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

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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01374451

Acronym

COOPERATE-2

Enrollment

160

Registered

2011-06-16

Start date

2011-06-30

Completion date

2015-02-28

Last updated

2016-12-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Islet Cell Tumor

Keywords

Pancreatic, Neuroendocrine tumors, PNET, Pasireotide, Everolimus, Advanced progressive pancreatic neuroendocrine tumor

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.

Interventions

DRUGEverolimus

Everolimus was supplied as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets

DRUGPasireotide 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).

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

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/

Design outcomes

Primary

Measure	Time frame	Description
Progression-free Survival (PFS) Per Local Radiological Review	Once 80 PFS events had occurred aproximately after 24 months	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

Measure	Time frame	Description
Objective Response Rate (ORR) as Per Radiology Review	Once 80 PFS events had occurred	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)	Once 80 PFS events had occurred	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	Once 80 PFS events had occurred	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	Once 105 PFS events had occurred occurred	105 PFS events expected after approximately 36 months
Disease Control Rate (DCR) as Per Radiology Review	Once 80 PFS events had occurred	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.
Safety and Tolerability Profile of Everolimus Alone or in Combination With Pasireotide LAR	Once 80 PFS events had occurred	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.
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	—
Summary of Pharmacokinetics (PK) for Everolimus for AUClast	Cycle 2 Day 1	—

Countries

Argentina, Australia, Belgium, Brazil, Canada, Denmark, France, Germany, Hungary, Italy, Japan, Netherlands, New Zealand, Spain, Sweden, Thailand, Turkey (Türkiye), United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
Paseriotide LAR + Everolimus everolimus 10 mg once daily po in combination with pasireotide LAR 60 mg every 28 days (q28d) im	79
Everolimus everolimus 10 mg once daily po alone	81
Total	160

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Administrative problems	1	0

Baseline characteristics

Characteristic	Paseriotide LAR + Everolimus	Everolimus	Total
Age, Continuous	56.52 Years STANDARD_DEVIATION 11.978	58.22 Years STANDARD_DEVIATION 12.65	57.38 Years STANDARD_DEVIATION 12.314
Gender Female	40 Participants	34 Participants	74 Participants
Gender Male	39 Participants	47 Participants	86 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	77 / 78	80 / 81
serious Total, serious adverse events	41 / 78	49 / 81

Outcome results

Primary

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.

Time frame: Once 80 PFS events had occurred aproximately after 24 months

Population: The FAS consisted of all randomized patients. Following the intention to treat principle patients were analyzed according to the treatment (and stratum) they were assigned to at randomization.~One patient in the everolimus + pasireotide LAR treatment arm was untreated due to administrative problems.

Arm	Measure	Value (MEDIAN)
Paseriotide LAR + Everolimus	Progression-free Survival (PFS) Per Local Radiological Review	16.82 months
Everolimus	Progression-free Survival (PFS) Per Local Radiological Review	16.59 months

p-value: 0.48895% CI: [0.636, 1.543]Log Rank

Secondary

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.

Time frame: Once 80 PFS events had occurred

Population: The FAS consisted of all randomized patients.1 patient in the everolimus + pasireotide LAR treatment arm was untreated due to administrative problems. The study was terminated because the study did not meet its primary objective so minimal efficacy data was obtained.

Arm	Measure	Value (NUMBER)
Paseriotide LAR + Everolimus	Disease Control Rate (DCR) as Per Radiology Review	77.2 Percentage of participants
Everolimus	Disease Control Rate (DCR) as Per Radiology Review	82.7 Percentage of participants

Secondary

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.

Time frame: Once 80 PFS events had occurred

Population: The FAS consisted of all randomized patients. Only a low number of objective responses per RECIST was 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.

Secondary

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.

Time frame: Once 80 PFS events had occurred

Arm	Measure	Value (NUMBER)
Paseriotide LAR + Everolimus	Objective Response Rate (ORR) as Per Radiology Review	20.3 Percentage of participants
Everolimus	Objective Response Rate (ORR) as Per Radiology Review	6.2 Percentage of participants

Secondary

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.

Time frame: Once 80 PFS events had occurred

Arm	Measure	Group	Value (NUMBER)
Paseriotide LAR + Everolimus	Overall Survival (OS) Using Kaplan Meier Method	6 months	93.5 Percentage of participants
Paseriotide LAR + Everolimus	Overall Survival (OS) Using Kaplan Meier Method	12 months	85.5 Percentage of participants
Paseriotide LAR + Everolimus	Overall Survival (OS) Using Kaplan Meier Method	18 months	81.4 Percentage of participants
Paseriotide LAR + Everolimus	Overall Survival (OS) Using Kaplan Meier Method	24 months	77.0 Percentage of participants
Everolimus	Overall Survival (OS) Using Kaplan Meier Method	24 months	71.0 Percentage of participants
Everolimus	Overall Survival (OS) Using Kaplan Meier Method	6 months	93.7 Percentage of participants
Everolimus	Overall Survival (OS) Using Kaplan Meier Method	18 months	75.5 Percentage of participants
Everolimus	Overall Survival (OS) Using Kaplan Meier Method	12 months	86.1 Percentage of participants

Secondary

PFS and the Predictive Probability of Success in Phase III

105 PFS events expected after approximately 36 months

Time frame: Once 105 PFS events had occurred occurred

Population: Since the study was terminated because the study did not meet its primary objective which was based on PFS as per local radiology assessment, minimal efficacy data was obtained. Only 80 PFS events occurred before study was terminated so 105 PFS events was not reached to analyze this data.

Secondary

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.

Time frame: Once 80 PFS events had occurred

Population: Safety analysis population included all patients who received any study medication (i.e. at least 1 dose of the study drug in case of monotherapy or at least 1 dose of any 1 compound of the study treatment in case of a combination therapy) with a post-Baseline safety assessment.~See Adverse Events (AE) section for all AEs collected.

Arm	Measure	Group	Value (NUMBER)
Paseriotide LAR + Everolimus	Safety and Tolerability Profile of Everolimus Alone or in Combination With Pasireotide LAR	Deaths	7 Participants
Paseriotide LAR + Everolimus	Safety and Tolerability Profile of Everolimus Alone or in Combination With Pasireotide LAR	Serious Adverse Events	41 Participants
Paseriotide LAR + Everolimus	Safety and Tolerability Profile of Everolimus Alone or in Combination With Pasireotide LAR	Adverse Events	78 Participants
Everolimus	Safety and Tolerability Profile of Everolimus Alone or in Combination With Pasireotide LAR	Deaths	10 Participants
Everolimus	Safety and Tolerability Profile of Everolimus Alone or in Combination With Pasireotide LAR	Serious Adverse Events	49 Participants
Everolimus	Safety and Tolerability Profile of Everolimus Alone or in Combination With Pasireotide LAR	Adverse Events	81 Participants

Secondary