Trial Outcomes & Findings for Everolimus and Octreotide in Patients With Advanced Carcinoid Tumor (NCT NCT00412061)

NCT ID: NCT00412061

Last Updated: 2014-11-21

Results Overview

Progression free survival (PFS) is defined as the time from randomization to the date of first documented disease progression or death from any cause. The primary analysis of PFS was based on the independent central adjudicated assessment using Kaplan-Meier method.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

429 participants

Primary outcome timeframe

Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010

Results posted on

2014-11-21

Participant Flow

Total 429 patients were randomized to double blind phase of treatment. 170 patients moved to the Open Label Phase.

Participant milestones

Participant milestones
Measure	Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.	Octreotide+ Placebo Followed by Open Label Arm Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1. Open Label - Patients who had progressive disease in this arm, can move to the open label Everolimus + depot octreotide by choice.
Double Blind Phase STARTED	216	213
Double Blind Phase Safety Set	215	211
Double Blind Phase COMPLETED	0	0
Double Blind Phase NOT COMPLETED	216	213
Open Label Phase STARTED	0	170
Open Label Phase COMPLETED	0	0
Open Label Phase NOT COMPLETED	0	170

Reasons for withdrawal

Reasons for withdrawal
Measure	Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.	Octreotide+ Placebo Followed by Open Label Arm Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1. Open Label - Patients who had progressive disease in this arm, can move to the open label Everolimus + depot octreotide by choice.
Double Blind Phase Disease Progression	101	154
Double Blind Phase Adverse Event	61	16
Double Blind Phase Final Primary Analysis	26	14
Double Blind Phase Withdrawal by Subject	18	20
Double Blind Phase Death	6	3
Double Blind Phase Protocol Violation	3	4
Double Blind Phase New Cander Therapy	1	1
Double Blind Phase Lost to Follow-up	0	1
Open Label Phase Disease Progression	0	86
Open Label Phase Adverse Event	0	46
Open Label Phase Withdrawal by Subject	0	15
Open Label Phase Administrative Problems	0	13
Open Label Phase Death	0	7
Open Label Phase Lost to Follow-up	0	2
Open Label Phase New Cancer Therapy	0	1

Baseline Characteristics

Everolimus and Octreotide in Patients With Advanced Carcinoid Tumor

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Octreotide+ Everolimus n=216 Participants Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.	Octreotide+ Placebo n=213 Participants Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.	Total n=429 Participants Total of all reporting groups
Age, Continuous	60.1 years STANDARD_DEVIATION 10.72 • n=5 Participants	59.4 years STANDARD_DEVIATION 11.13 • n=7 Participants	59.8 years STANDARD_DEVIATION 10.92 • n=5 Participants
Sex: Female, Male Female	119 Participants n=5 Participants	89 Participants n=7 Participants	208 Participants n=5 Participants
Sex: Female, Male Male	97 Participants n=5 Participants	124 Participants n=7 Participants	221 Participants n=5 Participants

PRIMARY outcome

Timeframe: Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010

Population: The Full Analysis Set (FAS) consisted of all randomized patients.

Outcome measures

Outcome measures
Measure	Octreotide+ Everolimus n=216 Participants Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.	Octreotide+ Placebo n=213 Participants Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
Progression Free Survival (PFS) as Per Adjudicated Central Radiology Review	16.43 Months Interval 13.67 to 21.19	11.33 Months Interval 8.44 to 14.59

SECONDARY outcome

Population: The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients.

The best overall response rate is defined as the percentage of patients having achieved confirmed Complete Response + Partial Response. Complete Response (CR) = at least two determinations of CR at least 4 weeks apart before progression. • Partial response (PR) = at least two determinations of PR or better at least 4 weeks apart before progression.

Outcome measures

Outcome measures
Measure	Octreotide+ Everolimus n=216 Participants Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.	Octreotide+ Placebo n=213 Participants Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
Best Overall Response Rate as Per Adjudicated Central Radiology Review Based on Response Evaluation Criteria in Solid Tumors (RECIST)	2.3 Percentage of patients Interval 0.8 to 5.3	1.9 Percentage of patients Interval 0.5 to 4.7

SECONDARY outcome

Timeframe: If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010

Population: The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients. This analysis includes PFS patients with non missing baseline 5-HIAA data.

5-HIAA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of 5-HIAA in urine were defined as 'High' if they exceeded the median value, and 'Low' if they were lower than or equal to the median.

Outcome measures

Outcome measures
Measure	Octreotide+ Everolimus n=187 Participants Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.	Octreotide+ Placebo n=191 Participants Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level 5-HIAA <=median (n=93,96)	21.75 Months Interval 13.93 to Upper Limit was not applicable or computable as median was just reached.	13.90 Months Interval 8.71 to 22.44
Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level 5-HIAA > median (n=94,95)	13.83 Months Interval 10.61 to 18.63	8.41 Months Interval 8.08 to 11.33

SECONDARY outcome

Timeframe: Months 12, 24, 36, 48

Population: The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients.

Overall survival was defined as the time from the date of randomization to the date of death from any cause. If a patient was not known to have died, survival was censored at the date of last contact. Kaplan-Meier methodology was used to estimate the median overall survival for each treatment group.

Outcome measures

Outcome measures
Measure	Octreotide+ Everolimus n=216 Participants Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.	Octreotide+ Placebo n=213 Participants Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
Overall Survival Using Kaplan-Meier Methodology 12 Months	80.5 Percentage of Participants Interval 74.5 to 85.3	81.8 Percentage of Participants Interval 75.8 to 86.4
Overall Survival Using Kaplan-Meier Methodology 24 Months	57.0 Percentage of Participants Interval 49.9 to 63.4	63.6 Percentage of Participants Interval 56.6 to 69.8
Overall Survival Using Kaplan-Meier Methodology 36 Months	42.9 Percentage of Participants Interval 36.0 to 49.6	48.5 Percentage of Participants Interval 41.4 to 55.3
Overall Survival Using Kaplan-Meier Methodology 48 Months	38.0 Percentage of Participants Interval 31.2 to 44.7	41.6 Percentage of Participants Interval 34.6 to 48.5

SECONDARY outcome

Timeframe: From first day of treatment up to 28 days after last day of treatment in double blind

Population: The Safety Set consists of all patients who received at least one dose of study drug and who had at least one valid post-baseline safety assessment.

AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.

Outcome measures

Outcome measures
Measure	Octreotide+ Everolimus n=215 Participants Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.	Octreotide+ Placebo n=211 Participants Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) Clinically notable AE	208 Patients	146 Patients
Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) Grade 3-4 Adverse Events	162 Patients	109 Patients
Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) On treatment death	19 Patients	11 Patients
Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) Serious adverse events	126 Patients	74 Patients

SECONDARY outcome

Timeframe: From first day of treatment up to 28 days after last day of treatment in double blind

Population: The Safety Set consists of all patients who received at least one dose of study drug and who had at least one valid post-baseline safety assessment.

Outcome measures

Outcome measures
Measure	Octreotide+ Everolimus n=170 Participants Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.	Octreotide+ Placebo Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase) Clinically notable AE	154 Patients	—
Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase) Grade 3-4 Adverse Events	115 Patients	—
Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase) On treatment death	22 Patients	—
Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase) Serious adverse events	93 Patients	—

SECONDARY outcome

Timeframe: If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010

Population: The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients. This analysis includes PFS patients with non missing baseline CgA data.

Serum CgA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of serum CgA were characterized relative to the upper limited of normal (ULN). CgA levels exceeding 2 x ULN were considered to be 'Elevated'; otherwise considered as "Non-elevated".

Outcome measures

Outcome measures
Measure	Octreotide+ Everolimus n=212 Participants Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.	Octreotide+ Placebo n=208 Participants Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA) CgA<=2x ULN (n=60,78)	31.31 Months Interval 19.32 to Upper Limit was not applicable or computable as median was just reached.	20.07 Months Interval 13.04 to Upper Limit was not applicable or computable as median was just reached.
Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA) CgA>2x ULN (n=152,130)	13.93 Months Interval 11.3 to 17.08	8.41 Months Interval 7.72 to 11.14

Adverse Events

Everolimus + Octreotide

Serious events: 126 serious events

Other events: 214 other events

Deaths: 0 deaths

Placebo + Octreotide

Serious events: 74 serious events

Other events: 194 other events

Deaths: 0 deaths

Everolimus Open Label

Serious events: 93 serious events

Other events: 162 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER