A Randomized Phase 2 Study of Ixabepilone Plus Carboplatin and Paclitaxel Plus Carboplatin in Advanced Nonsmall-Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine whether progression-free survival with ixabepilone is superior to that achieved with paclitaxel plus carboplatin in participants with advanced nonsmall-cell lung cancer and beta III (βIII)-tubulin-positive tumors.

Official Title
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A Randomized Phase 2 Study of Ixabepilone Plus Carboplatin and Paclitaxel Plus Carboplatin in Patients With Advanced Non-small Cell Lung Cancer

Conditions
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Advanced/Metastatic Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Ixabepilone, 32 mg/m^2
* Drug: Paclitaxel, 200 mg/m^2
* Drug: Carboplatin (area under the concentration curve [AUC] 6)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed non-small cell lung cancer (NSCLC)(squamous cell, adenocarcinoma, large cell, or bronchoalveolar carcinoma) Stage IIIB NSCLC with pleural effusion, Stage IV NSCLC, or recurrent disease following surgery with or without radiation therapy Available paraffin-embedded tissue to measure the expression levels of βIII tubulin Disease measurable by Response Evaluation Criteria in Solid Tumors, with at least 1 target lesion situated outside any previous radiotherapy field Karnofsky performance status of 70-100 Life expectancy of at least 3 months Men and women, ages 18 years and older Exclusion Criteria: Uncontrolled brain metastases Peripheral neuropathy greater than Grade 1 Fewer than 4 weeks from prior radiation therapy or locoregional surgeries to randomization date (less than 1 week from focal/palliative radiotherapy or minor surgery) Any concurrent malignancy other than nonmelanoma skin cancer or carcinoma in situ of the cervix Known HIV-positive status Absolute neutrophil count lower than 1500 cells mm^3 Total bilirubin level higher than upper limit of normal (ULN) as defined by the institution (with the exception of elevation due to Gilbert's syndrome) Aspartate transaminase or alanine transaminase level higher than 2.5*ULN Serum creatine level of 1.5 mg/dL or higher Renal function with a creatinine clearance of less than 50 mL/min (as calculated with the Cockcroft and Gault equation) Any prior antineoplastic systemic regimens.

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 |
| --- | --- |
| Experimental: Ixabepilone, 32 mg/m^2 + Carboplatin (AUC 6)<br> | Drug: Ixabepilone, 32 mg/m^2<br>* Intravenous (IV) solutions, ixabepilone, 32 mg/m^2<br>* Other names: BMS-247550;Drug: Carboplatin (area under the concentration curve [AUC] 6)<br>* Carboplatin (AUC 6) day 1, every 21 days, 6 cycles<br>|
| Active Comparator: Paclitaxel, 200 mg/m^2 + Carboplatin (AUC 6)<br> | Drug: Paclitaxel, 200 mg/m^2<br>* IV solutions, paclitaxel, 200 mg/m^2<br>* Other names: BMY-26575;Drug: Carboplatin (area under the concentration curve [AUC] 6)<br>* Carboplatin (AUC 6) day 1, every 21 days, 6 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival in the Subgroup of Participants With βIII-tubulin Positive Tumors | Progression-free survival is defined as the period from date of randomization to date of disease progression or death. For participants who do not progress or die at the end of the study, progression-free survival was censored at the last tumor assessment date. For those who have no on-study tumor assessment, progression-free survival was censored at the date of randomization. A tumor was considered to be beta III (βIII)-tubulin positive if 50% or more of the tumor cells had a βIII-tubulin immunohistochemistry staining intensity equal to or greater than that of the positive control. | Randomization to disease progression or death (maximum reached: 14.39 months ) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival in the Subgroup of Participants With βIII-tubulin Negative Tumors | Progression-free survival is defined as the period from date of randomization to date of disease progression or death. For participants who do not progress or die at the end of the study, progression-free survival was censored at the last tumor assessment date. For those who have no on study tumor assessment, progression-free survival was censored at the date of randomization. | Randomization to disease progression or death (maximum reached: 12.29 months) | 
| Progression-free Survival in the Overall Population | Progression-free survival is defined as the period from date of randomization to date of disease progression or death. For participants who do not progress or die at the end of the study, progression-free survival was censored at the last tumor assessment date. For those who have no on study tumor assessment, progression-free survival was censored at the date of randomization. | Randomization to disease progression or death, assessed to 12.29 months | 
| Percentage of Participants With Best Response of Complete Response (CR) or Partial Response (PR) | Response evaluated per Response Evaluaton in Solid Tumor (V1.0) guidelines and assessed using magnetic resonance imaging. Percentage of best response=the total number of participants with the best overall response of CR or PR divided by the total number of randomized participants in that treatment arm. CR=disappearance of all target lesions; PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. | At randomization and then every 6 weeks to date of CR, PR, or progression for 6 21-day cycles | 
| Time to Response | Time to Response is defined as the time from randomization date until the date of first response (Partial Response [PR] or Complete Response [CR]) | Randomization to date of first response (PR or CR) | 
| Number of Participants With Death as Outcome, Drug-related Adverse Events (AEs), Serious AEs (SAEs), Drug-related SAEs, AEs Leading to Discontinuation, and Drug-related Peripheral Neuropathy | An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related is defined as possibly, probably, or certainly related to and of unknown relationship to study treatment. | Days 1 through 21, continuously | 
| Number of Participants With Hematology Laboratory Results of Grade 3 or 4 | LLN=lower level of normal. Leukocytes (leukopenia) Grade 1: <LLN to 3.0*10^9/L, Grade 2:<3.0 to 2.0*10^9/L, Grade 3: <2.0 to 1.0*10^9/L, Grade 4: <1.0*10^9/L; Neutrophils (neutropenia) Grade 1: <LLN to 1.5*10^9/L, Grade 2: <1.5 to 1.0*10^9/L, Grade 3: <1.0 to 0.5*10^9/L, Grade 4: <0.5*10^9/L; Platelet count(thrombocytopenia) Grade 1: LLN to 75.0*10^9/L, Grade 2: <75.0 to 50.0*10^9/L, Grade 3: <50.0 to 25.0*10^9/L, Grade 4:<25.0 to 10^9/L; Hemoglobin (anemia) Grade 1: <LLN to 10.0 g/dL, Grade 2: <10.0 to 8.0 g/dL, Grade 3: <8.0 to 6.5 g/dL, Grade 4: <6.5 g/dL. | At screening and weekly during 21-day cycle | 
| Number of Participants With Grade 3 or 4 Abnormalities in Liver Function and Urine Laboratory Test Results | ULN=upper level of normal. Alkaline phosphatase (ALP) Gr 1:>ULN to 2.5*ULN, Gr 2: >2.5 to 5.0*ULN, Gr 3: >5.0 to 20.0*ULN, Gr 4: >20.0*ULN; Aspartate aminotransferase (AST) Gr 1: >ULN to 2.5*ULN, Gr 2: >2.5 to 5.0*ULN, Gr 3: >5.0 to 20.0*ULN, Gr 4: >20.0*ULN | At screening and within 72 hours of start of 21-day cycle (Cycle 2 and beyond) | 
| Median Length of Survival in the Overall Population and in the Subgroups of Patients With βIII-tubulin Positive (β3T+) and βIII-tubulin Negative (β3T-)Tumors | Overall Survival was computed for all randomized participants and was defined as the time between randomization and death. Participants who did not die at the end of the study were censored at their last known alive date. | Randomization to death or last known alive date, up to 31.34 months |