Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

This randomized phase II trial is studying how well giving carboplatin and paclitaxel together with cetuximab and/or cixutumumab 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

Further Study Information

PRIMARY OBJECTIVES:

I. To evaluate the progression-free survival of patients with NSCLC randomized to carboplatin plus paclitaxel plus cetuximab or carboplatin plus paclitaxel plus IMC-A12 (cixutumumab) or carboplatin plus paclitaxel plus cetuximab plus IMC-A12.

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 EGFR by IHC, mutation, and gene copy number, IGF-1R and IGF-2R expression (both phosphorylated and unphosphorylated states), expression of p-AKT 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 EGF and 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.

Eligibility Criteria

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 RECIST criteria

• Ineligible for or refused treatment with bevacizumab

• No small cell lung cancer or mixed small cell and NSCLC

• No untreated or symptomatic 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

• 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)

• 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

• PTT ≤ 1.2 times ULN and INR ≤ 1.5 (unless patient is on anticoagulation therapy)

• Not pregnant or nursing

• 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 peripheral neuropathy > grade 1 as per CTCAE v 4.0

• No history of or suspected interstitial pneumonitis or pulmonary fibrosis on imaging

• No 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

• No arterial thrombosis, pulmonary embolus, deep vein thrombosis, or hemorrhagic disorders within the past 28 days

• 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

• No 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

• No history of allergic reactions attributed to compounds of similar chemical or biological composition to cixutumumab

• 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

• No prior agents targeting the EGFR or IGFR pathways

• No prior therapy for advanced NSCLC, except for surgery and/or radiotherapy

• No prior systemic therapy, including bevacizumab for advanced stage NSCLC

• 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

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Nasser Hanna

Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00986674
Information obtained from ClinicalTrials.gov on March 19, 2013