Carboplatin and Paclitaxel Combined With Cetuximab and/or IMC-A12 in Patients With Advanced Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This randomized phase II trial is studying how well giving carboplatin and paclitaxel together with cetuximab and/or cixutumumab (IMC-A12) works in treating patients with stage IIIB or stage IV non-small cell lung cancer. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab and cixutumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving chemotherapy together with monoclonal antibody therapy may kill more tumor cells. It is not yet known whether carboplatin and paclitaxel are more effective when given with cetuximab and/or cixutumumab in treating non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the progression-free survival of patients with non-small cell lung cancer (NSCLC) randomized to carboplatin plus paclitaxel plus cetuximab or carboplatin plus paclitaxel plus cixutumumab (IMC-A12) or carboplatin plus paclitaxel plus cetuximab plus cixutumumab. SECONDARY OBJECTIVES: I. To evaluate the response rate, disease control rate (complete response plus partial response plus stable disease), and toxicities for each arm. II. To evaluate epidermal growth factor receptor (EGFR) by Immunohistochemistry (IHC), mutation, and gene copy number, Insulin-like growth factor 1 receptor (IGF-1R) and Insulin-like growth factor 2 receptor (IGF-2R) expression (both phosphorylated and unphosphorylated states), expression of p-AKT (ie, Protein Kinase B) by IHC, and k-ras mutation. III. Plasma-based biomarkers will be evaluated for total and free insulin-like growth factor 1 and 2, IGF-growth factor binding protein 3 (IGFBP3) and circulating levels of epidermal growth factor (EGF) and Transforming growth factor (TGF) alpha. IV. To evaluate overall survival on each of the three arms. OUTLINE: This is a multicenter study. Patients are stratified according to gender and histology (squamous cell vs non-squamous cell). Patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive carboplatin intravenously (IV) over 15-30 minutes and paclitaxel IV over 3 hours on days 1 and 22 and cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 42 days for 2 courses. Patients with stable or responding disease after 2 courses proceed to maintenance therapy with cetuximab alone on days 1, 8, 15, 22, 29, and 36. Treatment with cetuximab repeats every 42 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive carboplatin and paclitaxel as in arm I. Patients also receive cixutumumab IV over 1 hour on days 1, 15, and 29. Treatment repeats every 42 days for 2 courses. Patients with stable or responding disease after 2 courses proceed to maintenance therapy with cixutumumab alone on days 1, 15, and 29. Treatment with cixutumumab repeats every 42 days in the absence of disease progression or unacceptable toxicity. ARM III: Patients receive carboplatin, paclitaxel, and cetuximab as in arm I. Patients also receive cixutumumab as in arm II. Treatment repeats every 42 days for 2 courses. Patients with stable or responding disease after 2 courses proceed to maintenance therapy with cetuximab as in arm I and cixutumumab as in arm II. Tumor tissue samples are collected at baseline for analysis of EGFR expression by IHC, mutation, and gene copy number; IGF-1R and IGF-2R expression (both phosphorylated and unphosphorylated states); p-AKT expression by IHC; and k-ras mutation. Blood, serum, and plasma samples are collected periodically for biomarker analysis. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 1 year. PROJECTED ACCRUAL: 200 patients

Official Title
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Three-Arm Randomized Phase II Study of Carboplatin and Paclitaxel in Combination With Cetuximab, IMC-A12 or Both in Patients With Advanced Non-Small Cell Lung Cancer Who Will Not Receive Bevacizumab-Based Therapy

Conditions
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Recurrent Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

Intervention / Treatment
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* Biological: cixutumumab
* Drug: carboplatin
* Drug: paclitaxel
* Biological: cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) Stage IIIB disease T4, NX with nodule in ipsilateral lung lobe allowed provided patient is not a candidate for combined chemotherapy and radiotherapy Stage IV disease (includes M1a and M1b) Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria Ineligible for or refused treatment with bevacizumab No untreated or symptomatic central nervous system (CNS) metastases Patients with a history of CNS metastases that are definitively treated, stable, and controlled are eligible provided the following criteria are met: Definitive therapy (surgery and/or radiotherapy) has been administered Not planning to undergo additional treatment for brain metastases Clinically stable Off corticosteroids or on a stable dose of corticosteroids for ≥ 14 days before study entry ECOG performance status 0-1 Leukocytes > 3,000/mm^3 Absolute neutrophil count (ANC) > 1,500/mm^3 Hemoglobin > 9 g/dL Platelet count > 100,000/mm^3 Total bilirubin ≤ 1.5 times upper limit of normal (ULN) Aspartate Aminotransferase (AST) < 3 times ULN (< 5 times ULN if elevations due to liver metastases) Creatinine < 1.5 times ULN OR creatinine clearance > 60 mL/min Fasting serum glucose < 120 mg/dL Partial thromboplastin time (PTT) ≤ 1.2 times ULN and international normalized ratio (INR) ≤ 1.5 (unless patient is on anticoagulation therapy) Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after the last dose of cixutumumab No poorly controlled diabetes mellitus Patients with a history of diabetes mellitus are eligible provided their blood glucose is within normal range and they are on a stable dietary or therapeutic regimen for this condition No other prior or concurrent malignancy, except for the following: Curatively treated malignancy with no known active disease for ≥ 3 years AND is considered to be at low risk for recurrence by the treating physician Adequately treated nonmelanoma skin cancer or lentigo maligna with no evidence of disease Adequately treated cervical carcinoma in situ with no evidence of disease Prostatic intraepithelial neoplasia with no evidence of prostate cancer Concurrent therapeutic anticoagulation allowed provided there is no bleeding and patient is on a stable dose of anticoagulation therapy (e.g., Warfarin with an INR of 2-3) for > 2 weeks prior to study entry At least 21 days since prior radiotherapy More than 4 weeks since prior major surgery or hormonal therapy (other than hormone replacement therapy) and recovered More than 1 year since prior neoadjuvant or adjuvant chemotherapy Exclusion criteria: Small cell lung cancer or mixed small cell and NSCLC History of allergic reactions attributed to compounds of similar chemical or biological composition to cixutumumab History of any medical or psychiatric condition, addictive disorder, or laboratory abnormality that, in the opinion of the investigator, may increase the risks associated with study participation or study treatments or may interfere with the conduct of the study or interpretation of study results Prior agents targeting the EGFR or Insulin-like growth factor (IGFR) pathways Prior therapy for advanced NSCLC, except for surgery and/or radiotherapy Prior systemic therapy, including bevacizumab for advanced stage NSCLC Pregnant or nursing Peripheral neuropathy > grade 1 as per Common Terminology Criteria for Adverse Event (CTCAE) v 4.0 History of or suspected interstitial pneumonitis or pulmonary fibrosis on imaging Significant uncontrolled cardiac disease within the past 6 months, including any of the following: Uncontrolled hypertension (BP > 150/100 mm Hg) Unstable angina Recent myocardial infarction Uncontrolled congestive heart failure Cardiomyopathy with decreased ejection fraction Arterial thrombosis, pulmonary embolus, deep vein thrombosis, or hemorrhagic disorders within the past 28 days

Ages Eligible for Study
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Minimum Age: 18 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: Arm I (carboplatin, paclitaxel, cetuximab)<br>Patients receive carboplatin IV over 15-30 minutes and paclitaxel IV over 3 hours on days 1 and 22 and cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 42 days for 2 courses. Patients with stable or responding disease after 2 courses proceed to maintenance therapy with cetuximab alone on days 1, 8, 15, 22, 29, and 36. Treatment with cetuximab repeats every 42 days in the absence of disease progression or unacceptable toxicity. | Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Biological: cetuximab<br>* Given IV<br>* Other names: monoclonal antibody C225;|
| Experimental: Arm II (carboplatin, paclitaxel, cixutumumab)<br>Patients receive carboplatin and paclitaxel as in arm I. Patients also receive cixutumumab IV over 1 hour on days 1, 15, and 29. Treatment repeats every 42 days for 2 courses. Patients with stable or responding disease after 2 courses proceed to maintenance therapy with cixutumumab alone on days 1, 15, and 29. Treatment with cixutumumab repeats every 42 days in the absence of disease progression or unacceptable toxicity. | Biological: cixutumumab<br>* Given IV<br>* Other names: IMC-A12;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;|
| Experimental: Arm III (carboplatin, paclitaxel, cetuximab, cixutumumab)<br>Patients receive carboplatin, paclitaxel, and cetuximab as in arm I. Patients also receive cixutumumab as in arm II. Treatment repeats every 42 days for 2 courses. Patients with stable or responding disease after 2 courses proceed to maintenance therapy with cetuximab as in arm I and cixutumumab as in arm II. | Biological: cixutumumab<br>* Given IV<br>* Other names: IMC-A12;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Biological: cetuximab<br>* Given IV<br>* Other names: monoclonal antibody C225;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression free survival is defined as time from registration to disease progression or death from any cause, whichever occurred earlier. Disease progression was assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, and/or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions . All eligible and treated patients were included in the analysis. | Tumor measurements are repeated every 6 weeks while on treatment. After off treatment, assessed every 3 months if patient is < 2 years from study entry and every 6 months in year 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as time from registration to death from any cause. | assessed every 3 months if patient is < 2 years from study entry and every 6 months in year 3 | 
| Response Rate | Tumor response was assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Complete response (CR) was defined disappearance of all tumor lesions. Partial response (PR) was defined as as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter. Overall response rate= CR+PR. | Tumor measurements are repeated every 6 weeks while on treatment. After off treatment, assessed every 3 months if patient is < 2 years from study entry and every 6 months in year 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Non-small Cell Lung Cancer, Carboplatin, Paclitaxel, Cetuximab, IMC-A12