NCT01136733 · OUTCOME

Phase 2: Objective Response Rate (ORR)

A Study of E7080 Alone, and in Combination With Everolimus in Subjects With Unresectable Advanced or Metastatic Renal Cell Carcinoma Following One Prior Vascular Endothelial Growth Factor (VEGF)-Targeted Treatment · Source last updated 2019-02-27

Results reported by the registry submitting party. Population, time horizon, units and missing values must be read together.

Measure: NUMBER
Unit: Percentage of participants
Interval / dispersion: 95% Confidence Interval
Time frame: Randomization (Cycle 1 Day 1) until first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months

What was measured

The ORR was defined as the percentage of participants who had the best overall response (BOR) of complete response (CR) or partial response (PR) as determined by the investigator, using RECIST 1.1 in the evaluation of MRI or CT scans of targeted lesions. Tumor assessments were performed every 8 weeks (or sooner if there was evidence of progressive disease). The BOR was defined as the best response recorded from the start of the study treatment until discontinuation from the study. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR = CR + PR was calculated with exact 95% CIs using the method of Clopper and Pearson.

Analysis population: Full analysis set which included all randomized participants.

Groups in this outcome

Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus

Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped.

Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus

Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.

Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus

Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.

Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus

The DLT was achieved and no participants were enrolled into this cohort.

Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus

Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.

Phase 2 (Arm B): 24 mg Lenvatinib

Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.

Phase 2 (Arm C): 10 mg Everolimus

Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.

Group identifiers and denominators belong to this outcome only. They may differ in another outcome or in safety reporting.

Analysis denominator · Participants

Group	Source count
Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	0
Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	0
Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	0
Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	0
Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	51
Phase 2 (Arm B): 24 mg Lenvatinib	52
Phase 2 (Arm C): 10 mg Everolimus	50

Reported measurements

Source class 1

Values in Percentage of participants · Interval/dispersion: 95% Confidence Interval
Group	Value	Spread	Lower	Upper	Comment
Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	43.1	Not reported	29.3	57.8	Not reported
Phase 2 (Arm B): 24 mg Lenvatinib	26.9	Not reported	15.6	41.0	Not reported
Phase 2 (Arm C): 10 mg Everolimus	6.0	Not reported	1.3	16.5	Not reported

Source statistical analyses

Group order, estimate direction, methods and comments are retained. No treatment ranking is inferred.

ci Lower Limit
2.3
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
22.5
estimate Comment
Rate ratio was based on the normal approximation.
group Ids
OG004
OG006
non Inferiority Type
SUPERIORITY_OR_OTHER
p Value
<0.0001
p Value Comment
Analysis performed after database lock. P-value was based on the 2-sided Fisher's exact P-value.
param Type
Rate ratio
param Value
7.2
statistical Method
Fisher Exact
ci Lower Limit
1.4
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
14.7
group Ids
OG005
OG006
non Inferiority Type
SUPERIORITY_OR_OTHER
p Value
0.0067
p Value Comment
Analysis performed after database lock. P-value was based on the 2-sided Fisher's exact P-value.
param Type
Rate ratio
param Value
4.5
statistical Method
Fisher Exact
ci Lower Limit
0.9
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
2.8
group Ids
OG004
OG005
non Inferiority Type
SUPERIORITY_OR_OTHER
p Value
=0.1007
p Value Comment
Analysis performed after database lock. P-value was based on the 2-sided Fisher's exact P-value.
param Type
Rate ratio
param Value
1.6
statistical Method
Fisher Exact

Complete source fields

analyses

ci Lower Limit
2.3
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
22.5
estimate Comment
Rate ratio was based on the normal approximation.
group Ids
OG004
OG006
non Inferiority Type
SUPERIORITY_OR_OTHER
p Value
<0.0001
p Value Comment
Analysis performed after database lock. P-value was based on the 2-sided Fisher's exact P-value.
param Type
Rate ratio
param Value
7.2
statistical Method
Fisher Exact
ci Lower Limit
1.4
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
14.7
group Ids
OG005
OG006
non Inferiority Type
SUPERIORITY_OR_OTHER
p Value
0.0067
p Value Comment
Analysis performed after database lock. P-value was based on the 2-sided Fisher's exact P-value.
param Type
Rate ratio
param Value
4.5
statistical Method
Fisher Exact
ci Lower Limit
0.9
ci Num Sides
TWO_SIDED
ci Pct Value
95
ci Upper Limit
2.8
group Ids
OG004
OG005
non Inferiority Type
SUPERIORITY_OR_OTHER
p Value
=0.1007
p Value Comment
Analysis performed after database lock. P-value was based on the 2-sided Fisher's exact P-value.
param Type
Rate ratio
param Value
1.6
statistical Method
Fisher Exact

classes

categories
measurements
group Id
OG004
lower Limit
29.3
upper Limit
57.8
value
43.1
group Id
OG005
lower Limit
15.6
upper Limit
41.0
value
26.9
group Id
OG006
lower Limit
1.3
upper Limit
16.5
value
6.0

denoms

counts
group Id
OG000
value
0
group Id
OG001
value
0
group Id
OG002
value
0
group Id
OG003
value
0
group Id
OG004
value
51
group Id
OG005
value
52
group Id
OG006
value
50
units
Participants

description

dispersion Type

95% Confidence Interval

groups

description
Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped.
id
OG000
title
Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus
description
Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.
id
OG001
title
Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus
description
Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.
id
OG002
title
Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus
description
The DLT was achieved and no participants were enrolled into this cohort.
id
OG003
title
Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus
description
Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.
id
OG004
title
Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus
description
Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.
id
OG005
title
Phase 2 (Arm B): 24 mg Lenvatinib
description
Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.
id
OG006
title
Phase 2 (Arm C): 10 mg Everolimus

param Type

NUMBER

population Description

Full analysis set which included all randomized participants.

reporting Status

POSTED

time Frame

Randomization (Cycle 1 Day 1) until first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months

title

Phase 2: Objective Response Rate (ORR)

type

SECONDARY

unit Of Measure

Percentage of participants

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Preserved source evidence · Not medical advice