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

Study Overview
=================
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.

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.

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)

Conditions
-----------------
Non Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Biological: Necitumumab
* Drug: Gemcitabine
* Drug: Cisplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Time (OS) | 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. | Randomization to Death from Any Cause (Up to 31 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | 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. | Randomization to Measured Progressive Disease or Death from Any Cause (Up to 31 Months) | 
| Percentage of Participants Achieving Complete Response (CR) and Partial Response (PR) (Objective Response Rate [ORR]) | 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. | Baseline to Measured Progressive Disease (Up to 31 Months) | 
| Time to Treatment Failure (TTF) | 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. | Randomization to Measured Progressive Disease, Death From Any Cause, Discontinuation of Treatment or Initiation of New Anticancer Therapy (Up to 31 Months) | 
| Mean Change From Baseline in Patient Reported Outcomes (PRO) Using the European Quality of Life-5 Dimension (EQ-5D) | 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). | Baseline, Cycle 6 (Cycle = 3 Weeks) | 
| Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS) | 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. | Baseline, Cycle 6 (Cycle = 3 Weeks) | 
| Number of Participants With an Epidermal Growth Factor Hormone (EGFR) Protein Expression Measured by Immunohistochemistry (IHC) | 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. | 31 Months | 
| 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 | 
| Number of Participants With a Serum Anti-Necitumumab Antibody Assessment | A participant was considered to have an anti-Necitumumab antibody response if anti-drug antibodies (ADA) were detected at any time point. | Baseline through 31 Months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Squamous, Non Small Cell Lung Cancer, First line treatment, Monoclonal, Antibodies, Epidermal Growth Factor Receptor (EGFR)