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
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
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.
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
Inclusion Criteria:
Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)
Stage IIIB disease
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:
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
No other prior or concurrent malignancy, except for the following:
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:
Arterial thrombosis, pulmonary embolus, deep vein thrombosis, or hemorrhagic disorders within the past 28 days
Ann Arbor, Michigan 48106, United States
Mount Holly, New Jersey 08060, United States
Philadelphia, Pennsylvania 19104, United States
Stevens Point, Wisconsin 54481, United States