This study is planned to answer questions about how the drug, matuzumab (EMD 72000), works and is part of an effort aimed to develop better treatment for advanced lung cancer by combining matuzumab, a monoclonal antibody, with a chemotherapy treatment, called pemetrexed. Pemetrexed is commercially available and has been approved for treatment of locally advanced or metastatic non-small cell lung cancer that could not be successfully treated with other chemotherapy.

The study aims to examine how non-small cell lung cancer (NSCLC) responds to matuzumab in combination with pemetrexed, as compared with giving pemetrexed alone. The study also aims to examine how safe and effective matuzumab is and for how long it stays in the body (pharmacokinetics). Matuzumab is an experimental treatment which is currently only available for research studies.

Primary objective:

• To determine the tumor response rate (as assessed by the Independent Review Committee [IRC]) of 2 different regimens of matuzumab in combination with pemetrexed in comparison to pemetrexed alone in subjects with stage IV non-small cell lung cancer (NSCLC)

Secondary objectives: The secondary objectives of this study are to determine the following:

• Tumor response rate (as assessed by the Investigator)
• Overall survival
• Time to tumor progression
• Duration of response
• Safety and tolerability
• Quality of life (QoL)

Additional objectives: Additional objectives of this study include evaluation of:

• Human antihumanized antibody (HAHA)
• Pharmacokinetics (PK) of matuzumab
• Epidermal growth factor receptor (EGFR) mutation analysis and association of EGFR mutations with tumor response
• Biomarker identification in plasma using enzyme-linked immunosorbent assay (ELISA) and mass spectrometry-based techniques.

This study is an open-label, randomized, controlled phase II study of matuzumab at a dose of 800 mg every week or 1600 mg every 3 weeks administered intravenously in combination with a fixed dose of pemetrexed (500 mg/m2 every 3 weeks intravenously), in comparison to pemetrexed alone, as a second-line treatment in subjects with Stage IV NSCLC and progressive disease on or after first-line chemotherapy with a platinum analogue in combination with either taxanes or gemcitabine.

Randomization will be performed in a stratified manner by the following factors:

• Best response to first-line chemotherapy (complete response [CR]/partial response [PR]/stable disease [SD] versus progressive disease [PD])
• Time from previous chemotherapy to randomization (<3 months versus ≥3 months)

Subjects will be centrally randomized in a ratio of 1:1:1 as follows:

• Group A: pemetrexed alone (500 mg/m2 every 3 weeks)
• Group B: pemetrexed (every 3 weeks) plus matuzumab 800 mg every week
• Group C: pemetrexed (every 3 weeks) plus matuzumab 1600 mg every 3 weeks

Subjects will be evaluated for tumor response every 6 weeks (regardless of treatment delays) until PD. An IRC will conduct a blinded review of the computed tomography (CT) and/or magnetic resonance imaging (MRI) results to determine response and response duration. Response will be classified according to the modified criteria of the World Health Organization (WHO). The IRC assessments will be used for the primary statistical analyses.

The Lung Cancer Symptom Scale (LCSS) will be used to assess changes in QoL. EGFR mutation analysis will be conducted on archived tumor material. Blood samples will be taken for detection of biomarkers and HAHA (Groups B and C only). Matuzumab peak and trough concentrations will be measured at each matuzumab infusion (Groups B and C only).

Ages Eligible for Study:  18 Years   -   75 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• First written informed consent provided prior to any prescreening procedure and second written informed consent provided prior to any screening procedure
• Male or female, 18-75 years of age, inclusive
• Histologically or cytologically confirmed diagnosis of non-small cell lung cancer
• Demonstrated progressive disease on or after first-line chemotherapy for stage IV disease. The first-line therapy must consist of platinum-based regimens in combination with taxanes or gemcitabine
• A chemotherapy-free interval of at least 3 weeks between the end of first-line chemotherapy and start of study treatment
• At least 1 measurable lesion according to the modified WHO criteria
• Archived tissue or cytologic sample available for the determination of EGFR expression, and evidence of tumor EGFR (HER-1) expression in the most recent available sample
• ECOG performance status 0-1
• Life expectancy >12 weeks
• Adequate baseline organ functions, defined as follows: *Serum creatinine ≤1.5 × upper limit of normal (ULN). In case of borderline values for serum creatinine, creatinine clearance must be ≥45 mL/min; *Total bilirubin <1.5 × ULN; *Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 × ULN (Subjects with liver metastases should have ALT/AST <5 × ULN.); *Absolute neutrophil count ≥1500/mm3; *Platelet count ≥100,000/mm3; *Hemoglobin level ≥10 g/dL11
• If procreative potential (male or female), willingness to use effective contraceptive methods for the duration of treatment and continuing for 2 months after the last dose. Subjects of procreative potential are defined as any fertile male, or any female who has experienced menarche and who is not postmenopausal (defined as age-related amenorrhea ≥12 months) or who has not undergone successful surgical sterilization (hysterectomy or bilateral oophorectomy)

Exclusion Criteria:

• Radiotherapy or major surgery within 30 days prior to the start of study treatment
• Prior treatment with an EGFR-directed therapy or with EGFR signal transduction inhibitors
• Prior treatment with pemetrexed
• Pregnant (confirmed by β-HCG) or lactating female
• Weight loss >10% within 12 weeks prior to the start of study treatment
• Documented or symptomatic brain metastases or leptomeningeal disease
• Myocardial infarction within 6 months prior to the start of study treatment, uncontrolled congestive heart failure, or any current Grade 3 or 4 cardiovascular disorder despite treatment
• Presence of a ≥Grade 2 preexisting skin disorder (except for alopecia)
• Previous diagnosis of autoimmune disease
• History of drug-related acute infusion reaction
• Concurrent malignancies or invasive carcinomas diagnosed within the past 5 years, except for adequately treated basal cell carcinoma of the skin or in situ carcinoma of the cervix
• Any significant disease that, in the Investigator’s opinion, should exclude the subject from the study
• History of significant neurologic or psychiatric disorder (e.g., dementia, seizures, or bipolar disorder)
• History of drug abuse within 6 months prior to the start of study treatment
• Known conditions that require concurrent treatment with a nonpermitted drug
• Presence of a contraindication to the study treatment(s) according to the current Investigator’s Brochure (IB) for matuzumab and the labeling for pemetrexed
• Known hypersensitivity to the study treatment or any of its components
• Participation in another clinical study within 30 days prior to the start of study treatment
• Legal incapacity or limited legal capacity