Bronchioloalveolar Lung Carcinoma, Large Cell Lung Carcinoma, Lung Adenocarcinoma, Recurrent Non-Small Cell Lung Carcinoma, Stage IV Non-Small Cell Lung Cancer
Conditions
Keywords
Non-Small Cell Lung Cancer, cixutumumab
Brief summary
This randomized phase II trial studies how well carboplatin, paclitaxel, and bevacizumab (CPB) work when given with or without cixutumumab in treating patients with non-small cell lung cancer that is stage IV or has come back (recurrent). Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Other types of monoclonal antibodies, such as cixutumumab, may find tumor cells and help kill them. It is not yet known whether giving more than one drug (combination chemotherapy) together with bevacizumab is more effective when given with or without cixutumumab in treating patients with non-small cell lung cancer.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the progression-free survival with the combination of carboplatin, paclitaxel, and bevacizumab, and +/- IMC-A12 (cixutumumab) in patients with advanced, non-squamous, non-small cell lung cancer. SECONDARY OBJECTIVES: I. To evaluate overall survival and response rate of the above combination in patients with non-squamous, advanced non-small cell lung cancer. II. To evaluate the toxicities of the above combination in patients with non-squamous advanced non-small cell lung cancer. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A (CPB): Patients receive carboplatin intravenously (IV) over 30 minutes, paclitaxel IV over 3 hours, and bevacizumab IV over 30-90 minutes on day 1. ARM B (CPB+cixutumumab): Patients receive carboplatin, paclitaxel, and bevacizumab as in Arm A. Patients also receive cixutumumab (IMC-A12) IV over 1 hour on days 1, 8, and 15. In both arms, treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab and cixutumumab may continue in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Interventions
BIOLOGICALBevacizumab
Given IV
DRUGCarboplatin
Given IV
BIOLOGICALCixutumumab
Given IV
DRUGPaclitaxel
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 with non-squamous, non-small cell lung cancer (NSCLC) * Advanced NSCLC defined as either recurrent disease after prior radiation or surgery or stage IV (M1a or M1b) based on the TNM staging system (American Joint Committee on Cancer \[AJCC\] 2009) * Measurable disease as defined by the revised Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). All sites of disease (of target and non-target disease sites) must be obtained within 4 weeks prior to randomization * A head computed tomography (CT) or magnetic resonance imaging (MRI) required within 4 weeks prior to randomization * Prior radiation therapy (RT) is allowed if it has been completed 3 weeks prior to randomization and patient has recovered from any adverse events related to RT * Brain metastases are allowed, provided they have been treated with surgery and/or radiotherapy, the patient is neurologically stable, and repeat brain imaging shows no progression in the brain; at least 6 weeks should have elapsed from the time of craniotomy and at least 4 weeks from radiotherapy * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Absolute neutrophil count (ANC) ≥ 1500/mm³ * Platelet count ≥ 100,000/mm³ * Total bilirubin within institutional upper limit of normal (ULN) * Serum creatinine ≤ 1.5 x ULN * Fasting blood glucose within normal range (fasting \< 120 mg/dL or below ULN) * Alkaline phosphatase (ALP) ≤ 3 x ULN * Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN * Urine dipstick must be ≤ 0-1+ within 2 weeks (14 days) of randomization; if urine dipstick result is \> 1+, a calculation of urine protein creatinine (UPC) ratio is required; patients must have a UPC ratio \< 1.0 to participate in the study * Neuropathy, if present at baseline, must be ≤ Common Terminology Criteria for Adverse Events (CTCAE) grade 1 * Patients with a history of hypertension must be well-controlled (≤ 150/90) on a stable regimen of anti-hypertensive therapy * Women of childbearing potential and sexually active males should use an accepted and effective method of contraception while on treatment and for 3 months thereafter
Exclusion criteria
* Prior chemotherapy or biologic/molecular targeted therapy for advanced NSCLC. Prior chemotherapy and/or biological/molecular targeted therapy as part of initial potentially curative therapy (one regimen of induction and/or adjuvant and/or concurrent chemoradiotherapy) was allowed provided it had been completed 1 year or more prior to randomization * Prior treatment with IMC-A12 or another insulin-like growth factor 1 receptor (IGF-1R) inhibitor * Patients on therapeutic anticoagulation; patient's international normalized ratio (INR) must be ≤ 1.5 or partial thromboplastin time (PTT) ≤ upper limits of normal within 2 weeks prior to randomization to be eligible; prophylactic anticoagulation of venous access devices is allowed provided the above criteria have been met * Prior allergic reaction to compounds of chemical or biologic composition similar to those of IMC-A12 * Hypersensitivity to any component of bevacizumab * Poorly controlled diabetes mellitus * History of other invasive malignancies unless there is no active disease and all treatment has been completed ≥ 3 years prior to randomization; patients with history of in-situ malignancies and curatively resected nonmelanomatous skin cancer are eligible * History of thrombotic or hemorrhagic disorders * History of bleeding diathesis or coagulopathy * ≥ grade 2 bleeding or any bleeding requiring intervention within 4 weeks prior to randomization * History of gross hemoptysis (defined as ≥ 1/2 teaspoon of bright red blood) * Any of the following within 6 months prior to randomization: * Abdominal fistula * Gastrointestinal perforation * Intra-abdominal abscess * Previous myocardial infarction * History of any central nervous system (CNS) cerebrovascular ischemia * New York Heart Association (NYHA) \> class II congestive heart failure or severe heart failure * Unstable or symptomatic angina pectoris * History of stroke * Significant vascular disease * Symptomatic peripheral vascular disease * Ongoing, serious cardiac arrhythmia requiring medication at time of randomization * Ongoing, active infection or ongoing fever at the time of randomization or any co-existing medical condition, psychiatric illness or limitations that would interfere with compliance of study requirements * History of hypertensive crisis or hypertensive encephalopathy * Any of the following within 4 weeks prior to randomization: a serious non-healing wound, ulcer, bone fracture, or major surgical procedure * Anticipated major surgical procedure(s) during the course of the study * Receiving daily treatment with aspirin (\> 325 mg/day) or non-steroidal anti-inflammatory agents (NSAIDs) known to inhibit platelet function for chronic conditions; patients must not be receiving treatment with dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix), and/or cilostazol (Pletal); if patient was receiving any of the following: aspirin (\> 325 mg/day), NSAID, and/or anti-platelet drugs, patient must have discontinued its use ≥ 1 week prior to randomization * Pregnant or breast-feeding * Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; up to 5 years | Progression-free survival was defined as the time from randomization to progression or death without documentation of progression. For cases without progression, follow-up was censored at the date of last disease assessment without progression, unless death occurs within 3 months following the date last known progression-free, in which case the death was counted as a failure. Progression was evaluated using RECIST 1.1 criteria and defined as: 1. At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study and the sum must also demonstrate an absolute increase of at least 5 mm. OR 2. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; up to 5 years | Overall survival is defined as the time from randomization to death or date last known alive. |
| Proportion of Patients With Objective Response | Assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry; up to 5 years | Objective response was evaluated using the RECIST 1.1 criteria. Objective response includes complete response (CR) and partial response (PR). Objective response is defined as disappearance of all target lesions or at least a 30% decrease in the sum of the diameters of target lesions. In addition, non-target lesions do not meet the criteria for disease progression and no new lesions were observed. |
Countries
United States
Participant flow
Recruitment details
This study opened to accrual on March 9, 2010 and was suspended on February 24, 2011 for safety evaluation. As the safety criterion was met, this study reopened on May 16, 2011 and closed to accrual on June 28, 2013 due to the end of the clinical development program with cixutumumab (IMC-A12) with final accrual of 175 patients.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (CPB) Patients receive carboplatin intravenously (IV) over 30 minutes, paclitaxel IV over 3 hours, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab may continue in the absence of disease progression or unacceptable toxicity. | 78 |
| Arm B (CPB+Cixutumumab) Patients receive carboplatin, paclitaxel, and bevacizumab as in Arm A. Patients also receive cixutumumab (IMC-A12) IV over 1 hour on days 1, 8, and 15. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab and cixutumumab may continue in the absence of disease progression or unacceptable toxicity. | 75 |
| Total | 153 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 22 | 22 |
| Overall Study | Alternative therapy | 4 | 0 |
| Overall Study | Continued presence of residual disease | 0 | 1 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Disease progression | 39 | 41 |
| Overall Study | Functional decline | 2 | 0 |
| Overall Study | Ineligible | 5 | 7 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Maximum response achieved | 0 | 1 |
| Overall Study | Never started protocol treatment | 5 | 5 |
| Overall Study | No off-treatment reason submitted | 1 | 0 |
| Overall Study | Other complicating disease | 2 | 4 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 4 |
Baseline characteristics
| Characteristic | Arm A (CPB) | Arm B (CPB+Cixutumumab) | Total |
|---|---|---|---|
| Age, Continuous | 64 years | 61 years | 63 years |
| Sex: Female, Male Female | 40 Participants | 40 Participants | 80 Participants |
| Sex: Female, Male Male | 38 Participants | 35 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 80 / 83 | 78 / 82 |
| serious Total, serious adverse events | 58 / 83 | 74 / 82 |
Outcome results
Primary
Progression-free Survival (PFS)
Progression-free survival was defined as the time from randomization to progression or death without documentation of progression. For cases without progression, follow-up was censored at the date of last disease assessment without progression, unless death occurs within 3 months following the date last known progression-free, in which case the death was counted as a failure. Progression was evaluated using RECIST 1.1 criteria and defined as: 1. At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study and the sum must also demonstrate an absolute increase of at least 5 mm. OR 2. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; up to 5 years
Population: Eligible and treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (CPB) | Progression-free Survival (PFS) | 5.8 months |
| Arm B (CPB+Cixutumumab) | Progression-free Survival (PFS) | 7.0 months |
p-value: 0.33Log Rank
Secondary
Overall Survival (OS)
Overall survival is defined as the time from randomization to death or date last known alive.
Time frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; up to 5 years
Population: Eligible and treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (CPB) | Overall Survival (OS) | 16.2 months |
| Arm B (CPB+Cixutumumab) | Overall Survival (OS) | 16.1 months |
p-value: 0.95Log Rank
Secondary
Proportion of Patients With Objective Response
Objective response was evaluated using the RECIST 1.1 criteria. Objective response includes complete response (CR) and partial response (PR). Objective response is defined as disappearance of all target lesions or at least a 30% decrease in the sum of the diameters of target lesions. In addition, non-target lesions do not meet the criteria for disease progression and no new lesions were observed.
Time frame: Assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry; up to 5 years
Population: Eligible and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (CPB) | Proportion of Patients With Objective Response | 0.462 Proportion of participants |
| Arm B (CPB+Cixutumumab) | Proportion of Patients With Objective Response | 0.587 Proportion of participants |
p-value: 0.15Fisher Exact