A Study of Necitumumab in the First-Line Treatment of Stage IV Squamous Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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The purpose of the Phase 1b portion of the study is to investigate how the body tolerates necitumumab, in combination with gemcitabine and cisplatin chemotherapy as first line treatment in participants with Stage IV squamous NSCLC and to determine the recommended dose for the subsequent Phase 2 portion of the study. The purpose of the Phase 2 portion of the study is to evaluate the efficacy of necitumumab in combination with gemcitabine and cisplatin chemotherapy in participants with Stage IV squamous NSCLC in a first-line setting.

Official Title
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An Open-Label, Multicenter, Phase 1b/2 Study to Evaluate Necitumumab in Combination With Gemcitabine and Cisplatin in the First-Line Treatment of Patients With Advanced (Stage IV) Squamous Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Squamous Non-small Cell Lung Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Squamous Non-Small Cell Lung Cancer Disease (NSCLC) Clinical Stage IV NSCLC Measurable or nonmeasurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 No prior systematic chemotherapy, targeted therapy, surgery and chest radiotherapy Ha resolution to Grade less than or equal to (≤) 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0, of all clinically significant toxic effects of prior therapy for other than NSCLC Adequate-organ function defined as: Total bilirubin ≤1.5 x the upper limit of normal value (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN Serum creatinine ≤ 1.2 x ULN or calculated creatinine clearance (CrCL)>50 milliliter per minute (mL/min) (per the Cockcroft Gault formula or equivalent and/or 24-hour urine collection) Absolute neutrophil count (ANC) greater than or equal to ≥1.5 x 10^3/μL(microliter) Hemoglobin ≥10.0 g/dL(gram per deciliter) Platelets ≥100 x 10^3/μL At least 20 years of age Estimated life expectancy of at least 12 weeks A formalin-fixed, paraffin-embedded tumor tissue block or a minimum of 5 unstained slides of tumor sample prior to randomization for the evaluation of epidermal growth factor receptor (EGFR) protein expression (IHC). If women: 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 men: surgically sterile or compliant with a highly effective contraceptive regimen during and for 6 months after the treatment period. Has provided signed informed consent Exclusion Criteria: Has enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device Participant has undergone major surgery within 28 days prior to enrollment or have planned major surgery, subcutaneous venous access device placement within 7 days prior to enrollment Phase 1b) or randomization (Phase 2). Has undergone any prior radiation therapy, except for Gamma Knife radiation and palliative radiation treatment at least 14 days have elapsed from last radiation treatment prior to enrollment (Phase 1b) or randomization (Phase 2) Has brain metastases that are symptomatic or require surgery, medication and radiotherapy except for stereotactic irradiation Has superior vena cava syndrome Has clinically relevant coronary artery disease or uncontrolled congestive - heart failure Participant has uncontrolled hypertension defined as systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥90 mmHg despite standard medical management. Has diabetes requiring insulin Has an angina or has experienced myocardial infarction within 6 months prior to enrollment (Phase 1b) or randomization (Phase 2) Has an Acquired Immunodeficiency Syndrome (AIDS)-related illness or have evidence of or test positive test results for human immunodeficiency virus (HIV) Has evidence of or test positive test results for hepatitis B, or hepatitis C virus antibodies Has a known allergy and history of hypersensitivity reaction to any of the treatment components, including any ingredient used in the formulation of necitumumab, or any other contraindication to one of the administered treatments Has significant third-space fluid retention requiring drainage Has history of interstitial pneumonitis Has an ongoing or active infection Has a history of significant neurological or psychiatric disorders Has a Grade 2 peripheral neuropathy Pregnant (confirmed within 7 days prior to enrollment [Phase 1b] or randomization [Phase 2]), or breastfeeding Has known history of drug abuse Assessed as inadequate for the study by the investigator or sub investigator

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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 + Gem and Cis<br>Phase 1b Dose Escalation: Necitumumab 800 milligram (mg) on Days 1 and 8 of every 21 day cycle, administered as an intravenous (IV) infusion. Gemcitabine (Gem) dose escalation of 1000 or 1250 milligram per square meter (mg/m^2) on Days 1 and 8 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles. Cisplatin (Cis) 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles. Phase 2 Randomized: Necitumumab 800 mg on Days 1 and 8 of every 21 day cycle, administered as an IV infusion. Gemcitabine at fixed dose determined in Phase 1b (1000 or 1250 mg/m^2) on Days 1 and 8 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles. Cisplatin 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion for a maximum of 4 cycles. | Drug: Necitumumab<br>* Administered IV<br>* Other names: LY3012211;Drug: Gemcitabine<br>* Administered IV<br>* Other names: LY188011;Drug: Cisplatin<br>* Administered IV<br>|
| Active Comparator: Gemcitabine + Cisplatin<br>Phase 2 Randomized: Gemcitabine at fixed dose determined in Phase 1b (1000 to 1250 mg/m^2) on Day 1 and Day 8 of every 21 day cycle,administered as an IV infusion over approximately 30 minutes for a maximum of 4 cycles. Cisplatin 75 mg/m^2 on Day 1 of every 21 day cycle, administered as an IV infusion over approximately 120 minutes for a maximum of 4 cycles . | Drug: Gemcitabine<br>* Administered IV<br>* Other names: LY188011;Drug: Cisplatin<br>* Administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs) | DLT was defined as any of the following events graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, when the event occurred within 21 days from Day 1 in Cycle 1 and was considered to be definitely or probably related to necitumumab and/or gemcitabine-cisplatin chemotherapy: Grade 4 neutropenia ≥ 7 days, Grade ≥ 3 febrile neutropenia except for transient febrile neutropenia (Grade 3 neutropenia with fever ≥ 38.5 degrees Celsius (°C) for ≤ 24 hours), Grade 3 thrombocytopenia requiring platelet substitution, Grade 4 thrombocytopenia, ≥Grade 3 nonhematologic toxicity (excluding nausea, vomiting, arthralgia, myalgia, asthenia, fatigue, diarrhea, constipation, anorexia), any toxicity leading to the omission of necitumumab on Day 8 or 15 (for participants for whom necitumumab was delayed from Days 8 to 15) during the Cycle 1. | Day 1 to Day 21 in Cycle 1 (Up To 21 days) | 
| Phase 2: Overall Survival (OS) | OS defined as the time from the date of randomization to the date of death due to any cause. Participants who are alive at the time of study completion or are lost to follow-up will be censored at the time they were last known to be alive. | From Date of Randomization until Death Due to Any Cause (Up To 39 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Progression Free Survival (PFS) | PFS defined as time from date of randomization until first radiographic documentation of measured progressive disease(PD) defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. PD was at least 20% increase in sum of diameters of target lesions with reference being smallest sum on study and an absolute increase of at least 5 mm,or unequivocal progression of non-target lesions,or 1 or more new lesions.If participant does not have complete baseline disease assessment,PFS time censored at date of randomization,regardless of whether or not objectively determined disease progression or death observed for participant.If participant was not known to have died or have objective progression as of data inclusion cutoff date for analysis,the PFS time censored at last adequate tumor assessment date.The use of new anticancer therapy prior to occurrence of PD resulted in censoring at the date of last radiographic assessment prior to initiation of new therapy. | From Date of Randomization to Measured Progressive Disease or Death Due to Any Cause (Up To 39 Months) | 
| Phase 1b: Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response or Partial Response (Objective Tumor Response Rate [ORR]) | ORR was the percentage of participants achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of nontarget lesions, and no appearance of new lesions. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. | Baseline to Measured Progressive Disease (Up To 39 Months) | 
| Phase 2: Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response or Partial Response (Objective Tumor Response Rate [ORR]) | ORR was the percentage of participants achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of nontarget lesions, and no appearance of new lesions. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. | Baseline to Measured Progressive Disease (Up To 39 Months) | 
| Phase 2: Time to Treatment Failure (TTF) | TTF was time from the date of randomization until the date of the first observation of radiographically documented progressive disease (PD), death due to any cause, discontinuation of treatment for any reason, or initiation of new anticancer therapy. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. Time to treatment failure was censored at the date of the last follow-up visit for participants who did not discontinue early, who were still alive, and who have not progressed. | From Date of Randomization to Measured Progressive Disease, Death Due to Any Cause, Discontinuation of Treatment or Initiation of New Anticancer Therapy (Up To 39 Months) | 
| Phase 2: Change From Baseline in EuroQol 5-Dimensional 3 Level (EuroQol-5D-3L) Index Score | EQ-5D measures mobility, self-care, usual activities, pain/discomfort, anxiety/depression. 3 severity levels: no, some, severe problems. The index score was calculated from a set of item weights to derive a score on a theoretical scale of 0 to 1, with 1 representing the best health status and zero representing death based on item weights for the Japanese population. One Cycle = 3 weeks and it can be delayed up to 6 weeks. | Baseline, Cycle 4 (Cycle = 3 weeks) | 
| Phase 2: Change From Baseline in EuroQol 5-Dimensional 3 Level (EuroQol-5D-3L) Visual Analog Scale (VAS) | EQ-5D VAS allowed participants to rate their present health condition. Possible scores ranged from 0 (worst imaginable health state) to 100 (best imaginable health state). One Cycle = 3 weeks and it can be delayed up to 6 weeks. | Baseline, Cycle 4 (Cycle = 3 weeks) | 
| Phase 2: Change From Baseline in Lung Cancer Symptom Scale (LCSS) | The LCSS is a validated and reliable instrument to assess lung cancer-specific symptoms and their impact on QOL.The LCSS total score was defined as the mean of the 9 items of the scale and the average symptom burden index (ASBI) is defined as the mean of 6 symptom-specific lung cancer questions. Each of the 9 symptom or summary items is assessed on a 100-mm visual analogue scale (VAS), with 0 representing no symptoms or better QOL. | Baseline, Cycle 4 (Cycle = 3 weeks) | 
| Phase 1b: Pharmacokinetics (PK): Maximum Concentration (Cmax) of Necitumumab | The Cmax is observed maximum serum concentration, taken directly from the serum concentration-time profile. | Cycle 1 (C1) Day 1 (D1) and C3 D1: Predose, End-of-infusion and 1, 3, 6, 24, 96, 168 h post-end-of-infusion | 
| Phase 1b: PK: Cmax of Gemcitabine and Cisplatin | The Cmax is observed maximum plasma concentration, taken directly from the plasma concentration-time profile. | Gemcitabine: Cycle 1(C1) Day1(D1): Predose, End-of-infusion and 0.5, 1, 2 h post-end-of-infusion; Cisplatin:C1 D1: Predose, End-of-infusion and 3, 21, 93, 165 h post-end-of-infusion | 
| Phase 1b: PK: Area Under the Serum Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Necitumumab | The AUC(0-infinity) is area under the serum concentration-time curve from time zero to infinite time. | Cycle 1 (C1) Day 1 (D1) and C3 D1: Predose, End-of-infusion and 1, 3, 6, 24, 96, 168 h post-end-of-infusion | 
| Phase 1b: PK: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Gemcitabine and Cisplatin | The AUC(0-infinity) is area under the plasma concentration-time curve from time zero to infinite time. | Gemcitabine: C1D1: Predose, End-of-infusion and 0.5, 1, 2 h post-end-of-infusion; Cisplatin:C1D1: Predose, End-of-infusion and 3, 21, 93, 165 h post-end-of-infusion | 
| Phase 2: PK: Minimum Concentration (Ctrough) of Necitumumab | The minimum observed serum concentration (Ctrough) of Necitumumab was evaluated. | Predose Day 1 of Cycle 1, 2, 3, 4, and every 2 cycles after Cycle 5 | 
| Phase 2: Number of Participants With Serum Anti-Necitumumab Antibody Assessment (Immunogenicity) | A participant was considered to have an anti-Necitumumab antibody response if anti-drug antibodies (ADA) were detected at any time point. | Baseline up to 30 Days Post Last Infusion (estimated up to 39 months) |