Non-Small Cell Lung Carcinoma
Conditions
Keywords
Advanced Non-Small Cell Lung Cancer
Brief summary
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).
Interventions
DRUGAlbumin-bound paclitaxel
Administered by intravenous infusion.
DRUGPaclitaxel
Administered by intravenous infusion.
DRUGCarboplatin
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).
Sponsors
Celgene
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 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment | Objective response was evaluated every 6 weeks until progression or new anti-cancer therapy initiation, up to 22 months. | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Participant Survival | Up to 38 months | 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. |
| Percentage of Participants With Controlled Disease | Assessed every 6 weeks, up to 22 months | 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. |
| Duration of Response in Responding Patients | Assessed every 6 weeks, up to 38 months | 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. |
| Number of Participants With Adverse Events (AEs) | Up to 38 months | 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. |
| 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 | Archival tissue samples were used for SPARC analysis. Survival was assessed for up to 38 months. | 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). |
| Progression-free Survival by Blinded Radiology Assessment | Assessed every 6 weeks until progression or death, up to 38 months | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Maximal Degree of Neutropenia Based on Clinical Laboratory Values of Absolute Neutrophil Count | 38 months | The maximal degree of neutropenia (and myelosuppression) was assessed by the overall nadir of absolute neutrophil count (ANC) based on clinical laboratory measurements graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. |
| Maximal Degree of Thrombocytopenia Based on Clinical Laboratory Values of Platelet Count | 38 months | The maximal degree of thrombocytopenia (and myelosuppression) was assessed by the overall nadir of platelet count based on clinical laboratory measurements graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. |
| Time to Improvement of ≥ Grade 3 Treatment Related Peripheral Neuropathy | 38 months | Peripheral neuropathy was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 on the following scale: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = death. Improvement in peripheral neuropathy was evaluated as: * Time to improvement of grade 3 or higher peripheral neuropathy by at least one grade; * Time to improvement of grade 3 or higher peripheral neuropathy to grade 1. Time to improvement was defined as the time from the first occurrence of grade 3 or higher treatment related neuropathy to improvement, as defined. Participants not experiencing improvement were censored at the last time the participant was evaluated for adverse events. |
| Maximal Degree of Anemia Based on Clinical Laboratory Values for Hemoglobin | 38 months | The maximal degree of anemia (and myelosuppression) was assessed by the overall nadir of hemoglobin levels based on clinical laboratory measurements graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. |
| Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment, by Histology | Objective response was evaluated every 6 weeks until progression or new anti-cancer therapy initiation, up to 22 months. | 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). Histology was determined at the time of primary diagnosis. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Eligible patients were randomized on Day 1 in a 1:1 ratio into 1 of 2 treatment arms and were required to start treatment within 7 days of randomization. The data below represent a cut-off of 31 January 2011. One patient was randomized twice and not included in the Intent-to-treat population.
Participants by arm
| Arm | Count |
|---|---|
| Albumin-bound Paclitaxel + Carboplatin Participants received albumin-bound paclitaxel 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. | 521 |
| Paclitaxel + Carboplatin Participants received 200 mg/m\^2 paclitaxel 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. | 531 |
| Total | 1,052 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 20 | 24 |
| Overall Study | Excluded prior to treatment | 7 | 7 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Paclitaxel not available | 0 | 2 |
| Overall Study | Physician Decision | 86 | 99 |
| Overall Study | Protocol Deviation | 3 | 4 |
| Overall Study | Still on treatment | 3 | 0 |
| Overall Study | Unacceptable Toxicity | 61 | 62 |
| Overall Study | Withdrawal by Subject | 65 | 67 |
Baseline characteristics
| Characteristic | Paclitaxel + Carboplatin | Albumin-bound Paclitaxel + Carboplatin | Total |
|---|---|---|---|
| Age, Continuous | 59.7 years STANDARD_DEVIATION 9.53 | 59.5 years STANDARD_DEVIATION 9.14 | 59.6 years STANDARD_DEVIATION 9.33 |
| Anatomic Site of Primary Diagnosis Lung | 499 participants | 480 participants | 979 participants |
| Anatomic Site of Primary Diagnosis Other | 32 participants | 41 participants | 73 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active) | 113 participants | 133 participants | 246 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restrictive but ambulatory) | 416 participants | 385 participants | 801 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 (Ambulatory but unable to work) | 2 participants | 3 participants | 5 participants |
| Histology of Primary Diagnosis Carcinoma/ Adenocarcinoma | 264 participants | 254 participants | 518 participants |
| Histology of Primary Diagnosis Large Cell Carcinoma | 13 participants | 9 participants | 22 participants |
| Histology of Primary Diagnosis Other | 33 participants | 29 participants | 62 participants |
| Histology of Primary Diagnosis Squamous Cell Carcinoma | 221 participants | 229 participants | 450 participants |
| Race/Ethnicity, Customized Asian | 80 participants | 79 participants | 159 participants |
| Race/Ethnicity, Customized Black, of African Heritage | 8 participants | 12 participants | 20 participants |
| Race/Ethnicity, Customized North American Indian or Alaska Native | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Other | 5 participants | 2 participants | 7 participants |
| Race/Ethnicity, Customized White, Hispanic or Latino | 5 participants | 11 participants | 16 participants |
| Race/Ethnicity, Customized White, Non Hispanic and Non Latino | 433 participants | 416 participants | 849 participants |
| Region of Enrollment Australia | 9 participants | 5 participants | 14 participants |
| Region of Enrollment Canada | 23 participants | 21 participants | 44 participants |
| Region of Enrollment Japan | 75 participants | 74 participants | 149 participants |
| Region of Enrollment Russian Federation | 231 participants | 238 participants | 469 participants |
| Region of Enrollment Ukraine | 135 participants | 120 participants | 255 participants |
| Region of Enrollment United States | 58 participants | 63 participants | 121 participants |
| Sex: Female, Male Female | 134 Participants | 129 Participants | 263 Participants |
| Sex: Female, Male Male | 397 Participants | 392 Participants | 789 Participants |
| Smoking status Missing | 5 participants | 2 participants | 7 participants |
| Smoking status Never smoked | 144 participants | 137 participants | 281 participants |
| Smoking status Smoked and currently smokes | 234 participants | 214 participants | 448 participants |
| Smoking status Smoked and quit smoking | 148 participants | 168 participants | 316 participants |
| Stage at Primary Diagnosis I | 20 participants | 16 participants | 36 participants |
| Stage at Primary Diagnosis II | 24 participants | 18 participants | 42 participants |
| Stage at Primary Diagnosis IIIa | 24 participants | 22 participants | 46 participants |
| Stage at Primary Diagnosis IIIb | 116 participants | 135 participants | 251 participants |
| Stage at Primary Diagnosis IV | 344 participants | 325 participants | 669 participants |
| Stage at Primary Diagnosis Unknown | 3 participants | 5 participants | 8 participants |
| Stage at Randomization IIIb | 110 participants | 108 participants | 218 participants |
| Stage at Randomization IV | 421 participants | 413 participants | 834 participants |
| Time from 1st Documented Metastasis/Relapse to Study Entry | 0.8 months STANDARD_DEVIATION 1.25 | 0.9 months STANDARD_DEVIATION 2.11 | 0.9 months STANDARD_DEVIATION 1.73 |
| Time from Primary Diagnosis to Study Entry | 4.3 months STANDARD_DEVIATION 16.09 | 4.3 months STANDARD_DEVIATION 17.12 | 4.3 months STANDARD_DEVIATION 16.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 483 / 514 | 499 / 524 |
| serious Total, serious adverse events | 93 / 514 | 80 / 524 |
Outcome results
Primary
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).
Time frame: Objective response was evaluated every 6 weeks until progression or new anti-cancer therapy initiation, up to 22 months.
Population: The intent-to-treat population which includes all randomized patients regardless of whether the patient received any study drug or had any efficacy assessments collected.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Albumin-bound Paclitaxel + Carboplatin | Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment | 33 percentage of participants |
| Paclitaxel + Carboplatin | Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment | 25 percentage of participants |
Comparison: The null hypothesis is that the albumin-bound paclitaxel/carboplatin regimen response rate (PA) is equal to that of the paclitaxel (Taxol)/carboplatin regimen (PT). Superiority of albumin-bound paclitaxel/carboplatin to paclitaxel/carboplatin will be established if the lower bound of the 95.1% CI of the response rate ratio is \> 1.0.p-value: 0.00595.1% CI: [1.082, 1.593]Chi-squared
Secondary
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.
Time frame: Assessed every 6 weeks, up to 38 months
Population: Intent-to-treat patients with an objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Albumin-bound Paclitaxel + Carboplatin | Duration of Response in Responding Patients | 9.6 months |
| Paclitaxel + Carboplatin | Duration of Response in Responding Patients | 9.5 months |
p-value: 0.55195% CI: [0.652, 1.244]Log Rank
Secondary
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.
Time frame: Up to 38 months
Population: Treated population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Albumin-bound Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 AE | 483 participants |
| Albumin-bound Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 grade 3 or higher AE | 360 participants |
| Albumin-bound Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 treatment-related AE | 469 participants |
| Albumin-bound Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 treatment-related grade 3 or higher AE | 321 participants |
| Albumin-bound Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 serious AE | 93 participants |
| Albumin-bound Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 treatment-related serious AE | 37 participants |
| Albumin-bound Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 AE with taxane permanently discontinued | 80 participants |
| Albumin-bound Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 AE with action of taxane dosage reduced | 237 participants |
| Albumin-bound Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 AE with action of taxane interrupted | 0 participants |
| Albumin-bound Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 AE with action of taxane delayed | 365 participants |
| Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 AE with action of taxane dosage reduced | 120 participants |
| Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 AE | 504 participants |
| Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 treatment-related serious AE | 30 participants |
| Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 grade 3 or higher AE | 355 participants |
| Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 AE with action of taxane delayed | 214 participants |
| Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 treatment-related AE | 481 participants |
| Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 AE with taxane permanently discontinued | 84 participants |
| Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 treatment-related grade 3 or higher AE | 315 participants |
| Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 AE with action of taxane interrupted | 5 participants |
| Paclitaxel + Carboplatin | Number of Participants With Adverse Events (AEs) | At least 1 serious AE | 80 participants |
Secondary
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.
Time frame: Up to 38 months
Population: Intent-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Albumin-bound Paclitaxel + Carboplatin | Overall Participant Survival | 12.1 months |
| Paclitaxel + Carboplatin | Overall Participant Survival | 11.2 months |
p-value: 0.27195.1% CI: [0.797, 1.066]Log Rank
Secondary
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.
Time frame: Assessed every 6 weeks, up to 22 months
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Albumin-bound Paclitaxel + Carboplatin | Percentage of Participants With Controlled Disease | 53 percentage of participants |
| Paclitaxel + Carboplatin | Percentage of Participants With Controlled Disease | 49 percentage of participants |
p-value: 0.23995% CI: [0.953, 1.21]Chi-squared
Secondary
Pharmacokinetic (PK) Parameters
Time frame: Blood samples for PK analyses were taken during Cycle 1 at 0.25, 3.5 and 24 hours post-infusion.
Population: Patients randomized to receive albumin-bound paclitaxel/carboplatin treatment in Canada, Russia, Ukraine and United States had the option to participate in sparse PK sampling in this study. Only 15 participants consented to participate, an insufficient number to support the planned population PK analysis hence these analyses were not performed.
Secondary
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.
Time frame: Assessed every 6 weeks until progression or death, up to 38 months
Population: Intent-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Albumin-bound Paclitaxel + Carboplatin | Progression-free Survival by Blinded Radiology Assessment | 6.3 months |
| Paclitaxel + Carboplatin | Progression-free Survival by Blinded Radiology Assessment | 5.8 months |
p-value: 0.21495.1% CI: [0.767, 1.06]Log Rank
Secondary
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).
Time frame: Archival tissue samples were used for SPARC analysis. Survival was assessed for up to 38 months.
Population: SPARC biomarker Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Albumin-bound Paclitaxel + Carboplatin | SPARC Status and Correlation With Overall Survival | High-SPARC | 17 participants |
| Albumin-bound Paclitaxel + Carboplatin | SPARC Status and Correlation With Overall Survival | Low-SPARC | 18 participants |
| Paclitaxel + Carboplatin | SPARC Status and Correlation With Overall Survival | High-SPARC | 22 participants |
| Paclitaxel + Carboplatin | SPARC Status and Correlation With Overall Survival | Low-SPARC | 14 participants |
Comparison: SPARC correlation with overall survival for the overall SPARC population.p-value: 0.302Univariate Cox regression
Other Pre-specified
Maximal Degree of Anemia Based on Clinical Laboratory Values for Hemoglobin
The maximal degree of anemia (and myelosuppression) was assessed by the overall nadir of hemoglobin levels based on clinical laboratory measurements graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0.
Time frame: 38 months
Population: Treated population where laboratory data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albumin-bound Paclitaxel + Carboplatin | Maximal Degree of Anemia Based on Clinical Laboratory Values for Hemoglobin | 90.0 g/L | Standard Deviation 17.19 |
| Paclitaxel + Carboplatin | Maximal Degree of Anemia Based on Clinical Laboratory Values for Hemoglobin | 103.9 g/L | Standard Deviation 16.9 |
Other Pre-specified
Maximal Degree of Neutropenia Based on Clinical Laboratory Values of Absolute Neutrophil Count
The maximal degree of neutropenia (and myelosuppression) was assessed by the overall nadir of absolute neutrophil count (ANC) based on clinical laboratory measurements graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0.
Time frame: 38 months
Population: Treated population where laboratory data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albumin-bound Paclitaxel + Carboplatin | Maximal Degree of Neutropenia Based on Clinical Laboratory Values of Absolute Neutrophil Count | 1.39 × 10^9/L | Standard Deviation 1.721 |
| Paclitaxel + Carboplatin | Maximal Degree of Neutropenia Based on Clinical Laboratory Values of Absolute Neutrophil Count | 1.26 × 10^9/L | Standard Deviation 1.366 |
Other Pre-specified
Maximal Degree of Thrombocytopenia Based on Clinical Laboratory Values of Platelet Count
The maximal degree of thrombocytopenia (and myelosuppression) was assessed by the overall nadir of platelet count based on clinical laboratory measurements graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0.
Time frame: 38 months
Population: Treated population where laboratory data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albumin-bound Paclitaxel + Carboplatin | Maximal Degree of Thrombocytopenia Based on Clinical Laboratory Values of Platelet Count | 114.9 × 10^9/L | Standard Deviation 82.13 |
| Paclitaxel + Carboplatin | Maximal Degree of Thrombocytopenia Based on Clinical Laboratory Values of Platelet Count | 136.6 × 10^9/L | Standard Deviation 81.91 |
Other Pre-specified
Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment, by Histology
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). Histology was determined at the time of primary diagnosis.
Time frame: Objective response was evaluated every 6 weeks until progression or new anti-cancer therapy initiation, up to 22 months.
Population: The intent-to-treat population. N indicates the number of participants in each histology category for each treatment arm respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Albumin-bound Paclitaxel + Carboplatin | Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment, by Histology | Carcinoma/Adenocarcinoma [254, 264] | 26 percentage of participants |
| Albumin-bound Paclitaxel + Carboplatin | Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment, by Histology | Squamous Cell Carcinoma [229, 221] | 41 percentage of participants |
| Albumin-bound Paclitaxel + Carboplatin | Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment, by Histology | Large Cell Carcinoma [N=9, 13] | 33 percentage of participants |
| Albumin-bound Paclitaxel + Carboplatin | Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment, by Histology | Other [N=29, 33] | 24 percentage of participants |
| Paclitaxel + Carboplatin | Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment, by Histology | Other [N=29, 33] | 15 percentage of participants |
| Paclitaxel + Carboplatin | Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment, by Histology | Carcinoma/Adenocarcinoma [254, 264] | 27 percentage of participants |
| Paclitaxel + Carboplatin | Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment, by Histology | Large Cell Carcinoma [N=9, 13] | 15 percentage of participants |
| Paclitaxel + Carboplatin | Percentage of Participants Who Achieved an Objective Confirmed Complete Response or Partial Response by Blinded Radiology Assessment, by Histology | Squamous Cell Carcinoma [229, 221] | 24 percentage of participants |
p-value: 0.036Regression, Logistic
Other Pre-specified
Time to Improvement of ≥ Grade 3 Treatment Related Peripheral Neuropathy
Peripheral neuropathy was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 on the following scale: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = death. Improvement in peripheral neuropathy was evaluated as: * Time to improvement of grade 3 or higher peripheral neuropathy by at least one grade; * Time to improvement of grade 3 or higher peripheral neuropathy to grade 1. Time to improvement was defined as the time from the first occurrence of grade 3 or higher treatment related neuropathy to improvement, as defined. Participants not experiencing improvement were censored at the last time the participant was evaluated for adverse events.
Time frame: 38 months
Population: Treated population with ≥ grade 3 treatment-related peripheral neuropathy.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Albumin-bound Paclitaxel + Carboplatin | Time to Improvement of ≥ Grade 3 Treatment Related Peripheral Neuropathy | Improvement by ≥1 grade | 24.0 days |
| Albumin-bound Paclitaxel + Carboplatin | Time to Improvement of ≥ Grade 3 Treatment Related Peripheral Neuropathy | Improvement to grade 1 | 38.0 days |
| Paclitaxel + Carboplatin | Time to Improvement of ≥ Grade 3 Treatment Related Peripheral Neuropathy | Improvement by ≥1 grade | 26.0 days |
| Paclitaxel + Carboplatin | Time to Improvement of ≥ Grade 3 Treatment Related Peripheral Neuropathy | Improvement to grade 1 | 104.0 days |