Study of Taxane/Carboplatin +/- Cetuximab as First-Line Treatment for Patients With Advanced/Metastatic Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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The primary purpose of this clinical research study is to learn if patients treated with the combination of Taxane/Carboplatin plus Cetuximab (C/T/C) have a longer progression-free survival than patients treated with Taxane/Carboplatin (T/C) alone. The safety of this treatment will also be studied.

Official Title
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A Randomized Multicenter Phase III Study of Taxane/Carboplatin/Cetuximab Versus Taxane/Carboplatin as First-Line Treatment for Patients With Advanced/Metastatic Non-Small Cell Lung Cancer

Conditions
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Non-Small-Cell Lung Carcinoma

Intervention / Treatment
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* Drug: Paclitaxel (Taxane)
* Drug: Docetaxel (Taxane)
* Drug: Carboplatin
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have advanced or metastatic non-small cell lung cancer that has not been previously treated with any chemotherapy. Tumor/disease lesions that can be measured bidimensionally. Must be able to carry-out work of light or sedentary nature (e.g. light house work, office work). Adequate recovery from recent surgery or radiation therapy. Must be at least 4 weeks from last major surgery or prior treatment with an investigational agent. At least 12 weeks from any radiation therapy to chest. Accessible for treatment, follow-up and required visits at a participating center(s). Exclusion Criteria: Prior chemotherapy or adjuvant chemotherapy for the treatment of lung cancer. Prior treatment with cetuximab or other epidermal growth factor (EGFR)-targeted therapy. Prior severe infusion reaction to antibody therapy. Concurrent malignancy (previous malignancy without evidence of disease for 5 years will be allowed to enter trial). Concurrent chemotherapy or therapy with another investigational agent not indicated in the protocol. Serious uncontrolled medical disorders that would impair the ability to receive therapy. History of myocardial infarction within prior 3 months, uncontrolled angina, uncontrolled arrhythmia, or uncontrolled congestive heart failure. Symptomatic or uncontrolled metastases in the central nervous system. Subjects receiving a glucocorticoid for central nervous system (CNS) metastases are not eligible, but those receiving an anticonvulsant are eligible. Peripheral neuropathy >= grade 2 (Common Toxicity Criteria Adverse Event [CTCAE] Version 3.0). Inadequate hematologic and/or liver and/or kidney function. Sexually active and fertile individuals or partners of these individuals who are unwilling or unable to use an acceptable method of birth control for entire trial and up to 4 weeks after the study. Women who are pregnant or breastfeeding. Women with a positive pregnancy test on enrollment prior to study drug administration. Altered mental status or psychiatric condition that prohibits understanding or rendering of consent.

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 |
| --- | --- |
| Active Comparator: Cetuximab+Taxane+Carboplatin (C/T/C)<br>Cetuximab was administered at an initial dose (Week 1) of 400 mg/m^2 intravenous (IV) infusion (infused over 120 minutes) and a weekly maintenance dose of 250 mg/m^2 IV infusion (infused over 60 minutes). A cycle of therapy was defined as 3 weeks. Taxane was paclitaxel 225 mg/m^2 infused over 180 minutes on Day 1 and subsequently every 3 weeks or docetaxel 75 mg/m^2 infused over 60 minutes on Day 1 and subsequently every 3 weeks. Carboplatin was infused over 30 minutes on Day 1 and subsequently every 3 weeks. | Drug: Paclitaxel (Taxane)<br>* IV, 225 mg/m^2<br>Drug: Docetaxel (Taxane)<br>* IV, 75 mg/m^2<br>Drug: Carboplatin<br>* AUC=6, q 3 weeks (6 cycles maximum)<br>Drug: Cetuximab<br>* Intravenous, 400 mg/m^2, initial dose followed by 250 mg/m^2, weekly starting on Week 2<br>* Other names: Erbitux;|
| Active Comparator: Taxane+Carboplatin (T/C)<br>A cycle of therapy was defined as 3 weeks. Taxane was paclitaxel 225 mg/m^2 infused over 180 minutes on Day 1 and subsequently every 3 weeks or docetaxel 75 mg/m^2 infused over 60 minutes on Day 1 and subsequently every 3 weeks. Carboplatin was infused over 30 minutes on Day 1 and subsequently every 3 weeks. | Drug: Paclitaxel (Taxane)<br>* IV, 225 mg/m^2<br>Drug: Docetaxel (Taxane)<br>* IV, 75 mg/m^2<br>Drug: Carboplatin<br>* AUC=6, q 3 weeks (6 cycles maximum)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Number of Months of Progression-free Survival (PFS) | Interval between randomization date & earliest date of disease progression/death due to any cause, assessed by the Independent Radiology Review Committee (IRRC) using modified World Health Organization (WHO) criteria to define progressive disease (PD): >=25% increase in sum of products of diameters (SOPD) of lesions compared with smallest SOPD recorded for study period or progression of any non-index lesion/appearance of new lesion. If no progression/death, date of last tumor assessment used. For participants who had no on-study tumor assessments & were still alive, date of randomization used. | From randomization to evidence of disease progression/death or date of last tumor assessment (up to 26 months). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response (CR) or Partial Response (PR) | Tumor response was defined as the number of participants whose best response was CR or PR, per the IRRC assessment, using the modified WHO criteria: CR: disappearance of all index/non-index lesions; PR: >= 50% reduction in the SOPD of index lesions compared with the baseline SOPD, with no evidence of progression. To qualify as CR or PR, no new lesions could be present. | From randomization to end of study drug therapy (up to 174 weeks). | 
| Number of Participants With Complete Response (CR), Partial Response (PR) or Stable Disease (SD) | Disease control was defined as the number of participants whose best response was CR, PR, or SD, per the IRRC assessment, using the modified WHO criteria: CR: disappearance of all index/non-index lesions; PR:>= 50% reduction in the SOPD of index lesions compared with the baseline SOPD, with no evidence of progression (to qualify as CR or PR, no new lesions could be present); SD: participants who did not meet the criteria for CR, PR, or PD (PD:>=25% increase in SOPD of lesions compared with smallest SOPD recorded for study period or progression of any non-index lesion/appearance of new lesion). | From randomization to end of study drug therapy (up to 174 weeks). | 
| Median Number of Months of Response | Median number of months of response (time from first occurrence of CR/PR to date of PD/death, [per IRRC assessment,using modified WHO criteria]) calculated for participants whose best response=CR/PR.For participants who did not progress/die, date of last tumor assessment used.CR:disappearance of all index/non-index lesions;PR:>= 50% reduction in SOPD of index lesions compared with baseline, no evidence of progression.No new lesions present.PD:>=25% increase in SOPD of lesions compared with smallest SOPD recorded for study period or progression of any non-index lesion/appearance of new lesion. | Time from first occurrence of CR or PR (whichever was recorded first) to the date of PD, death or date of last tumor assessment (up to 19 months). | 
| Median Number of Months to Response | The median number of months to response was calculated for participants whose best response was CR or PR. It was defined as the time from the first dose of study therapy to the first date that criteria for PR or CR (whichever occurred first)were met. Response was assessed by the IRRC, using the modified WHO criteria: CR: disappearance of all index/non-index lesions; PR: >= 50% reduction in the SOPD of index lesions compared with the baseline SOPD, with no evidence of progression. To qualify as CR or PR, no new lesions could be present. | Time from first dose of study therapy to the date of PR or CR, whichever occurred first (up to 13 months). | 
| Median Number of Months of Survival | The median number of months of survival was defined as the time from randomization to the date of death. For participants who did not die, the date of last contact was used. | From randomization to death or date of last contact (up to 41 months). | 
| Number of Participants With Improvement of Symptoms | Symptoms were assessed using the Functional Assessment of Cancer Therapy - Lung Cancer Subscale (FACT-LCS) questionnaire. This 7-item scale has scores ranging from 0 (severely symptomatic in all symptoms assessed) to 28 (symptom-free on all symptoms assessed). Symptom response (improvement) was defined as >= 2-point increase from baseline in score (maintained for 2 consecutive assessments, at least 3 weeks apart). Participants with a baseline score of >= 27 were not evaluable, as it would not have been possible to show an improvement. Participants with no baseline data were also not evaluable. | From randomization to evidence of disease progression/death or date of last symptom assessment (up to 33 weeks). | 
| Median Number of Months Until Symptomatic Progression (Worsening of Symptoms) | Symptoms were assessed using the FACT-LCS questionnaire. This 7-item scale has scores ranging from 0 (severely symptomatic) to 28 (symptom-free). Symptomatic progression was defined as >= 2-point decrease from baseline in score (maintained for 2 consecutive assessments at least 3 weeks apart). Time to symptomatic progression was defined as the time from randomization to date of symptoms worsening. For participants with no symptom progression, the date of the last symptom assessment was used. See also Outcome Measure 15. | From randomization to evidence of disease progression/death or date of last symptom assessment (up to 33 weeks). | 
| Number of Participants Who Died, or Experienced Other Serious Adverse Events (SAEs) and Adverse Events (AEs) | An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition (even if not caused by the study drug). An SAE was defined as an AE that resulted in death, was life-threatening, required hospitalization (or prolongation of existing hospitalization), or was an important medical event. | From start of study drug therapy up to 30 days after the last dose (up to 178 weeks). | 
| Number of Participants Experiencing AEs Leading to Study Drug Discontinuation | An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition (even if not caused by the study drug). The results presented are stratified according to which drug was discontinued. | From start of study drug therapy up to 30 days after the last dose (up to 178 weeks). | 
| Number of Participants Experiencing Other Significant AEs: Acneform Rash | An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition (even if not caused by the study drug). For this study, it was decided that AEs that were categorized under the composite term acneform rash were of particular importance. These AEs were: rash, rash pustular, rash erythematous, dermatitis acneiform, dermatitis exfoliative, rash papular, rash pruritic, rash generalised, rash macular, rash maculo-papular, acne, acne pustular, skin desquamation and dry skin. | From start of study drug therapy up to 30 days after the last dose (up to 178 weeks). | 
| Number of Participants Experiencing Other Significant AEs: Infusion Reaction | AE=any new untoward medical occurrence or worsening of pre-existing medical condition (even if not caused by the study drug). For this study, it was decided that AEs that were categorized under the composite term infusion reaction were of particular importance. These AEs were: infusion-related reaction, hypersensitivity, anaphylactic reaction, anaphylactic shock, and anaphylactoid reaction regardless of when they occurred. The terms dyspnea, pyrexia and chills were also grouped under infusion reaction, provided the onset date of these toxicities occurred on the first day of study treatment. | From start of study drug therapy up to 30 days after the last dose (up to 178 weeks). | 
| Number of Participants Experiencing Other Significant AEs: Cardiac AEs | An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition (even if not caused by the study drug). For this study, it was decided that AEs that were categorized under the composite term cardiac AE were of particular importance. These AEs, coded as preferred or other level Medical Dictionary for Regulatory Activities [MedDRA] terms were: coronary artery disorders, cardiac arrhythmias, heart failures not elsewhere classified, left ventricular failures, sudden cardiac death, cardiac death and sudden death. | From start of study drug therapy up to 30 days after the last dose (up to 178 weeks). | 
| Number of Participants Who Exprienced the Most Frequent Grade 3-4 Hematology Abnormalities Occurring in >=5% Participants | Abnormalities were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 3.0. The scale is graded from 1 (least severe) to 4 (life threatening). Grade 3 and 4 criteria are defined as follows: Neutropenia: Grade 3, neutrophils <1.0 - 0.5 x 10^9/L; Grade 4, <0.5 x 10^9/L. Leukopenia: Grade 3, leukocytes <2.0 - 1.0 x 10^9/L; Grade 4, <1.0 x 10^9/L. Thrombocytopenia: Grade 3, platelets <50.0 - 25.0 x 10^9/L; Grade 4, <25.0 x 10^9/L. Anemia: Grade 3, hemoglobin <4.9 - 4.0 millimoles (mmol)/L, Grade 4, <4.0 mmol/L. | From start of study drug therapy up to 30 days after the last dose (up to 178 weeks). | 
| Number of Participants Who Experienced the Most Frequent Grade 3-4 Serum Chemistry Abnormalities Occurring in >=5% Participants | Abnormalities were graded according to the NCI CTC, version 3.0. The scale is graded from 1 (least severe) to 4 (life threatening). Grade 3 and 4 criteria are defined as follows: Hyperglycemia (non-fasting): Grade 3, serum glucose >13.9 - 27.8 mmol/L; Grade 4 >27.8 mmol/L or acidosis. Hypomagnesemia: Grade 3, serum magnesium >1.23 - 3.30 mmol/L; Grade 4 >3.30 mmol/L. Hyponatremia: Grade 3, serum sodium <130 - 120 mmol/L; Grade 4 <120 mmol/L. Low albumin: Grade 3, serum albumin <20 g/L; Grade 4 not applicable. | From start of study drug therapy up to 30 days after the last dose (up to 178 weeks). | 
| Number of Participants Who Had Unscheduled Visits to Physicians, Clinics, Hospitals and Other Unscheduled Major Medicinal Procedures | Participants were to complete log to collect information on unscheduled visits to physicians,clinics,hospitals & other unscheduled major procedures.If asked, participants were to complete and return log to site upon routinely scheduled visits.The purpose of this exploratory analysis was to understand the economical implications as a secondary objective.This was not a pivotal study & therefore not needed to support any arguments with regulatory authorities concerning cost-benefit,hence,it was not necessary to conduct this analysis. There is no intent on conducting this analysis in the future. | Day 1 of each cycle of treatment, at the end of study therapy evaluation and at the first follow-up visit (6 weeks after the end of study therapy evaluation). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Small Cell Lung Cancer