SQUIRE: First-line Treatment of Participants With Stage IV Squamous Non-Small Cell Lung Cancer With Necitumumab and Gemcitabine-Cisplatin

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00981058
• Collaborator: Parexel (Industry), PPD (Industry), Medidata Solutions (Industry), Laboratory Corporation of America (Industry), University of Colorado, Denver (Other), Thermo Fisher Scientific, Inc (Industry), ICON Clinical Research (Industry), Pacific Biomarkers (Other), Sysmex Inostics GmbH (Industry), Intertek (Industry)
• Enrollment: 1,093
• Locations: 182
• Arms: 2
• Anticipated Duration (Months): 162.7
• Patients Per Site: 6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The research study is testing the investigational drug necitumumab (IMC-11F8) in the treatment of advanced non-small cell lung cancer. The aim of this study is to determine if necitumumab, given together with a standard chemotherapy combination consisting of cisplatin and gemcitabine will be more effective in improving participant disease than the standard chemotherapy combination alone.

Condition or Disease	Intervention/Treatment	Phase
Non Small Cell Lung Cancer	Biological: Necitumumab; Drug: Gemcitabine; Drug: Cisplatin	Phase 3

Detailed Description

Multinational, randomized, multicenter, open-label, Phase III study of 1093 participants (age ≥ 18 years) with histologically- or cytologically-confirmed, stage IV squamous-cell NSCLC, who have received no prior therapy for metastatic disease, will be randomized on a 1:1 basis to receive first-line necitumumab plus chemotherapy consisting of gemcitabine and cisplatin in study Arm A, or gemcitabine-cisplatin chemotherapy alone in study Arm B. Baseline radiographic assessment of disease will be performed within 21 days prior to randomization (first treatment will be administered within 7 days following randomization). Participants will undergo radiographic assessment of disease status (computed tomography or magnetic resonance imaging) every 6 weeks (± 3 days), until there is radiographic documentation of progressive disease (PD). Chemotherapy will continue for a maximum of six cycles in each arm (or until there is radiographic documentation of PD, toxicity requiring cessation, protocol noncompliance or withdrawal of consent); participants in Arm A only will continue to receive necitumumab until there is radiographic documentation of PD, toxicity requiring cessation, protocol noncompliance, or withdrawal of consent.

After the end-of-study-visit (following PD), follow-up information regarding further anticancer treatment and survival will be collected every 2 months (± 7 days). For participants who discontinue study for reasons other than PD (eg, symptomatic deterioration), information on disease progression will also be collected until PD is documented. Follow-up will continue as long as the participant is alive, or until the end of the trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1093 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Multicenter, Open-Label Phase 3 Study of Gemcitabine-Cisplatin Chemotherapy Plus Necitumumab (IMC-11F8) Versus Gemcitabine-Cisplatin Chemotherapy Alone in the First-Line Treatment of Patients With Stage IV Squamous Non-Small Cell Lung Cancer (NSCLC)
• Actual Study Start Date: Jan 7, 2010
• Actual Primary Completion Date: Jun 17, 2013
• Anticipated Study Completion Date: Jul 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Necitumumab + Gemcitabine + Cisplatin	Biological: Necitumumab; 800 milligrams (mg) Intravenously IV infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal.; Other Names: IMC-11F8 LY3012211 ; Drug: Gemcitabine; 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles.; Other Names: LY2334737 ; Drug: Cisplatin; 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Active Comparator: Gemcitabine + Cisplatin	Drug: Gemcitabine; 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles.; Other Names: LY2334737 ; Drug: Cisplatin; 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.

Outcome Measures

Primary Outcome Measures

1. Overall Survival Time (OS) [Randomization to Death from Any Cause (Up to 31 Months)]

   Overall survival is defined as the time from randomization to death from any cause. Participants who do not die at the end of the extended follow-up period, or were lost to follow-up during the study, were censored at the last date they were known to be alive. OS was estimated by the Kaplan-Meier method.

Secondary Outcome Measures

1. Progression-Free Survival (PFS) [Randomization to Measured Progressive Disease or Death from Any Cause (Up to 31 Months)]

   PFS is defined as the time from randomization until the first radiographic documentation of objective measured progressive disease as defined by RECIST (Version 1.0), or death from any cause. Progressive Disease (PD) was defined as having at least a 20% increase in the sum of the longest diameter of target lesions. Participants who die without a reported prior progression were considered to have progressed on the day of their death. Participants who did not progress or were lost to follow-up were censored at the day of their last radiographic tumor assessment. If no baseline or postbaseline radiologic assessment was available, the participants were censored at the date of randomization. If death or PD occurs after two or more consecutive missing radiographic visits, censoring occurred at the date of the last radiographic visit prior to the missed visits.

2. Percentage of Participants Achieving Complete Response (CR) and Partial Response (PR) (Objective Response Rate [ORR]) [Baseline to Measured Progressive Disease (Up to 31 Months)]

   ORR is confirmed best overall tumor response of CR or PR. According to RECIST v1.0, CR was defined as the disappearance of all target and non-target lesions. PR defined as a >=30% decrease in the sum of the longest diameters (LD) of the target lesions, taking as reference the baseline sum of the LD; Percentage of participants was calculated as: (total number of participants with CR or PR from start of the treatment until disease progression or recurrence)/total number of participants treated) * 100.

3. Time to Treatment Failure (TTF) [Randomization to Measured Progressive Disease, Death From Any Cause, Discontinuation of Treatment or Initiation of New Anticancer Therapy (Up to 31 Months)]

   TTF is defined as the time from the date of randomization until the date of the first radiographic documentation of PD, death from any cause, discontinuation of treatment for any reason, or initiation of new cancer therapy. Participants who withdrew from the study for reasons other than progression or death were censored at the date of study withdrawal. Participants who did not meet any of the criteria for treatment failure were censored at their date of last contact in the study.

4. Mean Change From Baseline in Patient Reported Outcomes (PRO) Using the European Quality of Life-5 Dimension (EQ-5D) [Baseline, Cycle 6 (Cycle = 3 Weeks)]

   The EQ-5D is a generic, multidimensional, health-related, quality-of-life instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using a three level scale 1-3 (no problem, some problems, and major problems). These combinations of attributes were converted into a weighted health-state Index Score according to the United Kingdom (UK) population-based algorithm. The possible values for the Index Score ranged from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension).

5. Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS) [Baseline, Cycle 6 (Cycle = 3 Weeks)]

   The LCSS consisted of 9 items: 6 items focused on lung cancer symptoms [loss of appetite, fatigue, cough, dyspnea (shortness of breath), hemoptysis (blood in sputum), and pain] and 3 items were global items (symptom distress, interference with activity level, and global quality of life). Participant responses to each item were measured using visual analogue scales (VAS) with 100-mm lines. A higher score for any item represented a higher level of symptoms/problems. Scores for each of the reported categories ranged from 0 (for best outcome) to 100 (for worst outcome). The Average Symptom Burden Index (ASBI) was the mean of the 6 symptom items of the LCSS, and the Total LCSS was the mean of all 9 LCSS items. ASBI and Total LCSS were not computed for a participant if he/she had 1 or more missing values for the 6 and 9 items, respectively.

6. Number of Participants With an Epidermal Growth Factor Hormone (EGFR) Protein Expression Measured by Immunohistochemistry (IHC) [31 Months]

   EGFR IHC Histoscore H-score = weighted sum of % 1+ cells, twice % 2+ cells, and three times % 3+ cells. IHC H-score criteria was used to assess participants with a low EGFR expression defined by a H-score cutoff value of <200 and participants with a high EGFR expression defined by a H-score of cutoff value of >=200.

7. Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab [Day 1 of Cycle 2, 3, 4, 5 and 6 Prior to Necitumumab Drug Infusion, Up to 24 Months]

8. Number of Participants With a Serum Anti-Necitumumab Antibody Assessment [Baseline through 31 Months]

   A participant was considered to have an anti-Necitumumab antibody response if anti-drug antibodies (ADA) were detected at any time point.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Has histologically or cytologically confirmed squamous NSCLC

• Has Stage IV disease at the time of study entry

• Measurable or nonmeasurable disease at the time of study entry as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.0) (participants with only truly nonmeasurable disease are not eligible)

• Has resolution to Grade ≤ 1 of all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy (with the exception of alopecia)

• Has adequate hepatic function

• Has adequate renal function

• Has adequate hematologic function

• If female, is surgically sterile, postmenopausal, or compliant with a highly effective contraceptive method (failure rate < 1%) during and for 6 months after the treatment period (oral hormonal contraception alone is not considered highly effective and must be used in combination with a barrier method)

• If male, the participant is surgically sterile or compliant with a highly effective contraceptive regimen during and for 6 months after the treatment period

• Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization

• Has archived tumor tissue available for analysis of EGFR and KRAS mutation status (by PCR) and EGFR gene copy number (by FISH); minimum of four slides, paraffin-embedded tissue, required

Exclusion Criteria:

• Has nonsquamous NSCLC (adenocarcinoma/large cell or other)

• Has received prior anticancer therapy with monoclonal antibodies, signal transduction inhibitors, or any therapies targeting the EGFR, vascular endothelial growth factor (VEGF), or VEGF receptor

• Has received previous chemotherapy for advanced NSCLC (participants who have received adjuvant chemotherapy are eligible if the last administration of the prior adjuvant regimen occurred at least 1 year prior to randomization)

• Has undergone major surgery or received any investigational therapy in the 4 weeks prior to randomization

• Has undergone chest irradiation within 12 weeks prior to randomization (except palliative irradiation of bone lesions, which is allowed)

• Has brain metastases that are symptomatic or require ongoing treatment with steroids or anticonvulsants. Participants who have undergone previous radiotherapy for brain metastases, who are now nonsymptomatic and no longer require treatment with steroids or anticonvulsants, are eligible

• Has superior vena cava syndrome contraindicating hydration

• Has current clinically-relevant coronary artery disease or uncontrolled congestive heart failure

• Has experienced myocardial infarction within 6 months prior to randomization

• Has an ongoing or active infection (requiring antibiotics), including active tuberculosis or known infection with the human immunodeficiency virus

• Has a history of significant neurological or psychiatric disorders, including dementia, seizures, or bipolar disorder

• Has any National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 3.0 Grade ≥ 2 peripheral neuropathy

• Has significant third space fluid retention, requiring repeated drainage

• Has any other serious uncontrolled medical disorders or psychological conditions that would, in the opinion of the investigator, limit the participant's ability to complete the study or sign an informed consent document

• Has a known allergy / history of hypersensitivity reaction to any of the treatment components, including any ingredient used in the formulation of necitumumab (IMC-11F8), or any other contraindication to one of the administered treatments

• Is pregnant or breastfeeding

• Has a known history of drug abuse

• Has a concurrent active malignancy other than adequately-treated basal cell carcinoma of the skin or preinvasive carcinoma of the cervix. A participant with previous history of malignancy other than NSCLC is eligible, provided that he/she has been free of disease for ≥ 3 years

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ImClone Investigational Site	Chandler	Arizona	United States	85224
2	ImClone Investigational Site	Fayetteville	Arkansas	United States	72703
3	ImClone Investigational Site	Sacramento	California	United States	95816
4	ImClone Investigational Site	Galesburg	Illinois	United States	61401
5	ImClone Investigational Site	Goshen	Indiana	United States	46526
6	ImClone Investigational Site	Wichita	Kansas	United States	67214
7	ImClone Investigational Site	Hazard	Kentucky	United States	41701
8	ImClone Investigational Site	Baltimore	Maryland	United States	21204
9	ImClone Investigational Site	Jefferson City	Missouri	United States	65109
10	ImClone Investigational Site	Lincoln	Nebraska	United States	68510
11	ImClone Investigational Site	New York	New York	United States	10065
12	ImClone Investigational Site	Akron	Ohio	United States	44304
13	ImClone Investigational Site	Camp Hill	Pennsylvania	United States	17011
14	ImClone Investigational Site	Memphis	Tennessee	United States	38104
15	ImClone Investigational Site	Fairfax	Virginia	United States	22031
16	ImClone Investigational Site	Garran	New South Wales	Australia	2605
17	ImClone Investigational Site	Westmead	New South Wales	Australia	2145
18	ImClone Investigational Site	Wollongong	New South Wales	Australia	2500
19	ImClone Investigational Site	East Bentleigh	Victoria	Australia	3165
20	ImClone Investigational Site	Geelong	Victoria	Australia	3220
21	ImClone Investigational Site	Linz		Austria	4020
22	ImClone Investigational Site	Wien		Austria	1090
23	ImClone Investigational Site	Wien		Austria	1130
24	ImClone Investigational Site	Duffel		Belgium	2570
25	ImClone Investigational Site	Liege		Belgium	4000
26	ImClone Investigational Site	Namur		Belgium	5000
27	ImClone Investigational Site	Barretos		Brazil	14784-400
28	ImClone Investigational Site	Brasilia, Distrito Federal		Brazil	70710-904
29	ImClone Investigational Site	Goiania		Brazil	74884-606
30	ImClone Investigational Site	Ijui		Brazil	98700-000
31	ImClone Investigational Site	Itajai		Brazil	88301-220
32	ImClone Investigational Site	Lajeado		Brazil	95900-000
33	ImClone Investigational Site	Porto Alegre/RS		Brazil	90610-000
34	ImClone Investigational Site	Salvador		Brazil	40050-410
35	ImClone Investigational Site	Santo Andre		Brazil	09090-780
36	ImClone Investigational Site	Sao Paulo		Brazil	01224-010
37	ImClone Investigational Site	São Paulo - SP		Brazil	01246-000
38	ImClone Investigational Site	Saint John	New Brunswick	Canada	E2L 4L2
39	ImClone Investigational Site	Brampton	Ontario	Canada	L6R 3J7
40	ImClone Investigational Site	Saskatoon	Saskatchewan	Canada	S7N 4H4
41	ImClone Investigational Site	Dubrovnik		Croatia	20000
42	ImClone Investigational Site	Pula		Croatia	52100
43	ImClone Investigational site	Zagreb		Croatia	10000
44	ImClone Investigational Site	Brest Cedex		France	29609
45	ImClone Investigational Site	Caen		France	14076
46	ImClone Investigational Site	Draguignan		France	83300
47	ImClone Investigational Site	Grenoble		France	38043
48	ImClone Investigational Site	Le Mans Cedex		France	72037
49	ImClone Investigational Site	Le Mans		France	72000
50	ImClone Investigational Site	Lille		France	59020
51	ImClone Investigational Site	Lyon		France	69373
52	ImClone Investigational Site	Marseille		France	13009
53	ImClone Investigational Site	Paris		France	75005
54	ImClone Investigational Site	Paris		France	75010
55	ImClone Investigational Site	Paris		France	75571
56	ImClone Investigational Site	Paris		France	75651
57	ImClone Investigational Site	Rennes		France	35033
58	ImClone Investigational Site	Saint-Jean		France	31240
59	ImClone Investigational Site	Toulon Armées		France	83800
60	ImClone Investigational Site	Berlin		Germany	12200
61	ImClone Investigational Site	Essen		Germany	45122
62	ImClone Investigational Site	Essen		Germany	45136
63	ImClone Investigational Site	Frankfurt		Germany	60487
64	ImClone Investigational Site	Gauting		Germany	82131
65	ImClone Investigational Site	Großhansdorf		Germany	22927
66	ImClone Investigational Site	Halle		Germany	06120
67	ImClone Investigational Site	Hamburg		Germany	21075
68	ImClone Investigational Site	Hamburg		Germany	22087
69	ImClone Investigational Site	Heidelberg		Germany	69126
70	ImClone Investigational Site	Hemer		Germany	58675
71	ImClone Investigational Site	Hofheim		Germany	65719
72	ImClone Investigational Site	Karlsruhe		Germany	76137
73	ImClone Investigational Site	Lostau		Germany	39291
74	ImClone Investigational Site	Löwenstein		Germany	74245
75	ImClone Investigational Site	München		Germany	81675
76	ImClone Investigational Site	Münster		Germany	48149
77	ImClone Investigational Site	Regensburg		Germany	93042
78	ImClone Investigational Site	Regensburg		Germany	93049
79	ImClone Investigational Site	Ulm		Germany	89081
80	ImClone Investigational Site	Athens		Greece	11527
81	ImClone Investigational Site	Heraklion, Crete		Greece	71110
82	ImClone Investigational Site	Patras		Greece	26500
83	ImClone Investigational Site	Thessaloniki		Greece	57010
84	ImClone Investigational Site	Budapest		Hungary	1125
85	ImClone Investigational Site	Budapest		Hungary	1145
86	ImClone Investigational Site	Deszk		Hungary	6772
87	ImClone Investigational Site	Farkasgyepü		Hungary	8582
88	ImClone Investigational Site	Mosonmagyaróvár		Hungary	9200
89	ImClone Investigational Site	Szombathely		Hungary	9700
90	ImClone Investigational Site	Székesfehérvár		Hungary	8000
91	ImClone Investigational Site	Törökbálint		Hungary	2045
92	ImClone Investigational Site	Lido di Camaiore	Lucca	Italy	55041
93	ImClone Investigational Site	Aviano	Pordenone	Italy	33081
94	ImClone Investigational Site	Frosinone		Italy	03100
95	ImClone Investigational Site	Genova		Italy	16132
96	ImClone Investigational Site	Milano		Italy	20133
97	ImClone Investigational Site	Milano		Italy	20162
98	ImClone Investigational Site	Monza		Italy	20900
99	ImClone Investigational Site	Parma		Italy	43100
100	ImClone Investigational Site	Perugia		Italy	06126
101	ImClone Investigational Site	Incheon		Korea, Republic of	405760
102	ImClone Investigational Site	Jeonju-si		Korea, Republic of	561712
103	ImClone Investigational Site	Seongnam		Korea, Republic of	463-707
104	ImClone Investigational Site	Seoul		Korea, Republic of	120752
105	ImClone Investigational Site	Seoul		Korea, Republic of	135710
106	ImClone Investigational Site	Seoul		Korea, Republic of	138736
107	ImClone Investigational Site	Suwon		Korea, Republic of	442723
108	ImClone Investigational Site	Cebu City		Philippines	6000
109	ImClone Investigational Site	Cebu		Philippines	6000
110	ImClone Investigational Site	Davao City		Philippines	8000
111	ImClone Investigational Site	Makati City		Philippines	1229
112	ImClone Investigational Site	Manila		Philippines	1000
113	ImClone Investigational Site	Quezon City		Philippines	1000
114	ImClone Investigational Site	Quezon City		Philippines	1102
115	ImClone Investigational Site	Olsztyn		Poland	10357
116	ImClone Investigational Site	Otwock		Poland	05-400
117	ImClone Investigational Site	Poznan		Poland	60-569
118	ImClone Investigational Site	Radom		Poland	26-617
119	ImClone Investigational Site	Rzeszow		Poland	35-055
120	ImClone Investigational Site	Szczecin		Poland	70-891
121	ImClone Investigational Site	Torun		Poland	87-100
122	ImClone Investigational Site	Wroclaw		Poland	53-439
123	ImClone Investigational Site	Coimbra		Portugal	3041-801
124	ImClone Investigational Site	Lisboa		Portugal	1099-023
125	ImClone Investigational Site	Lisboa		Portugal	1649-035
126	ImClone Investigational Site	Porto		Portugal	4200-072
127	ImClone Investigational Site	Brasov		Romania	500366
128	ImClone Investigational Site	Bucharest		Romania	022328
129	ImClone Investigational Site	Bucharest		Romania	030171
130	ImClone Investigational Site	Cluj-Napoca		Romania	400015
131	ImClone Investigational Site	Craiova, Dolj		Romania	200385
132	ImClone Investigational Site	Iasi		Romania	700106
133	ImClone Investigational Site	Piatra Neamt		Romania	610136
134	ImClone Investigational Site	Sibiu		Romania	550245
135	ImClone Investigational Site	Ivanovo		Russian Federation	153013
136	ImClone Investigational Site	Kirov		Russian Federation	610021
137	ImClone Investigational Site	Krasnodar		Russian Federation	350040
138	ImClone Investigational Site	Moscow		Russian Federation	117997
139	ImClone Investigational Site	Omsk		Russian Federation	644013
140	ImClone Investigational Site	Smolensk		Russian Federation	214000
141	ImClone Investigational Site	St. Petersburg		Russian Federation	194044
142	ImClone Investigational Site	St. Petersburg		Russian Federation	194291
143	ImClone Investigational Site	St. Petersburg		Russian Federation	197022
144	ImClone Investigational Site	St. Petersburg		Russian Federation	198255
145	ImClone Investigational Site	Ufa		Russian Federation	450054
146	ImClone Investigational Site	Yaroslavl		Russian Federation	150054
147	ImClone Investigational Site	Belgrade		Serbia	11000
148	ImClone Investigational Site	Kragujevac		Serbia	34000
149	ImClone Investigational Site	Nis		Serbia	18204
150	ImClone Investigational Site	Sremska Kamenica		Serbia	21204
151	ImClone Investigational Site	Singapore		Singapore	308433
152	ImClone Investigational Site	Bratislava		Slovakia	826 06
153	ImClone Investigational Site	Nitra		Slovakia	949 88
154	ImClone Investigational Site	Poprad		Slovakia	058 01
155	ImClone Investigational Site	Bloemfontein	Free State	South Africa	9301
156	ImClone Investigational Site	Pretoria	Gauteng	South Africa	0002
157	ImClone Investigational Site	Durban	Kwazulu-Natal	South Africa	4091
158	ImClone Investigational Site	Sevilla	Andalucía	Spain	41013
159	ImClone Investigational Site	Avila	Castilla Y Leon	Spain	05004
160	ImClone Investigational Site	Barcelona	Cataluña	Spain	08035
161	ImClone Investigational Site	Barcelona	Cataluña	Spain	08041
162	ImClone Investigational Site	Terrassa	Cataluña	Spain	08221
163	ImClone Investigational Site	Madrid	Communidad De Madrid	Spain	28041
164	ImClone Investigational Site	Madrid	Communidad De Madrid	Spain	28050
165	ImClone Investigational Site	Majadahonda	Communidad De Madrid	Spain	28222
166	ImClone Investigational Site	Barcelona		Spain	08036
167	ImClone Investigational Site	L'Hospitalet de Llobregat		Spain	08908
168	ImClone Investigational Site	Madrid		Spain	28040
169	ImClone Investigational Site	Taichung		Taiwan	40447
170	ImClone Investigational Site	Taichung		Taiwan	40705
171	ImClone Investigational Site	Chiang Mai		Thailand	50002
172	ImClone Investigational Site	Songkhla		Thailand	90110
173	ImClone Investigational Site	Aberdeen		United Kingdom	AB25 2ZN
174	ImClone Investigational Site	Bournemouth		United Kingdom	BH7 7DW
175	ImClone Investigational Site	Dundee		United Kingdom	DD1 9SY
176	ImClone Investigational Site	Edinburgh		United Kingdom	EH4 2XU
177	ImClone Investigational Site	Guildford		United Kingdom	GU2 7XX
178	ImClone Investigational Site	Liverpool		United Kingdom	L14 3PE
179	ImClone Investigational Site	London		United Kingdom	SW10 9NH
180	ImClone Investigational Site	Manchester		United Kingdom	M20 4BX
181	ImClone Investigational Site	Manchester		United Kingdom	M23 9LT
182	ImClone Investigational Site	Preston		United Kingdom	PR2 9HT

Sponsors and Collaborators

• Eli Lilly and Company
• Parexel
• PPD
• Medidata Solutions
• Laboratory Corporation of America
• University of Colorado, Denver
• Thermo Fisher Scientific, Inc
• ICON Clinical Research
• Pacific Biomarkers
• Sysmex Inostics GmbH
• Intertek

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00981058
• Other Study ID Numbers: 13909; CP11-0806; I4X-IE-JFCC; 2009-013838-25
• First Posted: Sep 22, 2009
• Last Update Posted: Feb 11, 2022
• Last Verified: Feb 1, 2022

• Keywords provided by Eli Lilly and Company: Squamous; Non Small Cell Lung Cancer; First line treatment; Monoclonal; Antibodies; Epidermal Growth Factor Receptor (EGFR)
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Gemcitabine; Necitumumab

Study Results

Participant Flow

Pre-assignment Detail	Participants who completed the study include those who died due to any cause or were alive and on study at conclusion, but off treatment.

Arm/Group Title	Necitumumab + Gemcitabine + Cisplatin	Gemcitabine + Cisplatin
Arm/Group Description	Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 milligrams (mg) I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 milligrams/square meter (mg/m2) on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Period Title: Overall Study
STARTED	545	548
Received at Least 1 Dose of Study Drug	538	541
Death Due to Any Cause	418	442
COMPLETED	425	451
NOT COMPLETED	120	97

Baseline Characteristics

Arm/Group Title	Necitumumab + Gemcitabine + Cisplatin	Gemcitabine + Cisplatin	Total
Arm/Group Description	Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Total of all reporting groups
Overall Participants	545	548	1093
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62.0	62.0	62.0
Sex: Female, Male (Count of Participants)
Female	95 17.4%	90 16.4%	185 16.9%
Male	450 82.6%	458 83.6%	908 83.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	55 10.1%	56 10.2%	111 10.2%
Not Hispanic or Latino	489 89.7%	490 89.4%	979 89.6%
Unknown or Not Reported	1 0.2%	2 0.4%	3 0.3%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	1 0.2%	0 0%	1 0.1%
Asian	43 7.9%	42 7.7%	85 7.8%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.2%	1 0.1%
Black or African American	5 0.9%	6 1.1%	11 1%
White	457 83.9%	456 83.2%	913 83.5%
More than one race	1 0.2%	0 0%	1 0.1%
Other	38 7%	43 7.8%	81 7.4%
Region of Enrollment (participants) [Number]
Russian Federation	94 17.2%	101 18.4%	195 17.8%
Singapore	1 0.2%	2 0.4%	3 0.3%
United States	20 3.7%	16 2.9%	36 3.3%
Thailand	3 0.6%	6 1.1%	9 0.8%
Portugal	8 1.5%	9 1.6%	17 1.6%
Greece	18 3.3%	14 2.6%	32 2.9%
Austria	4 0.7%	4 0.7%	8 0.7%
Brazil	28 5.1%	30 5.5%	58 5.3%
Korea, Republic of	24 4.4%	23 4.2%	47 4.3%
Poland	69 12.7%	59 10.8%	128 11.7%
Slovakia	9 1.7%	10 1.8%	19 1.7%
France	34 6.2%	39 7.1%	73 6.7%
Serbia	11 2%	13 2.4%	24 2.2%
Croatia	2 0.4%	4 0.7%	6 0.5%
Romania	46 8.4%	45 8.2%	91 8.3%
Hungary	43 7.9%	41 7.5%	84 7.7%
Philippines	12 2.2%	8 1.5%	20 1.8%
United Kingdom	9 1.7%	10 1.8%	19 1.7%
Spain	33 6.1%	25 4.6%	58 5.3%
Canada	2 0.4%	4 0.7%	6 0.5%
Belgium	4 0.7%	4 0.7%	8 0.7%
Taiwan	3 0.6%	2 0.4%	5 0.5%
Italy	13 2.4%	12 2.2%	25 2.3%
South Africa	2 0.4%	2 0.4%	4 0.4%
Australia	4 0.7%	6 1.1%	10 0.9%
Germany	49 9%	59 10.8%	108 9.9%
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Baseline (participants) [Number]
0	164 30.1%	180 32.8%	344 31.5%
1	332 60.9%	320 58.4%	652 59.7%
2	49 9%	47 8.6%	96 8.8%
3	0 0%	1 0.2%	1 0.1%
Smoking History (participants) [Number]
Ex-Light Smoker	18 3.3%	26 4.7%	44 4%
Non-Smoker	26 4.8%	27 4.9%	53 4.8%
Smoker	500 91.7%	495 90.3%	995 91%
Missing	1 0.2%	0 0%	1 0.1%
Disease Stage at Study Entry (participants) [Number]
Stage IIIB	1 0.2%	1 0.2%	2 0.2%
Stage IV	543 99.6%	546 99.6%	1089 99.6%
Missing	1 0.2%	1 0.2%	2 0.2%
Disease Histology (participants) [Number]
Squamous	543 99.6%	545 99.5%	1088 99.5%
Other Histology	2 0.4%	3 0.5%	5 0.5%
Sites of Metastatic Disease (participants) [Number]
Bone	120 22%	131 23.9%	251 23%
Brain	28 5.1%	30 5.5%	58 5.3%
Liver	109 20%	117 21.4%	226 20.7%
Lung	453 83.1%	453 82.7%	906 82.9%
Lymph Nodes	431 79.1%	451 82.3%	882 80.7%
Peritoneal	20 3.7%	17 3.1%	37 3.4%
Pleural	149 27.3%	155 28.3%	304 27.8%
Skin	9 1.7%	8 1.5%	17 1.6%
Soft Tissue	23 4.2%	21 3.8%	44 4%
Other	156 28.6%	146 26.6%	302 27.6%

Outcome Measures

1. Primary Outcome

Title	Overall Survival Time (OS)
Description	Overall survival is defined as the time from randomization to death from any cause. Participants who do not die at the end of the extended follow-up period, or were lost to follow-up during the study, were censored at the last date they were known to be alive. OS was estimated by the Kaplan-Meier method.
Time Frame	Randomization to Death from Any Cause (Up to 31 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants. Censored participants: Necitumumab + Gemcitabine + Cisplatin = 127, Gemcitabine + Cisplatin = 106

Arm/Group Title	Necitumumab + Gemcitabine + Cisplatin	Gemcitabine + Cisplatin
Arm/Group Description	Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Measure Participants	545	548
Median (95% Confidence Interval) [Months]	11.5	9.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Necitumumab + Gemcitabine + Cisplatin, Gemcitabine + Cisplatin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0120
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.842
	Confidence Interval	(2-Sided) 95%; 0.736 to 0.962
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS is defined as the time from randomization until the first radiographic documentation of objective measured progressive disease as defined by RECIST (Version 1.0), or death from any cause. Progressive Disease (PD) was defined as having at least a 20% increase in the sum of the longest diameter of target lesions. Participants who die without a reported prior progression were considered to have progressed on the day of their death. Participants who did not progress or were lost to follow-up were censored at the day of their last radiographic tumor assessment. If no baseline or postbaseline radiologic assessment was available, the participants were censored at the date of randomization. If death or PD occurs after two or more consecutive missing radiographic visits, censoring occurred at the date of the last radiographic visit prior to the missed visits.
Time Frame	Randomization to Measured Progressive Disease or Death from Any Cause (Up to 31 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants. Censored participants: Necitumumab + Gemcitabine + Cisplatin = 114, Gemcitabine + Cisplatin = 131

Arm/Group Title	Necitumumab + Gemcitabine + Cisplatin	Gemcitabine + Cisplatin
Arm/Group Description	Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Measure Participants	545	548
Median (95% Confidence Interval) [months]	5.7	5.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Necitumumab + Gemcitabine + Cisplatin, Gemcitabine + Cisplatin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0201
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.851
	Confidence Interval	(2-Sided) 95%; 0.743 to 0.975
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants Achieving Complete Response (CR) and Partial Response (PR) (Objective Response Rate [ORR])
Description	ORR is confirmed best overall tumor response of CR or PR. According to RECIST v1.0, CR was defined as the disappearance of all target and non-target lesions. PR defined as a >=30% decrease in the sum of the longest diameters (LD) of the target lesions, taking as reference the baseline sum of the LD; Percentage of participants was calculated as: (total number of participants with CR or PR from start of the treatment until disease progression or recurrence)/total number of participants treated) * 100.
Time Frame	Baseline to Measured Progressive Disease (Up to 31 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	Necitumumab + Gemcitabine + Cisplatin	Gemcitabine + Cisplatin
Arm/Group Description	Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Measure Participants	545	548
Number (95% Confidence Interval) [percentage of participants]	31.2 5.7%	28.8 5.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Necitumumab + Gemcitabine + Cisplatin, Gemcitabine + Cisplatin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3997
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Time to Treatment Failure (TTF)
Description	TTF is defined as the time from the date of randomization until the date of the first radiographic documentation of PD, death from any cause, discontinuation of treatment for any reason, or initiation of new cancer therapy. Participants who withdrew from the study for reasons other than progression or death were censored at the date of study withdrawal. Participants who did not meet any of the criteria for treatment failure were censored at their date of last contact in the study.
Time Frame	Randomization to Measured Progressive Disease, Death From Any Cause, Discontinuation of Treatment or Initiation of New Anticancer Therapy (Up to 31 Months)

Outcome Measure Data

Analysis Population Description

All randomized participants. Censored participants: Necitumumab + Gemcitabine + Cisplatin = 16, Gemcitabine + Cisplatin =20

Arm/Group Title	Necitumumab + Gemcitabine + Cisplatin	Gemcitabine + Cisplatin
Arm/Group Description	Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Measure Participants	545	548
Median (95% Confidence Interval) [Months]	4.3	3.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Necitumumab + Gemcitabine + Cisplatin, Gemcitabine + Cisplatin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0061
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.844
	Confidence Interval	(2-Sided) 95%; 0.747 to 0.953
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Mean Change From Baseline in Patient Reported Outcomes (PRO) Using the European Quality of Life-5 Dimension (EQ-5D)
Description	The EQ-5D is a generic, multidimensional, health-related, quality-of-life instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using a three level scale 1-3 (no problem, some problems, and major problems). These combinations of attributes were converted into a weighted health-state Index Score according to the United Kingdom (UK) population-based algorithm. The possible values for the Index Score ranged from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension).
Time Frame	Baseline, Cycle 6 (Cycle = 3 Weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who had evaluable baseline and postbaseline EQ-5D data.

Arm/Group Title	Necitumumab + Gemcitabine + Cisplatin	Gemcitabine + Cisplatin
Arm/Group Description	Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Measure Participants	305	245
Mean (Standard Deviation) [units on a scale]	-0.0053 (0.23626)	-0.0083 (0.23866)

6. Secondary Outcome

Title	Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS)
Description	The LCSS consisted of 9 items: 6 items focused on lung cancer symptoms [loss of appetite, fatigue, cough, dyspnea (shortness of breath), hemoptysis (blood in sputum), and pain] and 3 items were global items (symptom distress, interference with activity level, and global quality of life). Participant responses to each item were measured using visual analogue scales (VAS) with 100-mm lines. A higher score for any item represented a higher level of symptoms/problems. Scores for each of the reported categories ranged from 0 (for best outcome) to 100 (for worst outcome). The Average Symptom Burden Index (ASBI) was the mean of the 6 symptom items of the LCSS, and the Total LCSS was the mean of all 9 LCSS items. ASBI and Total LCSS were not computed for a participant if he/she had 1 or more missing values for the 6 and 9 items, respectively.
Time Frame	Baseline, Cycle 6 (Cycle = 3 Weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who had evaluable data for LCSS.

Arm/Group Title	Necitumumab + Gemcitabine + Cisplatin	Gemcitabine + Cisplatin
Arm/Group Description	Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Measure Participants	545	548
Loss of Appetite (n=304, 242)	1.8 (31.84)	1.5 (29.30)
Fatigue (n=302, 242)	6.3 (29.15)	3.5 (25.29)
Cough (n=303, 243)	-7.8 (28.05)	-9.1 (25.74)
Dyspnea (n=305, 244)	-2.8 (26.52)	-1.8 (25.27)
Pain (n=302, 243)	-3.3 (17.98)	-2.2 (17.22)
Overall Symptoms (n=303, 242)	-0.3 (26.19)	-0.6 (26.92)
Interference (n=306,241)	3.8 (29.74)	2.2 (26.79)
Quality of Life (n=305, 243)	-0.3 (27.35)	-1.6 (24.71)
Average Symptom Burden Index (ASBI) (n=294, 234)	-1.9 (16.55)	-1.5 (16.52)
LCSS Total Score (n=290, 228)	-0.8 (17.03)	-0.8 (16.17)

7. Secondary Outcome

Title	Number of Participants With an Epidermal Growth Factor Hormone (EGFR) Protein Expression Measured by Immunohistochemistry (IHC)
Description	EGFR IHC Histoscore H-score = weighted sum of % 1+ cells, twice % 2+ cells, and three times % 3+ cells. IHC H-score criteria was used to assess participants with a low EGFR expression defined by a H-score cutoff value of <200 and participants with a high EGFR expression defined by a H-score of cutoff value of >=200.
Time Frame	31 Months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had evaluable data for EGFR IHC.

Arm/Group Title	Necitumumab + Gemcitabine + Cisplatin	Gemcitabine + Cisplatin
Arm/Group Description	Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.	Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Measure Participants	486	496
0	24 4.4%	23 4.2%
>0	462 84.8%	473 86.3%
<200	295 54.1%	313 57.1%
≥200	191 35%	183 33.4%

8. Secondary Outcome

Title	Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab
Time Frame	Day 1 of Cycle 2, 3, 4, 5 and 6 Prior to Necitumumab Drug Infusion, Up to 24 Months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had evaluable data for PK.

Arm/Group Title	Necitumumab + Gemcitabine + Cisplatin
Arm/Group Description	Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Measure Participants	545
Predose Cycle 2 Day 1 (n=419)	52.4 (95.9)
Predose Cycle3 Day 1 (n=386)	76.6 (80.6)
Predose Cycle 4 Day 1 (n=344)	94.5 (92.2)
Predose Cycle 5 Day 1 (n=297)	101 (90)
Predose Cycle 6 Day 1 (n=262)	98.5 (80)

9. Secondary Outcome

Title	Number of Participants With a Serum Anti-Necitumumab Antibody Assessment
Description	A participant was considered to have an anti-Necitumumab antibody response if anti-drug antibodies (ADA) were detected at any time point.
Time Frame	Baseline through 31 Months

Outcome Measure Data

Analysis Population Description

All randomized participants who received who received at least 1 dose of drug and had evaluable data for antibodies.

Arm/Group Title	Necitumumab + Gemcitabine + Cisplatin
Arm/Group Description	Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
Measure Participants	528
Participants with at least 1 positive titer	81 14.9%
Neutralizing antibody detected	5 0.9%

Adverse Events

Adverse Event Reporting Description	All participants who received at least 1 dose of study drug.
Arm/Group Title	Necitumumab + Gemcitabine + Cisplatin		Gemcitabine + Cisplatin
Arm/Group Description	Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 mg I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.		Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
All Cause Mortality
	Necitumumab + Gemcitabine + Cisplatin		Gemcitabine + Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Necitumumab + Gemcitabine + Cisplatin		Gemcitabine + Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	262/538 (48.7%)		208/541 (38.4%)
Blood and lymphatic system disorders
Agranulocytosis	1/538 (0.2%)	4	0/541 (0%)	0
Anaemia	22/538 (4.1%)	25	17/541 (3.1%)	20
Bone marrow failure	0/538 (0%)	0	1/541 (0.2%)	1
Febrile neutropenia	6/538 (1.1%)	6	7/541 (1.3%)	7
Leukopenia	6/538 (1.1%)	6	4/541 (0.7%)	6
Neutropenia	20/538 (3.7%)	24	33/541 (6.1%)	40
Pancytopenia	6/538 (1.1%)	6	3/541 (0.6%)	4
Thrombocytopenia	17/538 (3.2%)	28	20/541 (3.7%)	26
Thrombocytosis	1/538 (0.2%)	1	0/541 (0%)	0
Cardiac disorders
Acute coronary syndrome	0/538 (0%)	0	1/541 (0.2%)	1
Acute myocardial infarction	2/538 (0.4%)	2	1/541 (0.2%)	1
Atrial fibrillation	3/538 (0.6%)	7	4/541 (0.7%)	6
Atrial flutter	0/538 (0%)	0	1/541 (0.2%)	1
Cardiac arrest	2/538 (0.4%)	2	0/541 (0%)	0
Cardiac failure	0/538 (0%)	0	2/541 (0.4%)	2
Cardiac failure acute	0/538 (0%)	0	1/541 (0.2%)	1
Cardiac failure congestive	1/538 (0.2%)	1	1/541 (0.2%)	1
Cardiac tamponade	1/538 (0.2%)	1	0/541 (0%)	0
Cardio-respiratory arrest	3/538 (0.6%)	3	1/541 (0.2%)	1
Coronary artery disease	1/538 (0.2%)	1	0/541 (0%)	0
Myocardial infarction	2/538 (0.4%)	2	2/541 (0.4%)	2
Myocardial ischaemia	0/538 (0%)	0	1/541 (0.2%)	1
Pericardial effusion	0/538 (0%)	0	1/541 (0.2%)	2
Pericarditis	0/538 (0%)	0	1/541 (0.2%)	1
Supraventricular tachycardia	2/538 (0.4%)	2	0/541 (0%)	0
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula	1/538 (0.2%)	1	0/541 (0%)	0
Ear and labyrinth disorders
Deafness bilateral	0/538 (0%)	0	1/541 (0.2%)	1
Ototoxicity	1/538 (0.2%)	1	0/541 (0%)	0
Gastrointestinal disorders
Abdominal pain	2/538 (0.4%)	3	1/541 (0.2%)	1
Abdominal pain upper	1/538 (0.2%)	1	0/541 (0%)	0
Colitis ischaemic	1/538 (0.2%)	1	0/541 (0%)	0
Constipation	1/538 (0.2%)	1	1/541 (0.2%)	1
Diarrhoea	8/538 (1.5%)	8	5/541 (0.9%)	5
Duodenal ulcer	0/538 (0%)	0	1/541 (0.2%)	1
Duodenal ulcer perforation	0/538 (0%)	0	1/541 (0.2%)	1
Dysphagia	3/538 (0.6%)	3	1/541 (0.2%)	1
Enteritis	0/538 (0%)	0	1/541 (0.2%)	1
Gastric haemorrhage	1/538 (0.2%)	1	0/541 (0%)	0
Gastric ulcer	0/538 (0%)	0	1/541 (0.2%)	1
Gastroduodenal ulcer	1/538 (0.2%)	1	0/541 (0%)	0
Gastrointestinal disorder	1/538 (0.2%)	1	0/541 (0%)	0
Haematemesis	0/538 (0%)	0	1/541 (0.2%)	1
Haematochezia	2/538 (0.4%)	2	0/541 (0%)	0
Ileus	0/538 (0%)	0	1/541 (0.2%)	2
Intestinal obstruction	1/538 (0.2%)	1	2/541 (0.4%)	2
Mesenteric vein thrombosis	1/538 (0.2%)	1	1/541 (0.2%)	2
Nausea	4/538 (0.7%)	4	2/541 (0.4%)	3
Pancreatitis acute	1/538 (0.2%)	1	1/541 (0.2%)	1
Small intestinal obstruction	1/538 (0.2%)	1	0/541 (0%)	0
Stomatitis	2/538 (0.4%)	2	3/541 (0.6%)	3
Upper gastrointestinal haemorrhage	0/538 (0%)	0	1/541 (0.2%)	1
Vomiting	12/538 (2.2%)	13	2/541 (0.4%)	2
General disorders
Asthenia	2/538 (0.4%)	2	3/541 (0.6%)	3
Chills	0/538 (0%)	0	1/541 (0.2%)	1
Death	8/538 (1.5%)	8	3/541 (0.6%)	3
Fatigue	3/538 (0.6%)	3	4/541 (0.7%)	4
General physical health deterioration	8/538 (1.5%)	9	7/541 (1.3%)	7
Generalised oedema	0/538 (0%)	0	1/541 (0.2%)	1
Non-cardiac chest pain	1/538 (0.2%)	1	0/541 (0%)	0
Oedema	0/538 (0%)	0	1/541 (0.2%)	1
Oedema peripheral	1/538 (0.2%)	1	1/541 (0.2%)	1
Pyrexia	7/538 (1.3%)	8	4/541 (0.7%)	4
Sudden death	2/538 (0.4%)	2	0/541 (0%)	0
Hepatobiliary disorders
Bile duct stenosis	0/538 (0%)	0	1/541 (0.2%)	1
Cholelithiasis	1/538 (0.2%)	1	0/541 (0%)	0
Hepatorenal syndrome	1/538 (0.2%)	1	0/541 (0%)	0
Immune system disorders
Drug hypersensitivity	2/538 (0.4%)	2	0/541 (0%)	0
Infections and infestations
Appendicitis	0/538 (0%)	0	1/541 (0.2%)	1
Bacterial infection	0/538 (0%)	0	1/541 (0.2%)	1
Bronchitis	6/538 (1.1%)	6	3/541 (0.6%)	3
Cystitis	1/538 (0.2%)	1	0/541 (0%)	0
Dental gangrene	0/538 (0%)	0	1/541 (0.2%)	1
Device related infection	1/538 (0.2%)	1	0/541 (0%)	0
Escherichia urinary tract infection	1/538 (0.2%)	1	0/541 (0%)	0
Gastroenteritis	1/538 (0.2%)	1	1/541 (0.2%)	1
Infectious pleural effusion	0/538 (0%)	0	1/541 (0.2%)	1
Injection site abscess	1/538 (0.2%)	1	0/541 (0%)	0
Lower respiratory tract infection	4/538 (0.7%)	5	4/541 (0.7%)	4
Lung infection	1/538 (0.2%)	1	0/541 (0%)	0
Neutropenic sepsis	0/538 (0%)	0	2/541 (0.4%)	2
Oral fungal infection	1/538 (0.2%)	1	0/541 (0%)	0
Pneumonia	12/538 (2.2%)	12	20/541 (3.7%)	23
Pneumonia bacterial	1/538 (0.2%)	1	0/541 (0%)	0
Pneumonia necrotising	2/538 (0.4%)	2	0/541 (0%)	0
Pulmonary tuberculosis	0/538 (0%)	0	1/541 (0.2%)	1
Pyelonephritis acute	0/538 (0%)	0	1/541 (0.2%)	1
Respiratory tract infection	0/538 (0%)	0	1/541 (0.2%)	1
Respiratory tract infection bacterial	1/538 (0.2%)	1	0/541 (0%)	0
Sepsis	2/538 (0.4%)	2	5/541 (0.9%)	5
Septic shock	0/538 (0%)	0	3/541 (0.6%)	3
Upper respiratory tract infection	1/538 (0.2%)	1	0/541 (0%)	0
Upper respiratory tract infection bacterial	2/538 (0.4%)	2	0/541 (0%)	0
Urinary tract infection	2/538 (0.4%)	2	1/541 (0.2%)	1
Urosepsis	0/538 (0%)	0	1/541 (0.2%)	1
Injury, poisoning and procedural complications
Femoral neck fracture	1/538 (0.2%)	1	0/541 (0%)	0
Femur fracture	2/538 (0.4%)	2	0/541 (0%)	0
Head injury	1/538 (0.2%)	1	0/541 (0%)	0
Incorrect dose administered	0/538 (0%)	0	1/541 (0.2%)	1
Medication error	12/538 (2.2%)	16	21/541 (3.9%)	27
Overdose	1/538 (0.2%)	2	0/541 (0%)	0
Spinal compression fracture	1/538 (0.2%)	1	0/541 (0%)	0
Toxicity to various agents	0/538 (0%)	0	1/541 (0.2%)	1
Underdose	1/538 (0.2%)	1	0/541 (0%)	0
Vascular graft occlusion	1/538 (0.2%)	1	0/541 (0%)	0
Investigations
Alanine aminotransferase increased	1/538 (0.2%)	1	0/541 (0%)	0
Aspartate aminotransferase increased	1/538 (0.2%)	1	0/541 (0%)	0
Blood creatinine increased	6/538 (1.1%)	6	1/541 (0.2%)	1
Blood phosphorus decreased	1/538 (0.2%)	1	0/541 (0%)	0
C-reactive protein increased	1/538 (0.2%)	1	0/541 (0%)	0
Ecg signs of myocardial ischaemia	0/538 (0%)	0	1/541 (0.2%)	1
False positive investigation result	0/538 (0%)	0	1/541 (0.2%)	1
Gamma-glutamyltransferase increased	1/538 (0.2%)	1	0/541 (0%)	0
Haemoglobin decreased	1/538 (0.2%)	1	1/541 (0.2%)	1
Platelet count decreased	0/538 (0%)	0	1/541 (0.2%)	1
Metabolism and nutrition disorders
Decreased appetite	1/538 (0.2%)	1	1/541 (0.2%)	1
Dehydration	5/538 (0.9%)	7	8/541 (1.5%)	8
Diabetic ketoacidosis	0/538 (0%)	0	1/541 (0.2%)	1
Electrolyte imbalance	1/538 (0.2%)	1	0/541 (0%)	0
Hypercalcaemia	3/538 (0.6%)	3	2/541 (0.4%)	2
Hypercreatininaemia	0/538 (0%)	0	1/541 (0.2%)	4
Hyperglycaemia	1/538 (0.2%)	1	3/541 (0.6%)	4
Hyperkalaemia	1/538 (0.2%)	1	0/541 (0%)	0
Hyperuricaemia	1/538 (0.2%)	1	0/541 (0%)	0
Hypocalcaemia	2/538 (0.4%)	2	0/541 (0%)	0
Hypokalaemia	3/538 (0.6%)	3	2/541 (0.4%)	2
Hypomagnesaemia	3/538 (0.6%)	4	1/541 (0.2%)	1
Hyponatraemia	4/538 (0.7%)	4	6/541 (1.1%)	13
Hypophosphataemia	1/538 (0.2%)	1	0/541 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	5/538 (0.9%)	6	1/541 (0.2%)	1
Intervertebral disc protrusion	1/538 (0.2%)	1	0/541 (0%)	0
Musculoskeletal pain	1/538 (0.2%)	1	0/541 (0%)	0
Osteolysis	0/538 (0%)	0	1/541 (0.2%)	1
Pain in extremity	1/538 (0.2%)	1	1/541 (0.2%)	1
Pathological fracture	1/538 (0.2%)	1	0/541 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	1/538 (0.2%)	1	1/541 (0.2%)	1
Metastases to bone	0/538 (0%)	0	1/541 (0.2%)	1
Metastases to central nervous system	1/538 (0.2%)	1	2/541 (0.4%)	3
Metastatic pain	0/538 (0%)	0	2/541 (0.4%)	2
Non-small cell lung cancer	26/538 (4.8%)	27	23/541 (4.3%)	23
Pericardial effusion malignant	0/538 (0%)	0	1/541 (0.2%)	1
Nervous system disorders
Ataxia	1/538 (0.2%)	1	0/541 (0%)	0
Brain oedema	1/538 (0.2%)	1	0/541 (0%)	0
Cerebral haemorrhage	1/538 (0.2%)	1	0/541 (0%)	0
Cerebral infarction	1/538 (0.2%)	1	0/541 (0%)	0
Cerebral ischaemia	2/538 (0.4%)	2	0/541 (0%)	0
Convulsion	3/538 (0.6%)	3	0/541 (0%)	0
Dizziness	4/538 (0.7%)	4	0/541 (0%)	0
Encephalopathy	0/538 (0%)	0	2/541 (0.4%)	3
Epilepsy	1/538 (0.2%)	1	0/541 (0%)	0
Headache	1/538 (0.2%)	1	1/541 (0.2%)	1
Hemiplegia	1/538 (0.2%)	1	0/541 (0%)	0
Hydrocephalus	1/538 (0.2%)	1	0/541 (0%)	0
Ischaemic stroke	4/538 (0.7%)	4	0/541 (0%)	0
Loss of consciousness	0/538 (0%)	0	1/541 (0.2%)	1
Nerve root compression	0/538 (0%)	0	1/541 (0.2%)	1
Paraesthesia	1/538 (0.2%)	1	0/541 (0%)	0
Peripheral motor neuropathy	1/538 (0.2%)	1	0/541 (0%)	0
Presyncope	0/538 (0%)	0	1/541 (0.2%)	1
Radial nerve palsy	1/538 (0.2%)	1	0/541 (0%)	0
Sciatica	1/538 (0.2%)	1	1/541 (0.2%)	1
Spinal cord compression	1/538 (0.2%)	1	1/541 (0.2%)	2
Syncope	4/538 (0.7%)	4	3/541 (0.6%)	3
Transient ischaemic attack	2/538 (0.4%)	2	1/541 (0.2%)	1
Vocal cord paralysis	0/538 (0%)	0	2/541 (0.4%)	2
Psychiatric disorders
Abnormal behaviour	0/538 (0%)	0	1/541 (0.2%)	1
Alcohol abuse	1/538 (0.2%)	1	0/541 (0%)	0
Completed suicide	0/538 (0%)	0	1/541 (0.2%)	1
Confusional state	2/538 (0.4%)	3	1/541 (0.2%)	1
Delirium	1/538 (0.2%)	1	1/541 (0.2%)	1
Depression	1/538 (0.2%)	1	0/541 (0%)	0
Renal and urinary disorders
Nephropathy toxic	1/538 (0.2%)	1	1/541 (0.2%)	1
Nephrotic syndrome	1/538 (0.2%)	1	0/541 (0%)	0
Renal failure	8/538 (1.5%)	8	6/541 (1.1%)	11
Renal failure acute	4/538 (0.7%)	4	5/541 (0.9%)	5
Renal infarct	1/538 (0.2%)	1	0/541 (0%)	0
Renal tubular necrosis	0/538 (0%)	0	1/541 (0.2%)	1
Urinary retention	0/538 (0%)	0	1/541 (0.2%)	1
Reproductive system and breast disorders
Pelvic pain	1/538 (0.2%)	1	0/541 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/538 (0%)	0	1/541 (0.2%)	1
Acute respiratory distress syndrome	0/538 (0%)	0	1/541 (0.2%)	2
Acute respiratory failure	1/538 (0.2%)	1	1/541 (0.2%)	1
Bronchitis chronic	0/538 (0%)	0	1/541 (0.2%)	1
Chronic obstructive pulmonary disease	2/538 (0.4%)	2	0/541 (0%)	0
Cough	0/538 (0%)	0	1/541 (0.2%)	1
Dyspnoea	3/538 (0.6%)	3	4/541 (0.7%)	5
Epistaxis	0/538 (0%)	0	1/541 (0.2%)	1
Haemoptysis	11/538 (2%)	15	9/541 (1.7%)	9
Interstitial lung disease	1/538 (0.2%)	1	0/541 (0%)	0
Lung infiltration	0/538 (0%)	0	1/541 (0.2%)	1
Pharyngeal inflammation	1/538 (0.2%)	1	0/541 (0%)	0
Pleural effusion	4/538 (0.7%)	4	1/541 (0.2%)	1
Pneumonitis	1/538 (0.2%)	1	1/541 (0.2%)	1
Pneumothorax	1/538 (0.2%)	1	1/541 (0.2%)	1
Pulmonary artery thrombosis	0/538 (0%)	0	1/541 (0.2%)	1
Pulmonary embolism	19/538 (3.5%)	20	9/541 (1.7%)	9
Pulmonary haemorrhage	1/538 (0.2%)	1	5/541 (0.9%)	5
Pulmonary hypertension	0/538 (0%)	0	1/541 (0.2%)	1
Pulmonary oedema	1/538 (0.2%)	1	1/541 (0.2%)	2
Pulmonary toxicity	0/538 (0%)	0	1/541 (0.2%)	1
Pulmonary venous thrombosis	1/538 (0.2%)	1	0/541 (0%)	0
Respiratory failure	2/538 (0.4%)	2	2/541 (0.4%)	2
Respiratory tract haemorrhage	0/538 (0%)	0	2/541 (0.4%)	2
Skin and subcutaneous tissue disorders
Dermatitis acneiform	1/538 (0.2%)	1	0/541 (0%)	0
Dermatitis allergic	0/538 (0%)	0	1/541 (0.2%)	1
Rash maculo-papular	1/538 (0.2%)	1	0/541 (0%)	0
Skin fissures	1/538 (0.2%)	1	0/541 (0%)	0
Skin toxicity	1/538 (0.2%)	1	0/541 (0%)	0
Skin ulcer	1/538 (0.2%)	1	0/541 (0%)	0
Social circumstances
Social stay hospitalisation	1/538 (0.2%)	1	0/541 (0%)	0
Vascular disorders
Deep vein thrombosis	4/538 (0.7%)	4	1/541 (0.2%)	1
Femoral artery occlusion	0/538 (0%)	0	1/541 (0.2%)	1
Hypertensive crisis	1/538 (0.2%)	1	0/541 (0%)	0
Hypotension	2/538 (0.4%)	2	0/541 (0%)	0
Hypovolaemic shock	0/538 (0%)	0	1/541 (0.2%)	1
Orthostatic hypotension	0/538 (0%)	0	2/541 (0.4%)	2
Peripheral arterial occlusive disease	1/538 (0.2%)	1	0/541 (0%)	0
Peripheral artery thrombosis	2/538 (0.4%)	2	1/541 (0.2%)	1
Peripheral embolism	1/538 (0.2%)	1	0/541 (0%)	0
Superior vena cava syndrome	1/538 (0.2%)	1	1/541 (0.2%)	1
Thrombophlebitis superficial	0/538 (0%)	0	1/541 (0.2%)	1
Thrombosis	1/538 (0.2%)	1	1/541 (0.2%)	1
Vena cava thrombosis	1/538 (0.2%)	1	0/541 (0%)	0
Venous insufficiency	1/538 (0.2%)	1	0/541 (0%)	0
Venous thrombosis	1/538 (0.2%)	1	1/541 (0.2%)	1
Venous thrombosis limb	1/538 (0.2%)	1	0/541 (0%)	0
Other (Not Including Serious) Adverse Events
	Necitumumab + Gemcitabine + Cisplatin		Gemcitabine + Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	516/538 (95.9%)		506/541 (93.5%)
Blood and lymphatic system disorders
Anaemia	218/538 (40.5%)	519	241/541 (44.5%)	519
Leukopenia	71/538 (13.2%)	122	85/541 (15.7%)	168
Neutropenia	220/538 (40.9%)	512	229/541 (42.3%)	555
Thrombocytopenia	103/538 (19.1%)	224	124/541 (22.9%)	244
Gastrointestinal disorders
Abdominal pain upper	31/538 (5.8%)	35	28/541 (5.2%)	38
Constipation	110/538 (20.4%)	156	98/541 (18.1%)	122
Diarrhoea	81/538 (15.1%)	123	58/541 (10.7%)	70
Dyspepsia	27/538 (5%)	40	22/541 (4.1%)	29
Nausea	265/538 (49.3%)	587	283/541 (52.3%)	616
Stomatitis	57/538 (10.6%)	79	32/541 (5.9%)	35
Vomiting	152/538 (28.3%)	281	134/541 (24.8%)	202
General disorders
Asthenia	123/538 (22.9%)	257	111/541 (20.5%)	196
Fatigue	114/538 (21.2%)	200	121/541 (22.4%)	225
Oedema peripheral	42/538 (7.8%)	54	41/541 (7.6%)	51
Pyrexia	68/538 (12.6%)	83	58/541 (10.7%)	75
Infections and infestations
Paronychia	36/538 (6.7%)	58	1/541 (0.2%)	1
Urinary tract infection	27/538 (5%)	38	9/541 (1.7%)	11
Investigations
Blood creatinine increased	48/538 (8.9%)	86	40/541 (7.4%)	67
Weight decreased	72/538 (13.4%)	95	34/541 (6.3%)	43
Metabolism and nutrition disorders
Decreased appetite	158/538 (29.4%)	234	151/541 (27.9%)	251
Hyperglycaemia	27/538 (5%)	48	15/541 (2.8%)	26
Hypokalaemia	37/538 (6.9%)	54	26/541 (4.8%)	42
Hypomagnesaemia	159/538 (29.6%)	490	81/541 (15%)	139
Hyponatraemia	23/538 (4.3%)	34	28/541 (5.2%)	41
Musculoskeletal and connective tissue disorders
Back pain	36/538 (6.7%)	48	27/541 (5%)	30
Nervous system disorders
Dizziness	55/538 (10.2%)	65	42/541 (7.8%)	46
Dysgeusia	33/538 (6.1%)	36	18/541 (3.3%)	20
Headache	56/538 (10.4%)	72	31/541 (5.7%)	42
Psychiatric disorders
Insomnia	28/538 (5.2%)	33	27/541 (5%)	34
Respiratory, thoracic and mediastinal disorders
Cough	87/538 (16.2%)	126	68/541 (12.6%)	83
Dyspnoea	86/538 (16%)	119	77/541 (14.2%)	100
Epistaxis	40/538 (7.4%)	46	16/541 (3%)	20
Haemoptysis	45/538 (8.4%)	58	20/541 (3.7%)	22
Productive cough	27/538 (5%)	35	12/541 (2.2%)	14
Skin and subcutaneous tissue disorders
Acne	47/538 (8.7%)	79	3/541 (0.6%)	3
Alopecia	76/538 (14.1%)	87	70/541 (12.9%)	72
Dermatitis acneiform	80/538 (14.9%)	145	3/541 (0.6%)	4
Dry skin	35/538 (6.5%)	41	8/541 (1.5%)	8
Pruritus	38/538 (7.1%)	50	5/541 (0.9%)	5
Rash	235/538 (43.7%)	487	30/541 (5.5%)	36
Rash generalised	28/538 (5.2%)	65	2/541 (0.4%)	2
Skin fissures	27/538 (5%)	47	0/541 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.