Albumin-bound Paclitaxel (ABI-007) for Patients With Advanced Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of this study is to compare disease response of Albumin-bound paclitaxel (ABI-007) plus Carboplatin versus Taxol and Carboplatin as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC).

Official Title
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A Randomized, Phase III Trial of ABI-007 and Carboplatin Compared With Taxol and Carboplatin as First-Line Therapy in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Non-Small Cell Lung Carcinoma

Intervention / Treatment
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* Drug: Albumin-bound paclitaxel
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed stage IIIB or IV non-small cell lung cancer (NSCLC) Male or non-pregnant and non-lactating female, and equal or greater than age 18 If a female patient is of child-bearing potential, as evidence by regular menstrual periods, she must have a negative serum pregnancy test (beta human chorionic gonadotropin [βhCG]) documented within 72 hours of the first administration of study drug If sexually active, the patient must agree to utilize contraception considered adequate and appropriate by the investigator No other current active malignancy Radiographically-documented measurable disease (defined by the presence of at least 1 radiographically documented measurable lesion) Patients must have received no prior chemotherapy for the treatment of metastatic disease. Adjuvant chemotherapy permitted providing cytotoxic chemotherapy was completed 12 months prior to starting the study Patient has the following blood counts at baseline: Absolute neutrophil count (ANC) greater than or equal to 1.5x10^9/L Platelets greater than or equal to 100x10^9/L Hemoglobin (Hgb) greater than or equal to 9 g/dL Patient has the following blood chemistry levels at baseline: Aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT) less than or equal to 2.5 x upper limit of normal range (ULN) or less than or equal to 5.0 x ULN if liver metastases; Total bilirubin less than or equal to ULN Creatinine less than or equal to 1.5 mg/dL Expected survival of greater than 12 weeks Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Patient or his/her legally authorized representative or guardian has been informed about the nature of the study, and has agreed to participate in the study, and signed the Informed Consent form prior to participation in any study-related activities Exclusion Criteria: Evidence of active brain metastases, including leptomeningeal involvement. Prior evidence of brain metastasis permitted only if treated and stable and off therapy for greater than or equal to 1 month The only evidence of disease is non-measurable Patient has pre-existing peripheral neuropathy of Grade 2, 3, or 4 (per Common Terminology Criteria for Adverse Events [CTCAE] Version 3). Patient received radiotherapy in the last 4 weeks, except if to a non-target lesion only. Prior radiation to a target lesion is permitted only if there has been clear progression of the lesion since radiation was completed Patient has a clinically significant concurrent illness Patient has received treatment with any investigational drug within the previous 4 weeks Patient has a history of allergy or hypersensitivity to any of the study drugs Patient has serious medical risk factors involving any of the major organ systems such that the investigator considers it unsafe for the patient to receive an experimental research drug Patient is enrolled in any other clinical protocol or investigational trial that involves administration of experimental therapy and/or therapeutic devices.

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: Albumin-bound paclitaxel + Carboplatin<br>Participants received albumin-bound paclitaxel (ABRAXANE®) 100 mg/m^2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Carboplatin was given at an Area Under the Curve (AUC) = 6 mg*min/mL on Day 1 only of each 21-day cycle, beginning immediately after the completion of albumin-bound paclitaxel administration. Participants could continue treatment at the investigator's discretion until disease progression, development of an unacceptable toxicity, or withdrawal of consent. | Drug: Albumin-bound paclitaxel<br>* Administered by intravenous infusion.<br>* Other names: nab®-paclitaxel;Drug: Carboplatin<br>* Administered by intravenous infusion. Dosing was based on the Calvert formula: carboplatin dose (mg) = (Target AUC) x (glomerular filtration rate [GFR] + 25). For the purposes of this protocol, the GFR is considered to be equivalent to creatinine clearance (calculated by the method of Cockcroft and Gault, 1976).<br>|
| Active Comparator: Paclitaxel + Carboplatin<br>Participants received 200 mg/m^2 paclitaxel (Taxol®) administered by intravenous infusion followed by carboplatin at AUC = 6 mg*min/mL on Day 1 of a 21 day cycle. Participants could continue treatment at the investigator's discretion until disease progression, development of an unacceptable toxicity, or withdrawal of consent. | Drug: Paclitaxel<br>* Administered by intravenous infusion.<br>* Other names: Taxol®;Drug: Carboplatin<br>* Administered by intravenous infusion. Dosing was based on the Calvert formula: carboplatin dose (mg) = (Target AUC) x (glomerular filtration rate [GFR] + 25). For the purposes of this protocol, the GFR is considered to be equivalent to creatinine clearance (calculated by the method of Cockcroft and Gault, 1976).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment | Antitumor response was defined as the percentage of participants who achieved an objective response (Confirmed Response [CR] or Partial Response [PR]), confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. Response was based on the blinded radiological review using Response Evaluation Criteria in Solid Tumors (RECIST) response guidelines, Version 1.0. A complete response was defined as a disappearance of all target and non-target lesions and no new lesions. Partial response was defined as ≥ 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD, and the persistence of one or more non-target lesions not qualifying for CR or Progressive Disease (the unequivocal progression of existing non-target lesion(s) or appearance of one or more new lesions). | Objective response was evaluated every 6 weeks until progression or new anti-cancer therapy initiation, up to 22 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival by Blinded Radiology Assessment | Progression free survival time was defined as the time from the day of randomization to the start of disease progression or death (any cause), whichever occurred first, based on the blinded radiological review response assessment. Progressive disease was defined as a ≥ 20% increase in the SLD of target lesions, taking as reference the nadir SLD recorded since the treatment started, or the presence of one or more new lesions, or the unequivocal progression of existing non-target lesion(s) or appearance of one or more new lesion(s). Participants who did not have disease progression or had not died were censored at the last visit they were documented as progression free. If palliative radiotherapy or surgery at lesion sites occurred, the participant was censored at the last date without documented progression prior to radiotherapy or surgery. In follow-up, participants who began new therapy prior to progression were censored at the last documented date as progression-free. | Assessed every 6 weeks until progression or death, up to 38 months | 
| Overall Participant Survival | Overall survival was defined as the time from the day of randomization to participant death (due to any cause), as assessed by post study follow-up performed monthly for 6 months and every 3 months thereafter for 12 months. All participants who were lost to the follow-up prior to the end of the trial or who completed the 18 month follow up phase were censored at last known time the participant was alive. | Up to 38 months | 
| Percentage of Participants With Controlled Disease | Controlled disease was defined as the percentage of participants with stable disease for ≥ 16 weeks or confirmed complete or partial overall response, based on blinded radiological assessment. Stable disease was defined as neither sufficient shrinkage of target lesions to qualify for Partial Response, nor sufficient increase to qualify for Progressive Disease, or the persistence of one or more non-target lesions not qualifying for Complete Response or Progressive Disease. | Assessed every 6 weeks, up to 22 months | 
| Duration of Response in Responding Patients | Duration of response was assessed by progression free survival for participants who achieved a confirmed complete response or partial response based on blinded radiological assessment. | Assessed every 6 weeks, up to 38 months | 
| Number of Participants With Adverse Events (AEs) | A Treatment-emergent AE was any AE that began or worsened in grade after the start of study drug through 30 days after the last dose of study drug or end of study whichever is later. Treatment related toxicity was one considered by the investigator to be possibly, probably or definitely related to study drug. AEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 on the following scale: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = death. A serious adverse event (SAE) is any untoward medical occurrence at any dose that: is fatal or life-threatening; results in persistent or significant disability or incapacity; requires or prolongs in-patient hospitalization; is a congenital anomaly/birth defect in the offspring of a patient; and conditions not included in the above that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above. | Up to 38 months | 
| Pharmacokinetic (PK) Parameters |  | Blood samples for PK analyses were taken during Cycle 1 at 0.25, 3.5 and 24 hours post-infusion. | 
| SPARC Status and Correlation With Overall Survival | The expression and cellular distribution of Secreted Protein Acidic and Rich in cysteine (SPARC) in biopsies of lung tumor was examined by immunohistochemistry using a 2 antibody system by an approved central laboratory and analyzed by 2 pathologists. The following tissue components were scored: tumor cells, fibroblasts, inflammatory cells, acellular stroma/matrix, and blood vessels. To classify participants into high-SPARC and low-SPARC groups, an average z-score was calculated across variables and classified high-SPARC (average z-scores ≥0) and low-SPARC (average z-scores <0) groups. SPARC status was then correlated with overall survival (the time from the day of randomization to participant death due to any cause). | Archival tissue samples were used for SPARC analysis. Survival was assessed for up to 38 months. | 

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