL/F
Time Frame
Cycle 2 Day 1
Title
Summary of Pharmacokinetics (PK) for Everolimus for Cmax and Cmin
Time Frame
Cycle 2 Day 1
Title
Summary of Pharmacokinetics (PK) for Everolimus for Tmax
Time Frame
Cycle 2 Day 1
Title
Summary of Pasireotide Concentrations Following Intramuscular Injection of Pasireotide LAR 60mg
Time Frame
Cycle 1 Day 21, Cycle 2 Day 29

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Advanced histologically confirmed well differentiated pancreatic neuroendocrine tumor Progressive disease within the last 12 months Measurable disease per RECIST Version 1.0 determined by multiphase MRI or triphasic CT Exclusion Criteria: Patients currently requiring somatostatin analog treatment Prior therapy with mTOR inhibitors or pasireotide Patients with more than 2 prior systemic treatment regimens Previous cytotoxic chemotherapy, targeted therapy, somatostatin analogs, or biotherapy within the last 4 weeks Other protocol-defined inclusion/exclusion criteria may apply
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Dana Farber Cancer Institute SC-2
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Montefiore Medical Center MMC
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Facility Name
Oregon Health & Science University Knight Cancer Institute
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
University of Texas/MD Anderson Cancer Center UT MD Anderson Cancer Ctr
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-4009
Country
United States
Facility Name
Novartis Investigative Site
City
Caba
State/Province
Buenos Aires
ZIP/Postal Code
C1426ANZ
Country
Argentina
Facility Name
Novartis Investigative Site
City
Buenos Aires
ZIP/Postal Code
C1264AAA
Country
Argentina
Facility Name
Novartis Investigative Site
City
St. Leonards
State/Province
New South Wales
ZIP/Postal Code
2065
Country
Australia
Facility Name
Novartis Investigative Site
City
Herston
State/Province
Queensland
ZIP/Postal Code
4029
Country
Australia
Facility Name
Novartis Investigative Site
City
Bruxelles
ZIP/Postal Code
1070
Country
Belgium
Facility Name
Novartis Investigative Site
City
Bruxelles
ZIP/Postal Code
1200
Country
Belgium
Facility Name
Novartis Investigative Site
City
Gent
ZIP/Postal Code
9000
Country
Belgium
Facility Name
Novartis Investigative Site
City
Haine-saint-Paul
ZIP/Postal Code
7100
Country
Belgium
Facility Name
Novartis Investigative Site
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Novartis Investigative Site
City
Rio de Janeiro
State/Province
RJ
ZIP/Postal Code
20230-130
Country
Brazil
Facility Name
Novartis Investigative Site
City
São Paulo
State/Province
SP
ZIP/Postal Code
01246-000
Country
Brazil
Facility Name
Novartis Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
Facility Name
Novartis Investigative Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H1T 2M4
Country
Canada
Facility Name
Novartis Investigative Site
City
Copenhagen N
ZIP/Postal Code
DK-2200
Country
Denmark
Facility Name
Novartis Investigative Site
City
Århus
ZIP/Postal Code
8000
Country
Denmark
Facility Name
Novartis Investigative Site
City
Bordeaux Cedex
ZIP/Postal Code
33075
Country
France
Facility Name
Novartis Investigative Site
City
Clichy
ZIP/Postal Code
92110
Country
France
Facility Name
Novartis Investigative Site
City
Lyon
ZIP/Postal Code
69437
Country
France
Facility Name
Novartis Investigative Site
City
Marseille cedex 05
ZIP/Postal Code
13385
Country
France
Facility Name
Novartis Investigative Site
City
Villejuif Cedex
ZIP/Postal Code
94805
Country
France
Facility Name
Novartis Investigative Site
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Novartis Investigative Site
City
München
ZIP/Postal Code
81675
Country
Germany
Facility Name
Novartis Investigative Site
City
Budapest
ZIP/Postal Code
1062
Country
Hungary
Facility Name
Novartis Investigative Site
City
Budapest
ZIP/Postal Code
1085
Country
Hungary
Facility Name
Novartis Investigative Site
City
Debrecen
ZIP/Postal Code
4032
Country
Hungary
Facility Name
Novartis Investigative Site
City
Bologna
State/Province
BO
ZIP/Postal Code
40138
Country
Italy
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20141
Country
Italy
Facility Name
Novartis Investigative Site
City
Modena
State/Province
MO
ZIP/Postal Code
41100
Country
Italy
Facility Name
Novartis Investigative Site
City
Fukuoka-city
State/Province
Fukuoka
ZIP/Postal Code
812-8582
Country
Japan
Facility Name
Novartis Investigative Site
City
Rotterdam
ZIP/Postal Code
3015 CE
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Grafton, Auckland
Country
New Zealand
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08035
Country
Spain
Facility Name
Novartis Investigative Site
City
Hospitalet de LLobregat
State/Province
Catalunya
ZIP/Postal Code
08907
Country
Spain
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Facility Name
Novartis Investigative Site
City
Lund
ZIP/Postal Code
SE-221 85
Country
Sweden
Facility Name
Novartis Investigative Site
City
Uppsala
ZIP/Postal Code
SE-751 85
Country
Sweden
Facility Name
Novartis Investigative Site
City
Bangkok
ZIP/Postal Code
10330
Country
Thailand
Facility Name
Novartis Investigative Site
City
Bangkok
ZIP/Postal Code
10700
Country
Thailand
Facility Name
Novartis Investigative Site
City
Ankara
ZIP/Postal Code
06100
Country
Turkey
Facility Name
Novartis Investigative Site
City
Istanbul
ZIP/Postal Code
34303
Country
Turkey
Facility Name
Novartis Investigative Site
City
Cambridge
ZIP/Postal Code
CB2 2QQ
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Glasgow
ZIP/Postal Code
G12 0YN
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Manchester
ZIP/Postal Code
M20 9BX
Country
United Kingdom

12. IPD Sharing Statement

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Efficacy of Everolimus Alone or in Combination With Pasireotide LAR in Advanced PNET

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