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

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

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.

Study Overview

• Status: Terminated
• Conditions: Islet Cell Tumor
• Intervention / Treatment: Drug: Everolimus; Drug: Pasireotide LAR

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1264AAA
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1426ANZ
      • Novartis Investigative Site
• Australia
  • New South Wales
    • St. Leonards, New South Wales, Australia, 2065
      • Novartis Investigative Site
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Novartis Investigative Site
• Belgium
  • Bruxelles, Belgium, 1200
    • Novartis Investigative Site
  • Bruxelles, Belgium, 1070
    • Novartis Investigative Site
  • Gent, Belgium, 9000
    • Novartis Investigative Site
  • Haine-saint-Paul, Belgium, 7100
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Brazil
  • RJ
    • Rio de Janeiro, RJ, Brazil, 20230-130
      • Novartis Investigative Site
  • SP
    • São Paulo, SP, Brazil, 01246-000
      • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Novartis Investigative Site
• Denmark
  • Copenhagen N, Denmark, DK-2200
    • Novartis Investigative Site
  • Århus, Denmark, 8000
    • Novartis Investigative Site
• France
  • Bordeaux Cedex, France, 33075
    • Novartis Investigative Site
  • Clichy, France, 92110
    • Novartis Investigative Site
  • Lyon, France, 69437
    • Novartis Investigative Site
  • Marseille cedex 05, France, 13385
    • Novartis Investigative Site
  • Villejuif Cedex, France, 94805
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • München, Germany, 81675
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1085
    • Novartis Investigative Site
  • Budapest, Hungary, 1062
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
• Italy
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20141
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41100
      • Novartis Investigative Site
• Japan
  • Fukuoka
    • Fukuoka-city, Fukuoka, Japan, 812-8582
      • Novartis Investigative Site
• Netherlands
  • Rotterdam, Netherlands, 3015 CE
    • Novartis Investigative Site
• New Zealand
  • Grafton, Auckland, New Zealand
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Hospitalet de LLobregat, Catalunya, Spain, 08907
      • Novartis Investigative Site
• Sweden
  • Lund, Sweden, SE-221 85
    • Novartis Investigative Site
  • Uppsala, Sweden, SE-751 85
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Istanbul, Turkey, 34303
    • Novartis Investigative Site
• United Kingdom
  • Cambridge, United Kingdom, CB2 2QQ
    • Novartis Investigative Site
  • Glasgow, United Kingdom, G12 0YN
    • Novartis Investigative Site
  • Manchester, United Kingdom, M20 9BX
    • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute SC-2
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center MMC
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University Knight Cancer Institute
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center UT MD Anderson Cancer Ctr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Paseriotide LAR + Everolimus; everolimus 10 mg once daily po in combination with pasireotide LAR 60 mg every 28 days (q28d) im	Drug: Everolimus; Everolimus was supplied as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets; Other Names: RAD001; Drug: Pasireotide LAR; 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).; Other Names: SOM230 LAR
Experimental: Everolimus; everolimus 10 mg once daily po alone	Drug: Everolimus; Everolimus was supplied as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets; Other Names: RAD001

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Once 80 PFS events had occurred aproximately after 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Once 80 PFS events had occurred
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.	Once 80 PFS events had occurred
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.	Once 80 PFS events had occurred
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.	Once 80 PFS events had occurred
PFS and the Predictive Probability of Success in Phase III	105 PFS events expected after approximately 36 months	Once 105 PFS events had occurred occurred
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.	Once 80 PFS events had occurred
Summary of Pharmacokinetics (PK) for Everolimus for AUClast		Cycle 2 Day 1
Summary of Pharmacokinetics (PK) for Everolimus for CL/F		Cycle 2 Day 1
Summary of Pharmacokinetics (PK) for Everolimus for Cmax and Cmin		Cycle 2 Day 1
Summary of Pharmacokinetics (PK) for Everolimus for Tmax		Cycle 2 Day 1
Summary of Pasireotide Concentrations Following Intramuscular Injection of Pasireotide LAR 60mg		Cycle 1 Day 21, Cycle 2 Day 29

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: June 14, 2011
• First Submitted That Met QC Criteria: June 15, 2011
• First Posted (Estimate): June 16, 2011

Study Record Updates

• Last Update Posted (Estimate): December 20, 2016
• Last Update Submitted That Met QC Criteria: October 26, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Everolimus; Neuroendocrine tumors; PNET; Pancreatic; Pasireotide; Advanced progressive pancreatic neuroendocrine tumor
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Pancreatic Diseases; Adenoma; Pancreatic Neoplasms; Neuroendocrine Tumors; Adenoma, Islet Cell; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Everolimus; Pasireotide
• Other Study ID Numbers: CSOM230I2201; 2010-023183-40 (EudraCT Number)