BRISTOL-MYERS SQUIBB COMPANY - Clinical Trials

BRISTOL-MYERS SQUIBB COMPANY
CETUXIMAB
Final Clinical Study Report for Study CA225315
A Study to Evaluate the Relationship Between Cetuximab Therapy and
Corrected QT (QTc) Interval Changes in Patients with Advanced
Maligancies from Solid Tumors
Indication:
Phase:
Study Initiation Date:
Study Completion Date:
Report Date:
Oncology
2A
23-Feb-2009
01-Feb-2010
29-Jul-2010
Document Control Number: 930044979
THIS STUDY WAS CONDUCTED IN ACCORDANCE WITH GOOD CLINICAL PRACTICE
Sponsor’s Responsible Medical Officer:
Jaspreet Jaggi, MD, PhD
Bristol-Myers Squibb
Princeton, NJ 08536 USA
This document is a confidential communication of Bristol-Myers Squibb Company. Acceptance of this
document constitutes an agreement by the recipient that no unpublished information contained herein will
be published or disclosed without Bristol-Myers Squibb Company's prior written approval.
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Name of Sponsor/Company:
Eli Lilly and Bristol-Myers
Squibb
Name of Finished Product:
Erbitux ®
Name of Active Ingredient:
Cetuximab
Individual Study Table Referring
to the Dossier
CA225315
Final Clinical Study Report
(For National Authority Use
Only)
SYNOPSIS
Final Clinical Study Report for Study CA225315
TITLE OF STUDY: A Study to Evaluate the Relationship Between Cetuximab Therapy and Corrected
QT (QTc) Interval Changes in Patients with Advanced Malignancies from Solid Tumors
INVESTIGATORS/STUDY CENTERS: The study was conducted at 20 centers in the United States
(US), with 16 of the centers enrolling at least 1 subject and 14 of the centers treating at least 1 subject.
PUBLICATIONS: None
STUDY PERIOD: Study Initiation Date: 23-Feb-2009 CLINICAL PHASE: 2A
Study Completion Date: 01-Feb-2010
OBJECTIVES:
The primary objective was to assess the change in QT/QTc interval from time-matched baseline in the
study population.
The secondary objective was to assess the safety and tolerability of cetuximab administration in the study
population.
METHODOLOGY:
This was a multicenter, non-randomized, single-arm, monotherapy study to determine the effect, degree of
effect, or lack of effect of cetuximab on the QTc interval in subjects with advanced malignancies originated
from solid tumors.
The study consisted of a screening period for determination of study eligibility, a baseline
electrocardiogram (ECG) period (Day -7 to Day -4), an on-treatment ECG period (Day 1 to completion of
Day 29 ECGs), and an on-treatment post-ECG period (after completion of Day 29 ECGs to the off-study
day). In addition, subjects who discontinued treatment at or prior to the Week 8 infusion of cetuximab were
followed for toxicity during the post-treatment period.
Eligible subjects who met all criteria for enrollment received weekly cetuximab infusions at an initial dose
of 400 mg/m 2 intravenously (IV) on Day 1 (Week 1) followed by a maintenance dose of 250 mg/m 2 IV on
Days 8, 15, 22, and 29 (Weeks 2 to 5) and Weeks 6 through 8. Premedication with diphenhydramine
hydrochloride (HCl) 50 mg IV was administered prior to the first 5 infusions, and thereafter at the
discretion of the investigator. Diphenhydramine HCl was also administered during collection of baseline
ECGs on Days -7 to -4. During Weeks 6 to 8, subjects may have received additional therapies (e.g.,
chemotherapy, radiation therapy), if medically indicated. Holter monitoring for collection of digital 12-lead
ECGs and serum sampling for cetuximab concentrations were performed during the baseline ECG period
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and on Days 1, 8, 15, 22, and 29. Physical examinations, chest x-rays, clinical laboratory tests, and
assessments of vital signs and Eastern Cooperative Oncology Group (ECOG) performance status were also
performed at selected times during the study. Subjects were closely monitored for adverse events (AEs)
throughout the study. At the end of Week 8, subjects were evaluated for disease progression according to
institutional standard of care. Subjects with progressive disease were discontinued from cetuximab therapy,
while subjects without progressive disease or intolerable toxicity were permitted to continue to receive
cetuximab therapy via the post-study drug program.
A complete treatment cycle consisted of 4 weeks of cetuximab therapy. The approximate duration of study
participation for each subject who completed the study, from baseline through the last on-study day, was
approximately 9 weeks.
NUMBER OF SUBJECTS (Planned and Analyzed):
Thirty-two (32) evaluable subjects were planned, 51 subjects were treated, and 37 subjects were considered
evaluable for QT/QTc and were included in the ECG analyses.
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION:
Male and female subjects ≥ 18 years of age who had histologically or cytologically documented advanced
or metastatic malignant disease of solid tumor origin that was considered measurable and/or evaluable, and
who had adequately recovered from prior therapy or interventions, were eligible to participate in the study.
Women of childbearing potential (WOCBP) were excluded from participation if they were nursing,
pregnant, or unwilling or unable to use an acceptable method of contraception during the study and for a
period of at least 12 weeks after the last on-study dose of cetuximab. All WOCBP were required to have a
negative pregnancy test within 72 hours prior to administration of cetuximab on Day 1. Male subjects were
excluded from study participation if they were unwilling to use an acceptable method of contraception
during the study if having sexual relations with a female partner of childbearing potential.
TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, DURATION OF TREATMENT,
BATCH NUMBERS:
All subjects received cetuximab at an initial dose of 400 mg/m 2 IV over 120 minutes followed by weekly
maintenance dose of 250 mg/m 2 IV over 60 minutes for a total of up to 8 on-study infusions. Cetuximab
for injection was supplied by Bristol-Myers Squibb (BMS) in 50-mL single-use vials containing 100 mg of
cetuximab as a clear, colorless 2 mg/mL solution in phosphate buffered saline (Batch number 08C00190).
The contents of the vial were administered without dilution.
Prior to each IV infusion of cetuximab on Weeks 1 to 5, subjects received an IV infusion of
diphenhydramine HCl 50 mg over 15 minutes. On the baseline day, subjects received an IV infusion of
diphenhydramine HCl 50 mg over 15 minutes followed by 0.9% normal saline at 75 to 100 mL/hr.
Diphenhydramine HCl was administered at the discretion of the investigator on Weeks 6 to 8.
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, DURATION OF
TREATMENT, BATCH NUMBERS:
No reference therapy was administered in this study.
CRITERIA FOR EVALUATION:
Safety: The primary ECG endpoint was the time-matched mean change from baseline (designated as “∆”)
in QTc at each ECG sampling timepoint. Cetuximab concentration-to-QTc relationship was also evaluated.
Similar endpoints were evaluated for PR interval, QRS interval, and ECG-derived heart rate (HR). The
general safety assessment was based on medical review of reported AEs and the results of vital sign
measurements, physical examinations, and clinical laboratory tests. The incidence of observed AEs was
tabulated and reviewed for potential significance and clinical importance.
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Pharmacokinetics: Serum cetuximab concentrations were measured at pre-dose and each ECG timepoint
during/after infusion of cetuximab to permit a concentration-response analysis. Cetuximab pharmacokinetic
(PK) parameters were not estimated in this study.
STATISTICAL CONSIDERATIONS:
Sample Size Determination: This was a single-arm estimation trial; the sample size was not based on
statistical power calculation. At each ECG sampling timepoint, the time-matched mean ∆QTc was
estimated, and a one-sided upper 95% confidence limit was constructed for the population means of ∆QTc
based on the assumption that ∆QTc was normally distributed with a standard deviation of 20 msec. The
20 msec standard deviation was chosen based on data from single-arm Phase 2 oncology trials previously
conducted by BMS. Per protocol, the study remained open to enrollment until 32 evaluable subjects had
completed the required study assessments. If the estimated population mean for ∆QTc was 4 msec at a
given ECG sampling timepoint, then 32 subjects would have a one-sided upper 95% confidence limit
(-∞, 9.815). If the estimated population mean for ∆QTc was 0 msec at a given ECG sampling timepoint,
then 32 evaluable subjects would have a one-sided upper 95% confidence limit (-∞, 5.815).
Statistical Analysis:
Safety: Adverse events and laboratory tests were summarized for all treated subjects.
All treated subjects who met all inclusion criteria and none of the exclusion criteria, and who were not
considered unevaluable based on any of the protocol-specified criteria were included in the ECG analysis
described below. Fridericia’s correction formula was used to calculate the heart rate-corrected QT interval
(QTcF). For each ECG parameter (QT, QTc, RR, QRS, PR, and HR), the mean of the triplicate
measurements at each timepoint was considered for all analyses. ECG measurements collected on the
baseline day were used to compute time-matched change from baseline for each ECG parameter. Individual
ECG parameter measurements and corresponding changes from baseline were listed, and values outside a
normal range were flagged. ECG abnormalities identified by the ECG core laboratory were listed.
QTc Analysis of Central Tendency: The effect of cetuximab on the QTc interval was assessed by summary
statistics (n, mean, standard error, minimum, and maximum) for QTc and time-matched ∆QTc, and
examination of plots of mean (+ one-sided upper 95% confidence limit) QTc and time-matched ∆QTc
versus time since dosing. At each ECG sampling timepoint, the mean time-matched ∆QTc was estimated
and a one-sided upper 95% confidence limit was constructed for the population means of ∆QTc at the
timepoint.
QTc Categorical Analysis: The effect of cetuximab on QTc interval was also assessed by frequency
distributions (n, percentage) for subjects meeting or exceeding predefined values for maximum QTc (≤
450 msec, > 450-480 msec, > 480-500 msec, > 500 msec) and maximum time-matched ∆QTc (≤ 30 msec,
> 30-60 msec, > 60 msec).
QTc Concentration-Response Analysis: Cetuximab concentration-QTc response was explored graphically
using double y-axis plots of mean time-matched ∆QTc and mean drug concentration versus time since
dosing and scatter plots of individual subjects’ QTc and time-matched ∆QTc values versus the nearest
corresponding serum drug concentrations. For the plot of time-matched ∆QTc versus drug concentrations,
the estimated linear regression, taken from the results of fitting a random intercept and slope model with
cetuximab concentration as the only covariate to the data, was included in the plot.
QRS, PR, HR analyses: The effect of cetuximab on QRS and PR intervals and HR was assessed by
summary statistics for reported values and the corresponding time-matched changes from baseline, and
examination of plots of mean (+ standard error) reported values and time-matched mean changes from
baseline versus time since dosing. Cetuximab concentration-response was explored graphically as
described above for QTc, but regression analysis was not performed.
Pharmacokinetics: Cetuximab concentrations were listed. No PK data analysis was planned or conducted.
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SUMMARY OF RESULTS:
Disposition and Baseline/Demographic Characteristics:
Fifty-one (51) of the 79 enrolled subjects received at least 1 infusion of cetuximab in the study. The
disposition of these treated subjects is summarized in Table 1. Demographic and pretreatment
characteristics of treated subjects are summarized in Table 2.
Table 1:
Subject Disposition
Overall
No. of Subjects Enrolled 79
No. of Subjects Treated 51
No. of Subjects Excluded from ECG Analysis 14
No. of Subjects Discontinued a 18
Disease progression 7
AE unrelated to study drug 3
Study drug toxicity 2
Withdrawal of consent 2
Failure to meet criteria for continuing treatment 2
Other 2
a Includes subjects discontinuing prior to Week 8.
Table 2:
Characteristics
Age, years
Mean (SD)
Range
Gender, n (%)
Male
Female
Race, n (%)
White
Black
Asian
Other
ECOG Status, n (%)
0
1
2
Demographic and Pretreatment Characteristics
Treated Subjects
(N=51)
61 (12)
38, 84
30 (59)
21 (41)
45 (88)
1 (2)
4 (8)
1 (2)
16 (31)
30 (59)
5 (10)
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Safety Results:
Lack of effect on QTc interval was demonstrated at the approved dose and dosing schedule of cetuximab.
The one-sided upper 95% confidence limit for the time-matched mean ∆QTcF was < 10 msec at all
timepoints (Figure 1).
Figure 1:
Time-matched Mean (+95% CI) ∆QTcF Versus Time Since Dosing on Each
Study Day - All QTc Evaluable Subjects
There were no QTcF values > 500 msec and no time-matched ∆QTcF values ≥ 60 msec. One subject with a
history of hypertension and evidence of prior inferior myocardial infarction on baseline ECGs had mean
QTcF interval readings ≥ 480 msec and ≤ 500 msec at 2 timepoints on Day 22 (481 msec and 483 msec at 1
hour and 2 hours, respectively). Thirteen (13) subjects had a maximum time-matched ∆QTcF > 30 msec
and ≤ 60 msec at one or more timepoints during the study. There did not appear to be any trends over time
in the incidence of these outliers.
No concentration-related trends were apparent in QTcF or ∆QTcF based on examination of scatter plots of
QTcF and time-matched ∆QTcF (Figure 2) versus serum cetuximab concentration for each study day, and a
double y-axis plot of time-matched mean ∆QTcF and mean cetuximab concentration versus time since
dosing. Regression analysis on scatter plots for ∆QTcF yielded point estimates for the slope of the
regression line ranging from -0.018 to +0.026 msec per ng/mL with two-sided 90% confidence intervals
encompassing zero.
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Figure 2:
CA225315
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Scatter Plots of Time-matched ∆QTcF Versus Cetuximab Concentration on
Each Study Day - All QTc Evaluable Subjects
Cetuximab had no effect on PR interval, QRS interval, or HR based on examination of summary statistics
for each parameter and corresponding time-matched changes from baseline, as well as plots of mean values
and time-matched mean values versus time since dosing. Eight (8) subjects had PR interval measurements
> 200 msec on-study, each of whom also had baseline PR interval measurements > 200 msec. No subject
had a QRS interval measurement > 120 msec during the study. Fifteen (15) subjects had a HR measurement
> 100 bpm at baseline and/or on-study. There did not appear to be any trends over time in the incidence of
these outliers. No concentration-related trends were apparent in PR, QRS, or HR based on examination of
scatter plots of reported values and corresponding time-matched changes from baseline versus cetuximab
concentration. The most frequently reported ECG conduction abnormality was a non-specific
intraventricular conduction defect, and the most frequently reported ECG rhythm abnormality was sinus
tachycardia. Overall, 22 subjects had 1 or more abnormal ECGs that the consulting cardiologist assessed as
potentially clinically significant. Ten (10) of these subjects had abnormal ECGs of potential clinical
significance at screening or baseline only. In the other 12 subjects, abnormalities of potential clinical
significance were generally reported both prior to and after initiation of cetuximab treatment. These
abnormalities included but were not limited to evidence of MI and/or conduction defects such as inverted T
waves, ST depression, and first degree atrioventricular (AV) block. One ECG-related AE (anterolateral
myocardial infarction) was reported by the investigator, and was assessed as unrelated to treatment with
cetuximab.
Table 3 provides an overview of safety for treated subjects. Forty-nine (49) subjects reported at least 1 AE
while on study. These on-study AEs were consistent with the known safety profile for cetuximab, and most
frequently included rash, headache, dermatitis acneiform, and nausea. The majority of on-study AEs were
assessed by the investigator as Grade 1 or Grade 2.
No cetuximab-related deaths were reported. Six (6) subjects died on-study due to complications related to
underlying disease. An additional 10 subjects reported 1 or more non-fatal serious adverse events (SAEs).
SAEs in 8 subjects were assessed as unrelated to cetuximab, including the one Grade 4 event reported
during the study (pain). Two (2) subjects experienced serious infusion reactions during administration of
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the first infusion of cetuximab. These reactions were reported by the investigator as treatment-related
Grade 3 SAEs of infusion-related reaction in 1 subject and bronchospasm and dyspnoea in the other
subject, and resulted in discontinuation of cetuximab therapy. One (1) other subject discontinued therapy
due to disease progression coincident with treatment-related AEs that were reported as leading to
discontinuation of therapy (nausea, blisters, vomiting, and pustular rash). An additional 7 subjects
discontinued therapy due to AEs that were considered unrelated to cetuximab.
Table 3:
Summary of Safety - Treated Subjects
Number of Subjects (%)
Any Event
Treatment-Related Event
Deaths 6 (11.8) 0
SAEs 16 (31.4) 2 (3.9)
AEs leading to discontinuation 10 (19.6) 3 (5.9) a
Common AEs
Rash 22 (43.1) 21 (41.2)
Headache 12 (23.5) 3 (5.9)
Dermatitis acneiform 9 (17.6) 9 (17.6)
Nausea 6 (11.8) 2 (3.9)
a One (1) subject discontinued therapy due to disease progression coincident with the development of AEs
reported by the investigator as leading to discontinuation of cetuximab treatment.
Adverse events of special interest for cetuximab were evaluated in this study under the composite
categories of acneform rash, infusion reactions, and cardiac events. Acneform rash and infusion reactions
were reported (any grade) for 62.7% and 11.8% of treated subjects, respectively, and all of these events
were treatment-related with the exception of a single event of rash. Cardiac events were reported for
2 subjects (myocardial infarction and acute coronary syndrome, respectively) and were not considered
treatment-related or associated with unusual or clinically-important ECG findings.
The majority of laboratory values were Grade 0, 1, or 2, and only 1 Grade 4 abnormality
(hypomagnesemia) was reported during the on-study period. Review of laboratory data from this study do
not reveal any new safety concerns for cetuximab.
Pharmacokinetic Results: All subjects had quantifiable cetuximab concentrations at each ECG timepoint
after the initial infusion of cetuximab, with the exception of 1 subject with a non-quantifiable pre-dose level
on Week 4 and 1 subject with non-quantifiable levels at 2 hours and 3 hours on Week 1. CONCLUSIONS:
• Cetuximab treatment had no clinically-meaningful effect on QTc interval in humans at the
recommended dose.
• There was no apparent concentration-dependent effect of cetuximab on QTc interval.
• No effect of cetuximab treatment was apparent on PR interval, QRS interval, or HR, and no
concentration-response relationship was observed for any of these ECG parameters.
• Safety observations in subjects treated with cetuximab in this study were consistent with the
known safety profile for cetuximab.
DATE OF REPORT: 29-Jul-2010
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