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Erlotinib (Tarceva®) ISN OSI-774-302Non-small cell lung cancer (5901-CL-0302)CONFIDENTIAL EudraCT Number 2005-001747-29
Name of Sponsor/Company: Astellas Pharma Global
Development, Inc. on behalf of OSI Pharmaceuticals,
LLC
Name of Finished Product: Tarceva®
Name of Active Ingredient: Erlotinib
Dec 2014 Astellas Synopsis Page 1 of 19
SYNOPSIS
Title of Study: A multicenter, randomized, double-blind, placebo-controlled, phase 3 study of single-agent
Tarceva® (erlotinib) following complete tumor resection with or without adjuvant chemotherapy in patients
with stage IB-IIIA non-small cell lung carcinoma who have EGFR-positive tumors
(OSI-774-302 [5901-CL-0302])
This synopsis presents results from the subset of 277 patients who were originally enrolled in
Study OSI-774-302 but were evaluated separately from the main study population (randomized cohort) due to a
breach in the protocol.
Investigators/Coordinating Investigator: , MB BCh, MRCP, MD (
UK)
Study Centers: The study was conducted at 109 sites in a total of 16 countries and regions including Argentina,
Australia, Austria, Belgium, Canada, France, Germany, Hungary, Poland, Romania, Russia, South Korea,
Spain, Taiwan, the United Kingdom/England and the United States of America.
Publication Based on the Study: None.
Study Period: Up to 2 years on treatment with long-term follow-up until death or until the primary disease-free
survival (DFS) objective in the randomized cohort study was satisfied.
Study Initiation Date (Date of First Enrollment): 19 September 2006
Study Completion Date (Date of Last Evaluation): 08 April 2013
Phase of Development: Phase 3
Objectives: The study objectives remained the same as described in the randomized cohort Study OSI-774-302
clinical study report (CSR). Data from patients in the breached-protocol cohort (BPC) were not included in the
assessments of primary or secondary endpoints in the randomized cohort and were not considered part of the
primary analyses. Efficacy data were considered exploratory.
Methodology: After the initiation of the randomized cohort study, OSI Pharmaceuticals became aware of an
error in the drug dispensing module of the interactive voice response system (IVRS) that resulted in a protocol
violation for patients who were randomized prior to 07 November 2007. Codes associated with study drug
bottle assignments were incorrect, resulting in approximately 80% of the patients randomized by this date
having been assigned an incorrect bottle at least once and often multiple times during their participation in the
study. These patients (a total of 277) are referred to as the BPC. The independent Data Safety and Monitoring
Board (DSMB) overseeing Study OSI-774-302 was consulted, and in their judgment, the issue had no effect on
patient safety and did not introduce additional health risks to the patients.
Erlotinib (Tarceva®) ISN OSI-774-302Non-small cell lung cancer (5901-CL-0302)CONFIDENTIAL EudraCT Number 2005-001747-29
Name of Sponsor/Company: Astellas Pharma Global
Development, Inc. on behalf of OSI Pharmaceuticals,
LLC
Name of Finished Product: Tarceva®
Name of Active Ingredient: Erlotinib
Dec 2014 Astellas Synopsis Page 2 of 19
Study OSI-774-302 was an international, multicenter, phase 3 study in patients with stage IB to IIIA epidermal
growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) that was conducted under a
special protocol assessment (SPA) and had the following phases: screening, baseline, on-treatment,
posttreatment and long-term follow-up. The BPC of protocol OSI-774-302 consisted of patients randomized to
the study before 07 November 2007. The patients who permanently discontinued blinded study drug treatment
on or before 07 November 2007 were to be followed in long-term follow-up as outlined in the protocol. The
patients who had not discontinued blinded study drug treatment were offered the option of receiving open-label
erlotinib for up to 2 years (including posttreatment and long-term follow-up assessments), not receiving open-
label erlotinib but remaining in the study for posttreatment and long-term follow-up assessment, or withdrawing
consent from treatment and further assessments. Since these patients had completed the screening and baseline
assessments, patients who consented to receive open-label erlotinib continued on-treatment and were to resume
the prescribed visit schedule for on-treatment assessments as stipulated in the protocol. The posttreatment and
long-term follow-up assessments were also to be followed as per protocol. Patients who were eligible but who
chose not to receive open-label erlotinib had the option to be followed for all post-treatment and long-term
follow-up procedures according to the protocol or withdraw consent from further assessments.
Patients in the BPC who met all of the eligibility criteria and consented to receive open-label erlotinib were to
have received erlotinib at the same dose as the last dispensed dose during blinded treatment, regardless of
whether their last bottle assignment was placebo or erlotinib. These patients could receive erlotinib for up to
2 years from commencing open-label erlotinib or until 1 of the following occurred: relapse, death, patient
request or Investigator decision to discontinue study drug, intolerable toxicity, or until the primary objective of
the study was satisfied.
The DSMB continued to evaluate data for patients in the BPC when they reviewed safety for the blinded
treatment arms of the randomized cohort study.
Number of Patients (Planned, Enrolled and Analyzed): No sample size was planned. A total of 277 patients
comprised the BPC, with 145 patients in the BPC-no open-label cohort (BPC-NOLC; 71 [originally reported as
61 in the protocol] patients who discontinued blinded study drug treatment on or before 07 November 2007 and
74 patients who elected to not receive open-label erlotinib after the breach) and 132 patients in the BPC-open-
label cohort (BPC-OLC; patients who consented to continuing in the study).
Diagnosis and Main Criteria for Inclusion: The initial inclusion/exclusion criteria at screening and the
inclusion criteria for participation in the on-treatment phase of the randomized cohort study were provided in
the randomized cohort Study OSI-774-302 CSR. At the time of the breach, additional eligibility criteria were
established. To be eligible to receive open-label erlotinib or to be eligible for long-term follow-up without
receiving open-label erlotinib, patients in the BPC must have met all of the following criteria: were randomized
to Study OSI-774-302 before 07 November 2007, had not permanently discontinued from blinded study drug
Erlotinib (Tarceva®) ISN OSI-774-302Non-small cell lung cancer (5901-CL-0302)CONFIDENTIAL EudraCT Number 2005-001747-29
Name of Sponsor/Company: Astellas Pharma Global
Development, Inc. on behalf of OSI Pharmaceuticals,
LLC
Name of Finished Product: Tarceva®
Name of Active Ingredient: Erlotinib
Dec 2014 Astellas Synopsis Page 3 of 19
treatment and had not refused further follow-up, did not have evidence of NSCLC relapse at the time of consent
to receive open-label erlotinib based on their last clinical or radiological assessment, had provided written
informed consent by 01 March 2008 to receive open-label erlotinib or to participate in the long-term follow-up
assessments only.
Test Product, Dose and Mode of Administration, Batch Numbers: Erlotinib (OSI-774), 150 mg orally once
daily; dose reductions to 100 mg/day or 50 mg/day were allowed in the event of toxicities
Lot numbers:
Blinded Period
(25 mg tablets); (100 mg tablets); (150 mg tablets)
Open-label Period
and (25 mg tablets), , and (100 mg tablets),
and (150 mg tablets)
Duration of Treatment (or Duration of Study, if applicable): Patients received study drug once daily for
2 years or until 1 of the following: relapse, death, patient request or investigator decision to discontinue study
drug, or intolerable toxicity.
Reference Product, Dose and Mode of Administration, Batch Numbers: Matching placebo, 150 mg orally
once daily or matching placebo for dose reductions; administered while patients were in the blinded period
Lot numbers: (25 mg tablets); (100 mg tablets); (150 mg tablets),
Criteria for Evaluation:
Efficacy: Data from patients in the BPC were not included in the assessments of primary or secondary endpoints
in the randomized cohort and were not considered part of the primary analyses. Efficacy data were considered
exploratory. The primary efficacy endpoint was DFS in the overall population. The 3 key secondary efficacy
variables were overall survival (OS) in the overall population, DFS in patients with EGFR mutation-positive
tumors and OS in patients with EGFR mutation-positive tumors.
Safety: The safety assessments included evaluation of adverse events (AEs) (including serious adverse events
[SAEs] and discontinuations or dose modifications of study drug due to AEs) and clinical laboratory tests
(hematology, chemistry and hepatotoxicity). Eastern Cooperative Oncology Group (ECOG) performance status
was also assessed as a safety variable.
Statistical Methods: The BPC-NOLC included any patients who did not participate in the open-label erlotinib
period and who previously received or were randomized to receive either erlotinib or placebo. For data analysis
purposes, the following definitions of the treatment groups were used for all summaries of the BPC-NOLC: the
Erlotinib (Tarceva®) ISN OSI-774-302Non-small cell lung cancer (5901-CL-0302)CONFIDENTIAL EudraCT Number 2005-001747-29
Name of Sponsor/Company: Astellas Pharma Global
Development, Inc. on behalf of OSI Pharmaceuticals,
LLC
Name of Finished Product: Tarceva®
Name of Active Ingredient: Erlotinib
Dec 2014 Astellas Synopsis Page 4 of 19
erlotinib/placebo arm was composed of patients who had received at least 1 dose of erlotinib, and the placebo
arm was composed of patients who received at least 1 dose of placebo but never received erlotinib and patients
who did not receive any study drug. The BPC-OLC included patients who received at least 1 dose of study drug
after being randomized, who consented to participate in the open-label erlotinib period (whether or not the
patient was treated with open-label erlotinib) and who met all of the additional eligibility criteria established at
the time of the breach.
The primary efficacy variable was DFS. Summaries were provided for the BPC-NOLC erlotinib/placebo group
and the overall BPC-OLC. No statistical comparisons were provided. Kaplan-Meier curves were constructed
for each treatment arm. Median time to event and 95% CIs were estimated from the Kaplan-Meier curves. The
event-free rates and their 95% CIs at years 2, 3, 4 and 5 were also estimated. The 3 key secondary efficacy
variables were OS in the overall population, DFS in patients whose tumors were EGFR activating
mutation-positive and OS in patients whose tumors were EGFR activating mutation-positive. The same type of
summary as provided for the primary endpoint was provided for these secondary endpoints.
Exploratory DFS and OS analyses were also performed in subgroups of patients, including subgroups based on
tumor EGFR and Kirsten rat sarcoma (KRAS) mutation status.
Summary of Results/Conclusions:
Population: The most frequent reasons off treatment for patients who received erlotinib/placebo treatment in
the BPC-NOLC, were discontinuation due to an AE (59/134 [44.0%]) and patients who discontinued treatment
at their request (43/134 [32.1%]). In the BPC-OLC, the reason off treatment was reported for 33/134 (25.8%)
patients as due to an AE and for 7/132 (5.3%) patients was patient request Table 1 . Patients in the
BPC-NOLC who chose not to receive open-label erlotinib were not followed further in terms of routine study
assessments. In the BPC-OLC, nearly half of the patients completed 2 years of study therapy (60/132 [45.5%]).
A total of 34/132 (25.8%) of patients in the BPC-OLC discontinued the study due to an AE and 7/132 (5.3%)
patients discontinued treatment at their own request. A total of 61/134 (45.5%) patients in the BPC-NOLC
erlotinib/placebo group and 38/132 (28.8%) patients in the BPC-OLC died.
Of the 145 patients in the BPC-NOLC, 49 (33.8%) were female and 96 (66.2%) were male [Table 2 . The
majority of patients in this group were ≥ 65 years of age (78/145 [53.8%]) and most patients were white
(124/145 [85.5%]). Of the 132 patients in the BPC-OLC, 57 (43.2%) were female and 75 (56.8%) were male.
The majority of patients in the BPC-OLC were < 65 years of age (83/132 [62.9%]) and most patients were
white (111/132 [84.1%]). The majority of patients in both analysis sets were former smokers (BPC-NOLC
112/145 [77.2%], BPC-OLC 104/132 [78.8%]). Approximately 40% of the patients in the BPC-NOLC were
located in Western Europe (62/145 [42.8%]); this percentage included all 12 patients in France as an agreement
with the Central Ethics Committee had stipulated these patients would not receive open-label erlotinib.
Erlotinib (Tarceva®) ISN OSI-774-302Non-small cell lung cancer (5901-CL-0302)CONFIDENTIAL EudraCT Number 2005-001747-29
Name of Sponsor/Company: Astellas Pharma Global
Development, Inc. on behalf of OSI Pharmaceuticals,
LLC
Name of Finished Product: Tarceva®
Name of Active Ingredient: Erlotinib
Dec 2014 Astellas Synopsis Page 5 of 19
Approximately one-third of the patients in the BPC-NOLC were located in North America (47/145 [32.4%]).
Half the patients in the BPC-OLC were located in North America (66/132 [50.0%]).
Efficacy Results: Data from patients in the BPC were not included in the assessments of primary or secondary
endpoints in the randomized cohort, and were not considered part of the primary analyses. Efficacy data were
considered exploratory. No statistical comparisons were provided for the efficacy variables.
Median treatment duration in the BPC-NOLC erlotinib/placebo group was approximately 2 months, and the
median treatment duration in the BPC-OLC was approximately 20 months Table 3 . For the BPC-NOLC
erlotinib/placebo group, the median DFS was 22.2 months and the median OS was 51.9 months Table 4 and
Table 5 . For the BPC-OLC, the median DFS was 69.3 months and the median OS was not estimable. For both
groups, the OS data were immature. In the BPC-NOLC erlotinib/placebo group and the BPC-OLC, 10 and
16 patients, respectively, had tumors with EGFR activating mutations. The median DFS was 60.2 months for
this subgroup in the BPC-NOLC erlotinib/placebo group and 70.1 months for this subgroup in the BPC-OLC
Table 6]. The median OS for these subgroups was not estimable for either analysis set. Exploratory analyses
were also performed to evaluate DFS and OS by baseline characteristics and by a series of EGFR and KRAS
mutation assessments of patients’ tumors.
Safety Results:
No new safety findings were identified. The AEs observed in this trial were consistent with erlotinib’s
established safety profile [Tarceva™ (Erlotinib) Prescribing Information, 2013]. Drug-related TEAEs were
reported most frequently in the SOCs of Skin and Subcutaneous Tissue Disorders and Gastrointestinal
Disorders Table 7 . The proportion of patients with treatment-related AEs leading to study drug
discontinuation was higher (41.0% in the BPC-NOLC erlotinib/placebo group and 21.2% in the BPC-OLC)
Table 8] than that reported in advanced NSCLC studies (9.5% in EURTAC; 4.6% in SATURN; and 5% in
BR.21). The most common AEs consisted of the following: BPC-NOLC erlotinib/placebo group: diarrhea,
rash, acneiform dermatitis, fatigue, and pruritus; BPC-OLC: diarrhea, rash, acneiform dermatitis, dry skin,
fatigue, cough, pruritus, nausea, alopecia and anorexia [Table 9].
Drug-related TEAEs of “RASH” as defined by the standard AE group term “EGFR-associated rash” occurred in
most erlotinib-treated patients (BPC-NOLC erlotinib/placebo group 79.9%, BPC-OLC 91.7%) Table 10 . The
proportions of erlotinib-treated patients experiencing a severe (grade ≥ 3) RASH event (21.6% in the
BPC-NOLC erlotinib/placebo group and 25.8% in the BPC-OLC) were greater than that previously reported in
advanced NSCLC trials (9% in SATURN and BR.21 and 14% in EURTAC). The relationship between the
incidence of RASH events and treatment duration has not been assessed.
A TEAE coding to the MedDRA PT “interstitial lung disease” occurred in 1/134 (0.7%) and in 3/132 (2.3%) of
erlotinib-treated patients in the BPC-NOLC erlotinib/placebo group and BPC-OLC, respectively Table 11 .
When the broad SMQ for ILD events was used, the incidence of ILD-like events in erlotinib-treated patients
Erlotinib (Tarceva®) ISN OSI-774-302Non-small cell lung cancer (5901-CL-0302)CONFIDENTIAL EudraCT Number 2005-001747-29
Name of Sponsor/Company: Astellas Pharma Global
Development, Inc. on behalf of OSI Pharmaceuticals,
LLC
Name of Finished Product: Tarceva®
Name of Active Ingredient: Erlotinib
Dec 2014 Astellas Synopsis Page 6 of 19
was 1.5% (2/134) in the BPC-NOLC erlotinib/placebo group and 3.8% (5/132) in the BPC-OLC. Based on
sponsor assessment, 2 of these events ("radiology CT changes: small element of interstitial fibrosis" and
"necrotizing granulomas: left upper lobe lung"), both grade 1, which resolved while patient remained on study
drug, likely do not represent true events of “interstitial lung disease”. The incidence of ILD-like events reported
in erlotinib-treated patients in the RADIANT (Study OSI-774-302) randomized cohort was 1.8% (11/611) and
the overall incidence of ILD in approximately 32000 erlotinib-treated patients in uncontrolled studies and
studies with concurrent chemotherapy was approximately 1.1% [Tarceva™ (Erlotinib) Prescribing Information,
2013]. In the BR.21 study of erlotinib as second or third line therapy in patients with advanced NSCLC, the
incidence of ILD-like events was 3%. While interpretation is limited by the small sample size, the incidence of
ILD-like events in erlotinib-treated patients in the BPC is consistent with the large body of safety data for
erlotinib therapy in NSCLC.
CONCLUSIONS: No new safety findings were identified. The safety results observed in the BPC are
consistent with those observed in the RADIANT randomized cohort. In both populations, the safety results
were generally consistent with the established safety profile of erlotinib, although the proportion of
erlotinib-treated patients experiencing a severe (grade ≥ 3) RASH event was greater than that previously
reported in advanced NSCLC trials. Additionally, the proportion of erlotinib-treated patients experiencing
treatment-related TEAEs leading to permanent discontinuation was higher than that previously reported in
advanced NSCLC trials.
Efficacy data are considered exploratory due to the breach; therefore, no conclusions regarding efficacy can be
made.
Date of Report: 09 December 2014
Erlotinib (Tarceva®) ISN OSI-774-302Non-small cell lung cancer (5901-CL-0302)CONFIDENTIAL EudraCT Number 2005-001747-29
Dec 2014 Astellas Synopsis Page 7 of 19
Table 1 Patient Disposition
ParameterCategory
BPC-NOLC BPC-OLCErlotinib/Placebo
(n = 134)Placebo(n = 11)
Total(n = 145)
Erlotinib(n = 132)
Patients remaining on treatmentYes 0 0 0 0No 134 (100%) 11 (100%) 145 (100%) 132 (100%)
Not treated 0 4 (36.4%) 4 (2.8%) 0Reason not treated
Relapse of NSCLC 0 1 (9.1%) 1 (0.7%) 0Medical/ethical/ noncompliance reason
0 1 (9.1%) 1 (0.7%) 0
Patient request 0 2 (18.2%) 2 (1.4%) 0Treated 134 (100%) 7 (63.6%) 141 (97.2%) 132 (100%)
Reason off treatment†Completion of 2 years of study drug therapy
0 0 0 60 (45.5%)
Relapse of NSCLC 19 (14.2%) 1 (9.1%) 20 (13.8%) 26 (19.7%)Adverse event 59 (44.0%) 0 59 (40.7%) 34 (25.8%)Medical/ethical/ noncompliance reason
10 (7.5%) 1 (9.1%) 11 (7.6%) 5 (3.8%)
Patient request 43 (32.1%) 4 (36.4%) 47 (32.4%) 7 (5.3%)Patient death 3 (2.2%) 1 (9.1%) 4 (2.8%) 0
Death 61 (45.5%) 5 (45.5%) 66 (45.5%) 38 (28.8%)Death after withdrawal of consent
1 (0.7%) 0 1 (0.7%) 2 (1.5%)
Withdrawal of consent‡ 37 (27.6%) 2 (18.2%) 39 (26.9%) 17 (12.9%)Long-term follow-up 35 (26.1%) 3 (27.3%) 38 (26.2%) 71 (53.8%)Lost to follow-up 2 (1.5%) 1 (9.1%) 3 (2.1%) 8 (6.1%)
The BPC no open-label cohort (BPC-NOLC) included patients randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period.
The BPC open-label cohort (BPC-OLC) included patients randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who met all of the BPC eligibility criteria and who consented to enter the open-label erlotinib period. Data presented for the BPC-OLC included data from both the blinded period and the open-label erlotinib period.
BPC: breached-protocol cohort; NSCLC: non-small cell lung cancer
† Patients may have fit into multiple categories, but the primary reason for coming off treatment was reported in the case report form.
‡ Follow-up data beyond 5 years from the last treatment period visit was removed from the database for 4 patients (Patient Nos. , , and ) based on query responses that confirmed these patients did not sign the updated informed consent (issued in 2012) that extended the long-term follow-up period beyond 5 years. The patients appear in the disposition table as included in long-term follow-up because the investigator did not report withdrawal of consent for these patients.
Source: Tables 12.1.2.1 and 12.1.2.2
Erlotinib (Tarceva®) ISN OSI-774-302Non-small cell lung cancer (5901-CL-0302)CONFIDENTIAL EudraCT Number 2005-001747-29
Dec 2014 Astellas Synopsis Page 8 of 19
Table 2 Summary of Demographics and Baseline Characteristics
ParameterCategory/Statistics
BPC-NOLC BPC-OLCErlotinib/Placebo
(n = 134)Placebo(n = 11)
Total(n = 145)
Erlotinib(n = 132)
Sex, n (%)Female 47 (35.1%) 2 (18.2%) 49 (33.8%) 57 (43.2%)Male 87 (64.9%) 9 (81.8%) 96 (66.2%) 75 (56.8%)
Age, yearsMean (SD) 64.4 (9.33) 62.7 (6.23) 64.3 (9.13) 61.8 (9.35)Median 65.0 65.0 65.0 62.0Min - Max 33 - 85 52 - 70 33 - 85 34 - 83
Age, n (%)< 65 years 62 (46.3%) 5 (45.5%) 67 (46.2%) 83 (62.9%)≥ 65 years 72 (53.7%) 6 (54.5%) 78 (53.8%) 49 (37.1%)
Age, n (%)< 75 years 118 (88.1%) 11 (100%) 129 (89.0%) 120 (90.9%)≥ 75 years 16 (11.9%) 0 16 (11.0%) 12 (9.1%)
Race, n (%)White 114 (85.1%) 10 (90.9%) 124 (85.5%) 111 (84.1%)
4 (3.0%)17 (12.9%)16 (12.1%)
1 (0.8%)0
Black 4 (3.0%) 0 4 (2.8%)Asian 15 (11.2%) 1 (9.1%) 16 (11.0%)
Far East 13 (9.7%) 1 (9.1%) 14 (9.7%)Southeast Asia 2 (1.5%) 0 2 (1.4%)
American Indian/Alaska Native 1 (0.7%) 0 1 (0.7%)Ethnicity, n (%)
Not Hispanic or Latino 123 (91.8%) 11 (100%) 134 (92.4%) 124 (93.9%)Hispanic or Latino 11 (8.2%) 0 11 (7.6%) 8 (6.1%)
ECOG Performance Status, n (%)0 75 (56.0%) 5 (45.5%) 80 (55.2%) 77 (58.3%)1 55 (41.0%) 6 (54.5%) 61 (42.1%) 54 (40.9%)2 3 (2.2%) 0 3 (2.1%) 1 (0.8%)Not done at baseline 1 (0.7%) 0 1 (0.7%) NA
Cigarette smoking history, n (%)Never smoked or ≤ 100 cigarettes in lifetime
19 (14.2%) 1 (9.1%) 20 (13.8%) 19 (14.4%)
Former smoker 103 (76.9%) 9 (81.8%) 112 (77.2%) 104 (78.8%)Current smoker 12 (9.0%) 1 (9.1%) 13 (9.0%) 9 (6.8%)
Region, n (%)Asia Pacific 14 (10.4%) 1 (9.1%) 15 (10.3%) 17 (12.9%)Western Europe† 55 (41.0%) 7 (63.6%) 62 (42.8%) 22 (16.7%)Eastern Europe‡ 17 (12.7%) 1 (9.1%) 18 (12.4%) 26 (19.7%)Latin America 3 (2.2%) 0 3 (2.1%) 1 (0.8%)North America 45 (33.6%) 2 (18.2%) 47 (32.4%) 66 (50.0%)
Weight, kgn 133 11 144 131Mean (SD) 74.6 (15.91) 80.4 (20.59) 75.0 (16.30) 73.7 (18.18)Median 74.8 70.0 74.4 71.0Min - Max 42 - 116 61 - 130 42 - 130 39 - 133
Height, cmn 132 11 143 130Mean (SD) 169.2 (9.15) 171.0 (10.54) 169.3 (9.24) 167.7 (10.08)Median 169.0 172.0 169.5 168.0Min - Max 148 - 195 158 - 194 148 - 195 144 - 195
Footnotes appear on next page
Erlotinib (Tarceva®) ISN OSI-774-302Non-small cell lung cancer (5901-CL-0302)CONFIDENTIAL EudraCT Number 2005-001747-29
Dec 2014 Astellas Synopsis Page 9 of 19
The BPC no open-label cohort (BPC-NOLC) included patients randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period.
The BPC open-label cohort (BPC-OLC) included patients randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who met all of the BPC eligibility criteria and who consented to enter the open-label erlotinib period. Data presented for the BPC-OLC included data from both the blinded period and the open-label erlotinib period.
BPC: breached-protocol cohort; ECOG: Eastern Cooperative Oncology Group; Max: maximum; Min: minimum
† Western Europe included Austria, Belgium, France, Germany, Greece, Italy, Spain and the United Kingdom/England.
‡ Eastern Europe included the Czech Republic, Hungary, Poland, Romania and Russia.
Source: Tables 12.1.4.1.1 and 12.1.4.1.2
Erlotinib (Tarceva®) ISN OSI-774-302Non-small cell lung cancer (5901-CL-0302)CONFIDENTIAL EudraCT Number 2005-001747-29
Dec 2014 Astellas Synopsis Page 10 of 19
Table 3 Study Drug Exposure
A) BPC-NOLC
ParameterCategory/Statistic
BPC-NOLCErlotinib/Placebo
(n = 134)Placebo(n = 11)
Total(n = 145)
Total study drug exposure, months†n 134 7 141Mean (SD) 2.693 (2.2134) 0.780 (0.3791) 2.598 (2.1987)Median 2.085 0.990 1.910Min - Max 0.07 - 9.72 0.16 - 1.05 0.07 - 9.72
B) BPC-OLC
ParameterCategory/Statistic
Blinded Period for BPC-OLC‡Open-label Period
for BPC-OLCErlotinib/Placebo
(n = 126)Placebo(n = 6)
Total(n = 132)
Erlotinib(n = 132)
Total study drug exposure, months†n 126 6 132 130Mean (SD) 5.300 (3.0643) 0.948 (0.0392) 5.102 (3.1285) 14.747 (8.5528)Median 5.520 0.950 5.375 19.780Min - Max 0.56 - 13.54 0.89 - 0.99 0.56 - 13.54 0.23 - 25.95
C) Cumulative
ParameterCategory/Statistic
Cumulative Exposure in BPC-NOLC
Cumulative Exposure in BPC-OLC§
Erlotinib/Placebo(n = 134)
Placebo(n = 11)
Total(n = 145)
Erlotinib(n = 132)
Cumulative calendar months of exposure†, n (%)≤ 3 months 86 (64.2%) 7 (63.6%) 93 (64.1%) 5 (3.8%)> 3 to 6 months 42 (31.3%) 0 42 (29.0%) 10 (7.6%)> 6 to 12 months 6 (4.5%) 0 6 (4.1%) 21 (15.9%)> 12 to 18 months 0 0 0 17 (12.9%)> 18 to 20 months 0 0 0 2 (1.5%)> 20 to 22 months 0 0 0 4 (3.0%)> 22 to 24 months 0 0 0 19 (14.4%)> 24 months 0 0 0 54 (40.9%)
The BPC no open-label cohort (BPC-NOLC) included patients randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period.
The BPC open-label cohort (BPC-OLC) included patients randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who met all of the BPC eligibility criteria and who consented to enter the open-label erlotinib period. Data presented for the BPC-OLC included data from both the blinded period and the open-label erlotinib period.
BPC: breached-protocol cohort; Max: maximum; Min: minimum
† A month was defined as 30.4375 days.
‡ Dosing period when a patient took blinded study drug before open-label erlotinib began.
§ Data presented for the BPC-OLC included data from both the blinded period and the open-label erlotinib period.
Source: Tables 12.2.1.1.1, 12.2.1.1.2, 12.2.1.2.1 and 12.2.1.2.2
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Table 4 Summary of DFS
ParameterCategory/Statistic
BPC-NOLC BPC-OLCErlotinib/Placebo
(n = 134)Erlotinib(n = 132)
Patients with event, n (%) 67 (50.0%) 60 (45.5%)Death 12 (9.0%) 6 (4.5%)Relapse 55 (41.0%) 54 (40.9%)
Patients without event,† n (%) 67 (50.0%) 72 (54.5%)Time to event (months)
Median‡ 22.2 69.395% CI for median‡ [14.0, 40.3] [49.9, 73.7]25% and 75% percentiles 6.6, NE 28.1, 73.7Range§ 0.0+ to 74.3+ 0.0+ to 73.7
2-Year estimatePatients remaining at risk 46 94Event-free rate 0.48 0.7795% CI for rate [0.388, 0.582] [0.699, 0.847]
3-Year estimatePatients remaining at risk 38 83Event-free rate 0.43 0.7195% CI for rate [0.332, 0.527] [0.626, 0.787]
4-Year estimatePatients remaining at risk 33 70Event-free rate 0.38 0.6295% CI for rate [0.287, 0.481] [0.534, 0.707]
5-Year estimatePatients remaining at risk 14 46Event-free rate 0.34 0.5395% CI for rate [0.248, 0.441] [0.441, 0.625]
The BPC no open-label cohort (BPC-NOLC) included patients randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period.
The BPC open-label cohort (BPC-OLC) included patients randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who met all of the BPC eligibility criteria and who consented to enter the open-label erlotinib period.
BPC: breached-protocol cohort; DFS: disease-free survival; NE: not estimable
† Censored
‡ Kaplan-Meier estimates
§ Range includes censored observations which are indicated with ‘+’.
Source: Tables 12.3.1.1.1 and 12.3.1.1.2
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Table 5 Summary of OS
ParameterCategory/Statistic
BPC-NOLC BPC-OLCErlotinib/Placebo
(n = 134)Erlotinib(n = 132)
Patients with event, n (%) 61 (45.5%) 38 (28.8%)Death 61 (45.5%) 38 (28.8%)
Patients without event,† n (%) 73 (54.5%) 94 (71.2%)Time to event (months)
Median‡ 51.9 NE95% CI for median‡ [35.2, NE] NE25% and 75% percentiles 21.6, NE 61.3, NERange§ 0.5+ to 76.2+ 3.9+ to 76.4+
2-Year estimatePatients remaining at risk 71 116Event-free rate 0.70 0.9495% CI for rate [0.619, 0.790] [0.893, 0.979]
3-Year estimatePatients remaining at risk 59 109Event-free rate 0.59 0.9095% CI for rate [0.500, 0.688] [0.851, 0.955]
4-Year estimatePatients remaining at risk 54 93Event-free rate 0.54 0.8095% CI for rate [0.448, 0.639] [0.724, 0.867]
5-Year estimatePatients remaining at risk 42 85Event-free rate 0.44 0.7595% CI for rate [0.347, 0.539] [0.675, 0.829]
The BPC no open-label cohort (BPC-NOLC) included patients randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period.
The BPC open-label cohort (BPC-OLC) included patients randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who met all of the BPC eligibility criteria and who consented to enter the open-label erlotinib period.
BPC: breached-protocol cohort; NE: not estimable; OS: overall survival
† Censored
‡ Kaplan-Meier estimates
§ Range includes censored observations; ‘+’ indicates a censored observation.
Source: Tables 12.3.2.1.1 and 12.3.2.1.2
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Table 6 DFS in Patients with EGFR Activating Mutation-positive Tumors
ParameterCategory/Statistic
BPC-NOLC BPC-OLCErlotinib/Placebo
(n = 10)Erlotinib(n = 16)
Patients with event, n (%) 3 (30.0%) 8 (50.0%)Death 0 1 (6.3%)Relapse 3 (30.0%) 7 (43.8%)
Patients without event,† n (%) 7 (70.0%) 8 (50.0%)Time to event (months)
Median‡ 60.2 70.195% CI for median‡ [0.2, 60.2] [43.0, 70.1]25% and 75% percentiles 48.8, 60.2 46.0, 70.1Range§ 0.0+ to 60.2 23.2 to 70.1
2-Year estimatePatients remaining at risk 4 15Event-free rate 0.86 0.9495% CI for rate [0.598, 1.000] [0.819, 1.000]
3-Year estimatePatients remaining at risk 4 14Event-free rate 0.86 0.8895% CI for rate [0.598, 1.000] [0.713, 1.000]
4-Year estimatePatients remaining at risk 4 11Event-free rate 0.86 0.7595% CI for rate [0.598, 1.000] [0.538, 0.962]
5-Year estimatePatients remaining at risk 1 5Event-free rate 0.64 0.5195% CI for rate [0.230, 1.000] [0.243, 0.780]
The BPC no open-label cohort (BPC-NOLC) included patients randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period.
The BPC open-label cohort (BPC-OLC) included patients randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who met all of the BPC eligibility criteria and who consented to enter the open-label erlotinib period.
BPC: breached-protocol cohort; DFS: disease-free survival; EGFR: epidermal growth factor receptor
† Censored
‡ Kaplan-Meier estimates
§ Range includes censored observations; ‘+’ indicates a censored observation.
Source: Tables 12.3.3.1 and 12.3.3.2
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Table 7 Drug-related TEAEs by Body System (Reported in ≥ 5% of Patients in Either Analysis Set [BPC-NOLC or BPC-OLC])
SOC (MedDRA v9.1)†
BPC-NOLC BPC-OLCErlotinib/Placebo
(n = 134)Placebo(n = 11)
Total(n = 145)
Erlotinib(n = 132)
Skin and Subcutaneous Tissue Disorders 105 (78.4%) 1 (9.1%) 106 (73.1%) 125 (94.7%)Gastrointestinal Disorders 60 (44.8%) 1 (9.1%) 61 (42.1%) 91 (68.9%)General Disorders and Administration Site Conditions
31 (23.1%) 0 31 (21.4%) 35 (26.5%)
Metabolism and Nutrition Disorders 18 (13.4%) 0 18 (12.4%) 16 (12.1%)Eye Disorders 13 (9.7%) 0 13 (9.0%) 16 (12.1%)Respiratory, Thoracic and Mediastinal Disorders
13 (9.7%) 0 13 (9.0%) 19 (14.4%)
Infections and Infestations 11 (8.2%) 0 11 (7.6%) 28 (21.2%)Nervous System Disorders 9 (6.7%) 2 (18.2%) 11 (7.6%) 18 (13.6%)Investigations 3 (2.2%) 0 3 (2.1%) 8 (6.1%)Musculoskeletal and Connective Tissue Disorders
3 (2.2%) 0 3 (2.1%) 8 (6.1%)
The BPC no open-label cohort (BPC-NOLC) included patients randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period.
The BPC open-label cohort (BPC-OLC) included patients randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who met all of the BPC eligibility criteria and who consented to enter the open-label erlotinib period.
Within an SOC, a patient may have reported more than 1 type of adverse event.
A TEAE was defined as an adverse event with an onset date on or after starting administration of the study drug or any ongoing adverse event on the date of first dose that had worsened in severity after administration of the study drug. All adverse events that began within 30 days of taking the last dose of study drug were also counted as TEAEs. Long term follow-up adverse events were also counted as TEAEs. If an event was checked as related to treatment, it was considered to be a TEAE even if the onset date was missing. A drug-related TEAE was defined as any TEAE with at least a possible relationship to study treatment as assessed by the investigator or with missing assessment of the causal relationship.
BPC: breached-protocol cohort; TEAE: treatment-emergent adverse event
† Sorting order: descending in incidence by SOC within the BPC-NOLC total
Source: Tables 12.6.1.5.1 and 12.6.1.5.2
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Table 8 Overview of TEAEs
Category
BPC-NOLC BPC-OLCErlotinib/Placebo
(n = 134)Placebo(n = 11)
Total(n = 145)
Erlotinib(n = 132)
Any TEAE 129 (96.3%) 5 (45.5%) 134 (92.4%) 131 (99.2%)Grade 3 or higher TEAEs 61 (45.5%) 1 (9.1%) 62 (42.8%) 76 (57.6%)Serious TEAEs 21 (15.7%) 1 (9.1%) 22 (15.2%) 41 (31.1%)TEAEs leading to permanent discontinuation of study drug
64 (47.8%) 1 (9.1%) 65 (44.8%) 35 (26.5%)
TEAEs leading to death 3 (2.2%) 1 (9.1%) 4 (2.8%) 1 (0.8%)TEAEs leading to dose reduction 17 (12.7%) 0 17 (11.7%) 41 (31.1%)TEAEs leading to dose interruption 28 (20.9%) 0 28 (19.3%) 45 (34.1%)TEAEs leading to dose interruption and reduction
13 (9.7%) 0 13 (9.0%) 36 (27.3%)
Drug-related TEAEs† 115 (85.8%) 2 (18.2%) 117 (80.7%) 128 (97.0%)Drug-related serious TEAEs† 7 (5.2%) 0 7 (4.8%) 5 (3.8%)Drug-related TEAEs leading to permanent discontinuation of study drug
55 (41.0%) 0 55 (37.9%) 28 (21.2%)
The BPC no open-label cohort (BPC-NOLC) included patients randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period.
The BPC open-label cohort (BPC-OLC) included patients randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who met all of the BPC eligibility criteria and who consented to enter the open-label erlotinib period.
A TEAE was defined as an adverse event with an onset date on or after starting administration of the study drug or any ongoing adverse event on the date of first dose that had worsened in severity after administration of the study drug. All adverse events that began within 30 days of taking the last dose of study drug were also counted as TEAEs. Long term follow-up adverse events were also counted as TEAEs. If an event was checked as related to treatment, it was considered to be a TEAE even if the onset date was missing. Serious TEAEs included both investigator agreed and sponsor upgraded serious adverse events based on the Astellas Always Serious List.
BPC: breached-protocol cohort; TEAE: treatment-emergent adverse event
† A drug-related TEAE was defined as any TEAE with at least a possible relationship to study treatment as assessed by the investigator or with missing assessment of the causal relationship.
Source: Tables 12.6.1.1.1 and 12.6.1.1.2
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Table 9 Common TEAEs (Reported in ≥ 5.0% of Patients in Either Analysis Set [BPC-NOLC or BPC-OLC])
SOC (MedDRA v9.1)Preferred Term†
BPC-NOLC BPC-OLCErlotinib/Placebo
(n = 134)Placebo(n = 11)
Total(n = 145)
Erlotinib(n = 132)
Skin and Subcutaneous Tissue DisordersRash 51 (38.1%) 0 51 (35.2%) 72 (54.5%)Dermatitis acneiform 37 (27.6%) 0 37 (25.5%) 45 (34.1%)Pruritus 21 (15.7%) 0 21 (14.5%) 29 (22.0%)Dry skin 15 (11.2%) 0 15 (10.3%) 41 (31.1%)Alopecia 12 (9.0%) 0 12 (8.3%) 22 (16.7%)Erythema 10 (7.5%) 0 10 (6.9%) 13 (9.8%)Rash erythematous 6 (4.5%) 0 6 (4.1%) 12 (9.1%)Skin exfoliation 6 (4.5%) 0 6 (4.1%) 8 (6.1%)Rash maculo-papular 4 (3.0%) 0 4 (2.8%) 7 (5.3%)Exfoliative rash 2 (1.5%) 0 2 (1.4%) 11 (8.3%)Rash macular 2 (1.5%) 0 2 (1.4%) 8 (6.1%)Nail disorder 1 (0.7%) 0 1 (0.7%) 9 (6.8%)Rash papular 1 (0.7%) 0 1 (0.7%) 7 (5.3%)Skin fissures 1 (0.7%) 0 1 (0.7%) 9 (6.8%)
Gastrointestinal DisordersDiarrhoea 55 (41.0%) 0 55 (37.9%) 86 (65.2%)Nausea 18 (13.4%) 1 (9.1%) 19 (13.1%) 28 (21.2%)Vomiting 11 (8.2%) 0 11 (7.6%) 13 (9.8%)Stomatitis 8 (6.0%) 0 8 (5.5%) 15 (11.4%)Constipation 7 (5.2%) 0 7 (4.8%) 14 (10.6%)Dry mouth 7 (5.2%) 0 7 (4.8%) 7 (5.3%)Abdominal pain 6 (4.5%) 0 6 (4.1%) 14 (10.6%)Dyspepsia 4 (3.0%) 0 4 (2.8%) 15 (11.4%)Abdominal pain upper 0 0 0 11 (8.3%)Cheilitis 0 0 0 8 (6.1%)
General Disorders and Administration Site ConditionsFatigue 23 (17.2%) 0 23 (15.9%) 34 (25.8%)Pyrexia 6 (4.5%) 1 (9.1%) 7 (4.8%) 9 (6.8%)Mucosal inflammation 6 (4.5%) 0 6 (4.1%) 12 (9.1%)
Respiratory, Thoracic and Mediastinal DisordersCough 17 (12.7%) 0 17 (11.7%) 29 (22.0%)Dyspnoea 15 (11.2%) 0 15 (10.3%) 18 (13.6%)Epistaxis 4 (3.0%) 0 4 (2.8%) 11 (8.3%)Rhinorrhea 3 (2.2%) 0 3 (2.1%) 7 (5.3%)
Metabolism and Nutrition DisordersAnorexia 20 (14.9%) 1 (9.1%) 21 (14.5%) 20 (15.2%)
Nervous System DisordersDizziness 9 (6.7%) 1 (9.1%) 10 (6.9%) 14 (10.6%)Headache 10 (7.5%) 0 10 (6.9%) 14 (10.6%)Dysgeusia 5 (3.7%) 0 5 (3.4%) 13 (9.8%)
Psychiatric DisordersInsomnia 6 (4.5%) 0 6 (4.1%) 16 (12.1%)Anxiety 5 (3.7%) 0 5 (3.4%) 7 (5.3%)
Table continued on next page
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SOC (MedDRA v9.1)Preferred Term†
BPC-NOLC BPC-OLCErlotinib/Placebo
(n = 134)Placebo(n = 11)
Total(n = 145)
Erlotinib(n = 132)
Musculoskeletal and Connective Tissue DisordersArthralgia 4 (3.0%) 0 4 (2.8%) 14 (10.6%)Back pain 3 (2.2%) 0 3 (2.1%) 12 (9.1%)Pain in extremity 3 (2.2%) 0 3 (2.1%) 13 (9.8%)Musculoskeletal pain 2 (1.5%) 0 2 (1.4%) 9 (6.8%)Muscle spasms 1 (0.7%) 0 1 (0.7%) 10 (7.6%)
Infections and InfestationsRash pustular 3 (2.2%) 0 3 (2.1%) 13 (9.8%)Sinusitis 3 (2.2%) 0 3 (2.1%) 7 (5.3%)Nasopharyngitis 2 (1.5%) 0 2 (1.4%) 18 (13.6%)Bronchitis 1 (0.7%) 0 1 (0.7%) 9 (6.8%)Upper respiratory tract infection 0 0 0 13 (9.8%)
InvestigationsWeight decreased 2 (1.5%) 0 2 (1.4%) 19 (14.4%)
Vascular DisordersHypertension 2 (1.5%) 0 2 (1.4%) 8 (6.1%)
The BPC no open-label cohort (BPC-NOLC) included patients randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period.
The BPC open-label cohort (BPC-OLC) included patients randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who met all of the BPC eligibility criteria and who consented to enter the open-label erlotinib period.
Within an SOC, a patient may have reported more than 1 type of adverse event.
A TEAE was defined as an adverse event with an onset date on or after starting administration of the study drug or any ongoing adverse event on the date of first dose that had worsened in severity after administration of the study drug. All adverse events that began within 30 days of taking the last dose of study drug were also counted as TEAEs. Long term follow-up adverse events were also counted as TEAEs. If an event was checked as related to treatment, it was considered to be a TEAE even if the onset date was missing.
BPC: breached-protocol cohort; TEAE: treatment-emergent adverse event
† Sorting order: descending in incidence by SOC and within that descending by preferred term in the BPC-NOLC total
Source: Tables 12.6.1.2.1, 12.6.1.2.2, 12.6.1.4.2.1 and 12.6.1.4.2.2
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Table 10 Overview of Sponsor-defined Constellation of RASH TEAEs (BPC-NOLC or BPC-OLC)
Category
BPC-NOLC BPC-OLCErlotinib/Placebo
(n = 134)Placebo(n = 11)
Total(n = 145)
Erlotinib(n = 132)
Any RASH† 109 (81.3%) 1 (9.1%) 110 (75.9%) 123 (93.2%)Severity Grade of RASH TEAEs
Grade 1 31 (23.1%) 1 (9.1%) 32 (22.1%) 33 (25.0%)Grade 2 49 (36.6%) 0 49 (33.8%) 56 (42.4%)Grade 3 27 (20.1%) 0 27 (18.6%) 34 (25.8%)Grade 4 2 (1.5%) 0 2 (1.4%) 0Grade 5 0 0 0 0
Drug-related TEAEs of RASH 107 (79.9%) 1 (9.1%) 108 (74.5%) 121 (91.7%)TEAEs of RASH leading to permanent discontinuation of study drug
39 (29.1%) 0 39 (26.9%) 15 (11.4%)
TEAEs of RASH leading to dose reduction
13 (9.7%) 0 13 (9.0%) 32 (24.2%)
TEAEs of RASH leading to dose interruption
14 (10.4%) 0 14 (9.7%) 19 (14.4%)
TEAEs of RASH leading to dose interruption and reduction
7 (5.2%) 0 7 (4.8%) 23 (17.4%)
Serious TEAEs of RASH 1 (0.7%) 0 1 (0.7%) 0
The BPC no open-label cohort (BPC-NOLC) included patients randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period.
The BPC open-label cohort (BPC-OLC) included patients randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who met all of the BPC eligibility criteria and who consented to enter the open-label erlotinib period.
A TEAE was defined as an adverse event with an onset date on or after starting administration of the study drug or any ongoing adverse event on the date of first dose that had worsened in severity after administration of the study drug. All adverse events that began within 30 days of taking the last dose of study drug were also counted as TEAEs. If an event was checked as related to treatment, it was considered to be a TEAE even if the onset date was missing.
BPC: breached-protocol cohort; TEAE: treatment-emergent adverse event
† The term RASH (capitalized) represents a sponsor-defined constellation of adverse event preferred terms associated with rash including rash, macular rash, acne, dermatitis, acneiform dermatitis, eczema, urticaria, etc.
Source: Tables 12.6.1.26.1 and 12.6.1.26.2
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Table 11 Summary of Interstitial Lung Disease (BPC-NOLC or BPC-OLC)
Interstitial Lung Disease(Broad Standardized MedDRA Query)
Preferred Term
BPC-NOLC BPC-OLC
Erlotinib/Placebo(n = 134)
Placebo(n = 11)
Total(n = 145)
Erlotinib(n = 132)
Patients with ≥ 1 adverse event 2 (1.5%) 0 2 (1.4%) 5 (3.8%)Interstitial lung disease 1 (0.7%) 0 1 (0.7%) 3 (2.3%)Acute respiratory distress syndrome 1 (0.7%) 0 1 (0.7%) 0Pneumonitis 0 0 0 1 (0.8%)Pulmonary fibrosis 0 0 0 1 (0.8%)Pulmonary granuloma 0 0 0 1 (0.8%)
The BPC no open-label cohort (BPC-NOLC) included patients randomized prior to 07 November 2007 who did not participate in the open-label erlotinib period and who were previously randomized to receive either erlotinib or placebo in the blinded period.
The BPC open-label cohort (BPC-OLC) included patients randomized prior to 07 November 2007 who received at least 1 dose of study drug after being randomized, who met all of the BPC eligibility criteria and who consented to enter the open-label erlotinib period.
Within an SOC, a patient may have reported more than 1 type of adverse event.
BPC: breached-protocol cohort
Source: Tables 12.6.1.25.5.1 and 12.6.1.25.5.2
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Protocol Amendments Protocol Version
Number Date Summary of Substantial Changes
Original Protocol 09 May 2006 ● Original Protocol Amendment 1 21 November
2007 ● Addressed the error in the drug dispensing
procedure, defined the Breached Protocol Cohort (BPC) and stipulated the procedures to be followed for this cohort
Amendment 2 13 December 2010
● Revised the coprimary and secondary endpoints in response to new findings relating to EGFR gene copy number and activating mutations in NSCLC. All patients were enrolled prior to the issuance of amendment 2