Recurrent Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer
Conditions
Keywords
Advanced Non-small Cell Lung Cancer, Carboplatin, Paclitaxel, Cetuximab, IMC-A12
Brief summary
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
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
Interventions
BIOLOGICALcixutumumab
Given IV
DRUGcarboplatin
Given IV
DRUGpaclitaxel
Given IV
BIOLOGICALcetuximab
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | assessed every 3 months if patient is < 2 years from study entry and every 6 months in year 3 | Overall survival is defined as time from registration to death from any cause. |
| Response Rate | 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 | 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. |
Countries
United States
Participant flow
Recruitment details
This study was activated on September 11, 2009. The trial was suspended to accrual on December 17, 2010 after accruing 140 patients and accrual was subsequently terminated on April 19, 2011 due to excessive grade 5 events within 30 days of study registration.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Carboplatin, Paclitaxel, Cetuximab) 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.
carboplatin: Given IV
paclitaxel: Given IV
cetuximab: Given IV | 39 |
| Arm II (Carboplatin, Paclitaxel, Cixutumumab) 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.
cixutumumab: Given IV
carboplatin: Given IV
paclitaxel: Given IV | 41 |
| Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) 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.
cixutumumab: Given IV
carboplatin: Given IV
paclitaxel: Given IV
cetuximab: Given IV | 47 |
| Total | 127 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 8 | 9 |
| Overall Study | alternative therapy | 0 | 0 | 1 |
| Overall Study | Death | 5 | 0 | 4 |
| Overall Study | Lack of Efficacy | 28 | 25 | 23 |
| Overall Study | not start protocol therapy | 4 | 3 | 1 |
| Overall Study | unknown/not specify | 0 | 7 | 9 |
| Overall Study | Withdrawal by Subject | 6 | 2 | 1 |
Baseline characteristics
| Characteristic | Arm I (Carboplatin, Paclitaxel, Cetuximab) | Arm II (Carboplatin, Paclitaxel, Cixutumumab) | Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) | Total |
|---|---|---|---|---|
| Age, Continuous | 60 years | 60 years | 60 years | 60 years |
| Sex: Female, Male Female | 19 Participants | 17 Participants | 22 Participants | 58 Participants |
| Sex: Female, Male Male | 20 Participants | 24 Participants | 25 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 43 / 44 | 40 / 42 | 46 / 48 |
| serious Total, serious adverse events | 27 / 44 | 27 / 42 | 36 / 48 |
Outcome results
Primary
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.
Time frame: 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
Population: eligible and treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Carboplatin, Paclitaxel, Cetuximab) | Progression Free Survival | 3.4 months |
| Arm II (Carboplatin, Paclitaxel, Cixutumumab) | Progression Free Survival | 4.2 months |
| Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) | Progression Free Survival | 4.0 months |
Secondary
Overall Survival
Overall survival is defined as time from registration to death from any cause.
Time frame: assessed every 3 months if patient is < 2 years from study entry and every 6 months in year 3
Population: eligible and treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Carboplatin, Paclitaxel, Cetuximab) | Overall Survival | 9.8 months |
| Arm II (Carboplatin, Paclitaxel, Cixutumumab) | Overall Survival | 7.7 months |
| Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) | Overall Survival | 8.8 months |
Secondary
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.
Time frame: 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
Population: eligible and treated patients who have response data. 3 patients on arm I and 1 patient on arm III had unknown/missing tumor response and were excluded from the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Carboplatin, Paclitaxel, Cetuximab) | Response Rate | 11.1 percentage of participants |
| Arm II (Carboplatin, Paclitaxel, Cixutumumab) | Response Rate | 22.0 percentage of participants |
| Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) | Response Rate | 21.7 percentage of participants |