Adenocarcinoma, Carcinoma, Carcinoma, Large Cell, Lung Neoplasm, Non-Small Cell Lung Cancer, Squamous Cell Carcinoma
Conditions
Keywords
NSCLC advanced non-small cell lung cancer squamous adenocarcinoma large cell carcinoma lung cancer elderly first line treatment abraxane carbo nab-paclitaxel
Brief summary
Study comparing two regimens of nab-paclitaxel and carboplatin combination in elderly subjects (≥ 70 years old) with advanced NSCLC
Detailed description
This is a Phase IV, randomized, open-label, multicenter study of continuous weekly versus weekly times three with one-week break nab-paclitaxel in combination with carboplatin as first-line treatment in elderly subjects (≥ 70 years old) with advanced non small cell lung cancer who have not received prior chemotherapy for their advanced disease and are not candidates for curative surgery or radiation therapy. The primary study endpoint is the percentage of subjects with either peripheral neuropathy or myelosuppression adverse events. Patients will continue treatment until they develop progressive disease, unacceptable side-effects or wish to withdraw from the study, according to local standard of care. Patients will have radiographic evaluations every 6 weeks while on treatment.
Interventions
DRUGnab-paclitaxel
DRUGCarboplatin
Sponsors
Celgene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
70 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- * Inclusion Criteria: - 1. Age ≥ 70 years at the time of signing the Informed Consent Form. 2. Understand and voluntarily provide written informed consent prior to the conduct of any study related assessments/procedures. 3. Able to adhere to the study visit schedule and other protocol requirements. 4. Histologically or cytologically confirmed locally advanced or metastatic non small cell lung cancer who are not candidates for curative surgery or radiation therapy. 5. No other current active malignancy requiring anticancer therapy. 6. Radiographically documented measurable disease per RECIST v 1.1 7. No prior chemotherapy for the treatment of metastatic disease. Adjuvant chemotherapy is permitted providing that cytotoxic chemotherapy was completed 12 months prior to signing the informed consent form (ICF) and without disease recurrence. Participans with previously known epidermal growth factor receptor mutation or anaplastic lymphoma kinase gene translocation must have failed or had intolerance to one treatment with epidermal growth factor receptor tyrosine kinase inhibitor or anaplastic lymphoma kinase inhibitor therapy, respectively. 8. Absolute neutrophil count ≥ 1500 cells/cubic millimetre. 9. Platelets ≥ 100,000 cells/cubic millimetre. 10. Hemoglobin ≥ 9 grams/decilitre. 11. Aspartate transaminase/serum glutamic oxaloacetic transaminase/ alanine transaminase/serum glutamic pyruvic transaminase ≤ 2.5 × upper limit of normal range or ≤ 5.0 × upper limit of normal range if liver metastases. 12. Total bilirubin ≤ 1.5 millilitre/decilitre (unless there is a known history of Gilberts Syndrome). 13. Creatinine clearance \> 40 millilitre/minute calculated using Cockcroft-Gault equation (if renal impairment is suspected 24 hour urine collection for measurement is required). 14. Eastern Cooperative Oncology Group performance status 0 or 1. 15. Females who (1) have undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or (2) have been naturally postmenopausal for at least 24 consecutive months (ie, has not had menses at any time during the preceding 24 consecutive months). 16. Male subjects must: Practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for 6 months following study drug discontinuation, even if he has undergone a successful vasectomy.
Exclusion criteria
* 1\. Evidence of active brain metastases, including leptomeningeal involvement (prior evidence of brain metastasis are permitted only if treated and stable and off therapy for ≥ 4 weeks prior to signing Informed consent form. Magnetic Resonance Imaging of the brain (or Computed Tomography scan w/contrast) is preferred for diagnosis. 2\. History of leptomeningeal disease. 3. Only evidence of disease is non measurable. 4. Preexisting peripheral neuropathy of Grade 2, 3, or 4 (per Common Terminology Criteria for Adverse Events v4.0). 5\. Participant has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting investigational product, and/or from whom ≥ 30% of the bone marrow was irradiated. Prior radiation therapy to a target lesion is permitted only if there has been clear progression of the lesion since radiation was completed. 6\. Venous thromboembolism within 1 month prior to signing informed consent form. 7\. Current congestive heart failure (New York Heart Association Class II-IV). 8. History of the following within 6 months prior to first administration of a study drug: a myocardial infarction, severe/unstable angina pectoris,coronary/peripheral artery bypass graft, New York Heart Association Class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically significant Electrocardiogram abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorder. 9\. Participant has a known infection with hepatitis B or C, or history of human immunodeficiency virus infection, or participant is receiving immunosuppressive or myelosuppressive medications that would in the opinion of the investigator, increase the risk of serious neutropenic complications. 10\. Participant has an active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy, defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment. 11.History of interstitial lung disease, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or pulmonary hypersensitivity pneumonitis. 12\. Treatment with any investigational product within 28 days prior to signing the informed consent form. 13\. History of allergy or hypersensitivity to nab-paclitaxel or carboplatin. 14. Currently enrolled in any other clinical protocol or investigational trial that involves administration of experimental therapy and/or therapeutic devices. 15. Any other clinically significant medical condition, psychiatric illness, and/or organ dysfunction that will interfere with the administration of the therapy according to this protocol or which, in the views of investigator, preclude combination chemotherapy. 16\. Participant has any other malignancy within 5 years prior to randomization. Exceptions include the following: squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, uteri, non-melanomatous skin cancer, carcinoma in situ of the breast, or incidental histological finding of prostate cancer Tumor, Lymph Node, Metastatic (TNM stage of T1a or T1b). All treatment of which should have been completed 6 months prior to signing Informed consent form. 17\. Any condition including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study. 18\. Any medical condition that confounds the ability to interpret data from the study. 19\. Females who (1) have not undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or (2) have not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time during the preceding 24 consecutive months).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Either Peripheral Neuropathy ≥ Grade 2 or Myelosuppression Adverse Events (AEs) ≥ Grade 3 Based on Local Laboratory Values | From the date of the first dose of investigational product (IP) until 28 days after the last dose of IP; up to data cut-off date of 20 November 2016; The median treatment duration for Arms A and B were 3.04 months and 5.17 months respectively. | Peripheral neuropathy (sensory or motor) assessment was done at screening, on Days 1, 8, 15 of every treatment cycle, at the End-of-Treatment visit and at the 28-day Follow-up Visit. Changes in neuropathy grade from baseline was reported as an AE as assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Myelosuppression in participants receiving chemotherapy may have manifested as neutropenia, thrombocytopenia, or anemia. Grade 3 neutropenia including an absolute neutropenia count (ANC) of 500 to 1,000 cells/mm\^3; anemia hemoglobain levels (Hgb) \<8.0 - 6.5 g/dL; \<4.9 - 4.0 mmol/L; \<80 - 65 g/L; transfusion indicated; and thrombocytopenia with platelet levels \<100,000 cells/mm\^3. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least 1 Treatment Emergent Adverse Event With Action Taken as Study Drug Withdrawn | From the date of the first dose of IP until 28 days after the last dose of IP; up to a later data cut-off date of 14 July 2017 the maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively | The percentage of participants with at least 1 TEAE with action taken as studydrug withdrawn during the treatment period of the trial was assessed throughout the conduct of the study. Study drug withdrawn (treatment permanently discontinued) was attributed to the part in which the onset of the adverse event took place. |
| Dose Intensity Per Week of Nab-Paclitaxel During the Entire Study | From day 1 of study treatment to the end date of study treatment; up to data cut off date of 20 November 2016; the maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively | Dose intensity was the cumulative dose divided by the dosing period in weeks. |
| Dose Intensity Per Week of Carboplatin During the Entire Study | From day 1 of study treatment to the end date of study treatment; up to data cut off date of 20 November 2016; the maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively | Dose intensity for carboplatin was the cumulative dose divided by the dosing period in weeks. |
| Percentage of Participants With Dose Reductions During the Entire Study | From the first dose of study treatment to discontinuation date of study treatment; up to date cut off date of 20 November 2016; the maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively | A dose reduction occurred when the dose assigned at a visit was lower than the dose assigned at the previous visit. Dose reductions were typically caused by clinically significant laboratory abnormalities and/or TEAEs or toxicities. |
| Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | From the date of the first dose of IP until 28 days after the last dose of IP; up to a later data cut-off date of 14 July 2017; maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively. | Treatment-emergent adverse events (TEAEs) were defined as any AE or serious adverse event (SAE) that occurred or worsened on or after the day of the first dose of the IP through 28 days after the last dose of IP. Any SAE with an onset date more than 28 day after the last dose of IP that was assessed by the investigator as related to IP was considered a TEAE. The severity of AEs was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and based on the scale: Grade 1 = Mild - transient or mild discomfort; Grade 2 = Moderate - mild to moderate limitation in activity, assistance may be needed; minimal medical intervention required; Grade 3 = Severe - marked limitation in activity, assistance usually required; medical intervention required, hospitalization is possible; Grade 4 = Life threatening - extreme limitation in activity, assistance required; medical intervention, hospitalization or hospice care probable; Grade 5 = death. |
| Kaplan Meier Estimate of Progression-Free Survival (PFS) | From first dose of IP to the date of disease progression; up to a later clinical cut-off date of 14 July 2017; for Arms A and B participants were followed for PFS for 31 months and 20 months respectively | Progression-free survival was defined as the time in months from day 1 of treatment to the date of disease progression based on the investigator's assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria (documented by radiological assessment) or death (any cause) on or prior to the clinical cut-off date, which ever occurred earlier. RECIST V1.1 criteria includes: - Complete Response (CR) is the disappearance of all target lesions; - Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions from baseline; - Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease (PD); - Progressive Disease is at least a 20% increase in the sum of diameters of target lesions from nadir |
| Kaplan Meier Estimate of Overall Survival (OS) | From first dose of IP to the date of death due to any cause; up to a later clinical cut-off date of 14 July 2017; for Arms A and B participants were followed for OS for 31 months and 33 months respectively | Overall survival was defined as the time in months between day 1 of treatment and death from any cause). Participants who were still alive as of the clinical cut-off date had their OS censored at the date of last contact or clinical cut-off, whichever was earlier. Participants who were lost to follow-up prior to the end of the study or who were withdrawn from the study were censored at the time of last contact. |
| Percentage of Participants Who Achieved a Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST 1.1 Criteria | From the first dose of IP to the date of documented first response; up to the data cut-off date of 14 July 2017; maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively. | Overall response rate (ORR) was defined as the percentage of participants who had radiologic CR or PR compared to baseline (radiographic evaluation on the day of or within 28 days prior to randomization) according to RECIST Version 1.1 criteria as determined by the investigator, which was confirmed by repeated radiologic assessment performed no less than 28 days after the criteria for response were first met and occurred between Day 1 of treatment and the start of subsequent anticancer therapy, death or study discontinuation. A complete response and partial response per RECIST V 1.0 criteria was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of diameters of target lesions from baseline. |
| Percentage of Participants With a Dose Delay During the Entire Study | From the first dose of study treatment to discontinuation date of study treatment; up to date cut off date of 16 November 2016; the maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively | A dose delay occurred when the dose assigned at a visit was held compared to the previous visit. Dose delays were typically caused by clinically significant laboratory abnormalities and/or TEAEs or toxicities. |
Countries
United States
Participant flow
Recruitment details
This multicenter study was conducted in the United States and enrolled participants at a total of 41 sites.
Pre-assignment details
Participants ≥ 70 years old were randomized 1:1 to nab-paclitaxel and carboplatin on a 21-day treatment regimen or nab-paclitaxel and carboplatin on a 28-day treatment regimen; participants were stratified by Eastern Cooperative Oncology Group performance status (0 versus 1) and histology (squamous cell carcinoma versus non-squamous cell carcinoma)
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) Participants ≥ 70 years old received nab-paclitaxel 100 mg/m\^2 by intravenous (IV) infusion over 30 minutes on Days 1, 8, and 15 of each 21-day treatment cycle and carboplatin area under the curve (AUC) at 6 mg\*min/mL IV on Day 1 of each 21-day cycle after completion of nab-paclitaxel infusion until disease progression, development of an unacceptable toxicity, death, lost to follow-up, or withdrawal of consent, in accordance with local standard of care. | 71 |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) Participant ≥ 70 years old received nab-paclitaxel 100 mg/m\^2 by intravenous infusion over 30 minutes on Days 1, 8 and 15 followed by a one week break in each 28-day treatment cycle and carboplatin area under the curve (AUC) = 6 mg\*min/mL IV on Day 1 of each treatment cycle after completion of nab-paclitaxel infusion until disease progression, development of an unacceptable toxicity, death, lost to follow-up, or withdrawal of consent, in accordance with local standard of care. | 72 |
| Total | 143 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-Up Period | Death | 37 | 34 |
| Follow-Up Period | Lost to Follow-up | 2 | 3 |
| Treatment Period | Adverse Event | 17 | 14 |
| Treatment Period | Death | 2 | 3 |
| Treatment Period | Miscellaneous | 8 | 7 |
| Treatment Period | Participants randomized but not treated | 3 | 2 |
| Treatment Period | Progressive Disease | 25 | 24 |
| Treatment Period | Symptomatic Deterioration | 2 | 10 |
| Treatment Period | Withdrawal by Subject | 13 | 11 |
Baseline characteristics
| Characteristic | Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Total |
|---|---|---|---|
| Age, Continuous | 76.7 years STANDARD_DEVIATION 4.13 | 76.4 years STANDARD_DEVIATION 5.18 | 76.6 years STANDARD_DEVIATION 4.67 |
| Age, Customized 70-74 years | 20 Participants | 33 Participants | 53 Participants |
| Age, Customized 75-79 years | 30 Participants | 18 Participants | 48 Participants |
| Age, Customized 80-84 years | 19 Participants | 17 Participants | 36 Participants |
| Age, Customized 85-89 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Customized ≥ 90 years | 0 Participants | 2 Participants | 2 Participants |
| Body Mass Index (BMI) | 26.357 Kg/m^2 STANDARD_DEVIATION 4.6805 | 26.033 Kg/m^2 STANDARD_DEVIATION 4.7562 | 26.193 Kg/m^2 STANDARD_DEVIATION 4.7051 |
| Confirmed Histology Non-Squamous Cell Carcinoma | 44 Participants | 44 Participants | 88 Participants |
| Confirmed Histology Squamous Cell Carcinoma | 27 Participants | 28 Participants | 55 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 = Fully Active | 21 Participants | 20 Participants | 41 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 1 = Restricted in Physical Activity; Ambulatory | 50 Participants | 52 Participants | 102 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 2 = Ambulatory and Capable of All Self-care | 0 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 3 = Capable of Only Limited Self-care | 0 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 4 = Completely Disabled. | 0 Participants | 0 Participants | 0 Participants |
| Number of Participants with Peripheral Neuropathy at Baseline Data Missing | 2 Participants | 2 Participants | 4 Participants |
| Number of Participants with Peripheral Neuropathy at Baseline Grade 1 | 14 Participants | 13 Participants | 27 Participants |
| Number of Participants with Peripheral Neuropathy at Baseline Grade 2 | 1 Participants | 0 Participants | 1 Participants |
| Number of Participants with Peripheral Neuropathy at Baseline No Peripheral Neuropathy | 54 Participants | 57 Participants | 111 Participants |
| Number of Prior Systemic Anticancer Therapies for Non-Small Cell Lung Cancer (NSCLC) | 2.0 Therapies | 2.0 Therapies | 2.0 Therapies |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 7 Participants | 10 Participants |
| Race/Ethnicity, Customized Data Missing | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 64 Participants | 57 Participants | 121 Participants |
| Sex: Female, Male Female | 30 Participants | 32 Participants | 62 Participants |
| Sex: Female, Male Male | 41 Participants | 40 Participants | 81 Participants |
| Stage of Disease at Enrollment Data Missing | 1 Participants | 0 Participants | 1 Participants |
| Stage of Disease at Enrollment IIIa | 4 Participants | 5 Participants | 9 Participants |
| Stage of Disease at Enrollment IIIb | 6 Participants | 8 Participants | 14 Participants |
| Stage of Disease at Enrollment IV | 60 Participants | 59 Participants | 119 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 45 / 71 | 46 / 72 |
| other Total, other adverse events | 68 / 68 | 69 / 70 |
| serious Total, serious adverse events | 23 / 68 | 32 / 70 |
Outcome results
Primary
Percentage of Participants With Either Peripheral Neuropathy ≥ Grade 2 or Myelosuppression Adverse Events (AEs) ≥ Grade 3 Based on Local Laboratory Values
Peripheral neuropathy (sensory or motor) assessment was done at screening, on Days 1, 8, 15 of every treatment cycle, at the End-of-Treatment visit and at the 28-day Follow-up Visit. Changes in neuropathy grade from baseline was reported as an AE as assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Myelosuppression in participants receiving chemotherapy may have manifested as neutropenia, thrombocytopenia, or anemia. Grade 3 neutropenia including an absolute neutropenia count (ANC) of 500 to 1,000 cells/mm\^3; anemia hemoglobain levels (Hgb) \<8.0 - 6.5 g/dL; \<4.9 - 4.0 mmol/L; \<80 - 65 g/L; transfusion indicated; and thrombocytopenia with platelet levels \<100,000 cells/mm\^3.
Time frame: From the date of the first dose of investigational product (IP) until 28 days after the last dose of IP; up to data cut-off date of 20 November 2016; The median treatment duration for Arms A and B were 3.04 months and 5.17 months respectively.
Population: Treated Population included all participants who were randomized and received at least 1 dose of the study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Percentage of Participants With Either Peripheral Neuropathy ≥ Grade 2 or Myelosuppression Adverse Events (AEs) ≥ Grade 3 Based on Local Laboratory Values | 76.5 Percentage of Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Percentage of Participants With Either Peripheral Neuropathy ≥ Grade 2 or Myelosuppression Adverse Events (AEs) ≥ Grade 3 Based on Local Laboratory Values | 77.1 Percentage of Participants |
p-value: 0.925895% CI: [0.84, 1.21]Cochran-Mantel-Haenszel
Secondary
Dose Intensity Per Week of Carboplatin During the Entire Study
Dose intensity for carboplatin was the cumulative dose divided by the dosing period in weeks.
Time frame: From day 1 of study treatment to the end date of study treatment; up to data cut off date of 20 November 2016; the maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively
Population: Treated Population included all randomized participants who received any study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Dose Intensity Per Week of Carboplatin During the Entire Study | 1.51 mg*min/mL/week | Standard Deviation 0.384 |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Dose Intensity Per Week of Carboplatin During the Entire Study | 1.33 mg*min/mL/week | Standard Deviation 0.671 |
Secondary
Dose Intensity Per Week of Nab-Paclitaxel During the Entire Study
Dose intensity was the cumulative dose divided by the dosing period in weeks.
Time frame: From day 1 of study treatment to the end date of study treatment; up to data cut off date of 20 November 2016; the maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively
Population: Treated Population included all randomized participants who received any study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Dose Intensity Per Week of Nab-Paclitaxel During the Entire Study | 64.07 mg/m^2/week | Standard Deviation 17.374 |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Dose Intensity Per Week of Nab-Paclitaxel During the Entire Study | 56.57 mg/m^2/week | Standard Deviation 16.645 |
Secondary
Kaplan Meier Estimate of Overall Survival (OS)
Overall survival was defined as the time in months between day 1 of treatment and death from any cause). Participants who were still alive as of the clinical cut-off date had their OS censored at the date of last contact or clinical cut-off, whichever was earlier. Participants who were lost to follow-up prior to the end of the study or who were withdrawn from the study were censored at the time of last contact.
Time frame: From first dose of IP to the date of death due to any cause; up to a later clinical cut-off date of 14 July 2017; for Arms A and B participants were followed for OS for 31 months and 33 months respectively
Population: Intent to Treat Population included all randomized participants regardless of whether the participant received any study drug or had any efficacy assessments performed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Kaplan Meier Estimate of Overall Survival (OS) | 14.52 months |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Kaplan Meier Estimate of Overall Survival (OS) | 14.98 months |
p-value: 0.353795% CI: [0.54, 1.25]Stratified log-rank test
Secondary
Kaplan Meier Estimate of Progression-Free Survival (PFS)
Progression-free survival was defined as the time in months from day 1 of treatment to the date of disease progression based on the investigator's assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria (documented by radiological assessment) or death (any cause) on or prior to the clinical cut-off date, which ever occurred earlier. RECIST V1.1 criteria includes: - Complete Response (CR) is the disappearance of all target lesions; - Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions from baseline; - Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease (PD); - Progressive Disease is at least a 20% increase in the sum of diameters of target lesions from nadir
Time frame: From first dose of IP to the date of disease progression; up to a later clinical cut-off date of 14 July 2017; for Arms A and B participants were followed for PFS for 31 months and 20 months respectively
Population: Intent to Treat Population all randomized participants regardless of whether the participant received any study drug or had any efficacy assessments performed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Kaplan Meier Estimate of Progression-Free Survival (PFS) | 3.88 months |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Kaplan Meier Estimate of Progression-Free Survival (PFS) | 7.20 months |
p-value: 0.003695% CI: [0.33, 0.81]Stratified Log Rank
Secondary
Number of Participants With Treatment Emergent Adverse Events During the Treatment Period
Treatment-emergent adverse events (TEAEs) were defined as any AE or serious adverse event (SAE) that occurred or worsened on or after the day of the first dose of the IP through 28 days after the last dose of IP. Any SAE with an onset date more than 28 day after the last dose of IP that was assessed by the investigator as related to IP was considered a TEAE. The severity of AEs was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and based on the scale: Grade 1 = Mild - transient or mild discomfort; Grade 2 = Moderate - mild to moderate limitation in activity, assistance may be needed; minimal medical intervention required; Grade 3 = Severe - marked limitation in activity, assistance usually required; medical intervention required, hospitalization is possible; Grade 4 = Life threatening - extreme limitation in activity, assistance required; medical intervention, hospitalization or hospice care probable; Grade 5 = death.
Time frame: From the date of the first dose of IP until 28 days after the last dose of IP; up to a later data cut-off date of 14 July 2017; maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively.
Population: Safety population included all participants who were randomized and received at least 1 dose of the study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Treatment Emergent Adverse Event | 68 Participants |
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Serious Treatment Emergent Adverse Event | 23 Participants |
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Grade 3 or 4 Treatment Emergent Adverse Event | 60 Participants |
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Grade 3 or Higher Treatment Emergent Adverse Event | 60 Participants |
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Treatment Related TEAE | 65 Participants |
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Treatment-Related Serious TEAE | 12 Participants |
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | TEAE with Action to Reduce or Interrupt IP Dose | 60 Participants |
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Treatment-Related Action to Reduce/Interrupt IP | 56 Participants |
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | TEAE with Action Taken as Study Drug Withdrawn | 17 Participants |
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Treatment-related TEAE with Action to Halt IP | 13 Participants |
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | TEAE with Fatal Outcome | 1 Participants |
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Treatment-related TEAE with Fatal Outcome | 0 Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | TEAE with Fatal Outcome | 3 Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Treatment Emergent Adverse Event | 69 Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | TEAE with Action to Reduce or Interrupt IP Dose | 54 Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Serious Treatment Emergent Adverse Event | 32 Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Treatment-related TEAE with Action to Halt IP | 13 Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Grade 3 or 4 Treatment Emergent Adverse Event | 59 Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Treatment-Related Action to Reduce/Interrupt IP | 51 Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Grade 3 or Higher Treatment Emergent Adverse Event | 61 Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Treatment-related TEAE with Fatal Outcome | 0 Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Treatment Related TEAE | 66 Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | TEAE with Action Taken as Study Drug Withdrawn | 14 Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Number of Participants With Treatment Emergent Adverse Events During the Treatment Period | Treatment-Related Serious TEAE | 12 Participants |
Secondary
Percentage of Participants Who Achieved a Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST 1.1 Criteria
Overall response rate (ORR) was defined as the percentage of participants who had radiologic CR or PR compared to baseline (radiographic evaluation on the day of or within 28 days prior to randomization) according to RECIST Version 1.1 criteria as determined by the investigator, which was confirmed by repeated radiologic assessment performed no less than 28 days after the criteria for response were first met and occurred between Day 1 of treatment and the start of subsequent anticancer therapy, death or study discontinuation. A complete response and partial response per RECIST V 1.0 criteria was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of diameters of target lesions from baseline.
Time frame: From the first dose of IP to the date of documented first response; up to the data cut-off date of 14 July 2017; maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively.
Population: Intent to Treat Population included all randomized participants regardless of whether the participant received any study drug or had any efficacy assessments performed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Percentage of Participants Who Achieved a Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST 1.1 Criteria | 26.8 Percentage of participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Percentage of Participants Who Achieved a Best Overall Response of Complete Response (CR) or Partial Response (PR) According to RECIST 1.1 Criteria | 41.7 Percentage of participants |
p-value: 0.059795% CI: [0.971, 2.511]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With a Dose Delay During the Entire Study
A dose delay occurred when the dose assigned at a visit was held compared to the previous visit. Dose delays were typically caused by clinically significant laboratory abnormalities and/or TEAEs or toxicities.
Time frame: From the first dose of study treatment to discontinuation date of study treatment; up to date cut off date of 16 November 2016; the maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively
Population: The safety population consisted of all participants who received at least 1 dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Percentage of Participants With a Dose Delay During the Entire Study | nab-Paclitaxel | 58.8 Percentage of Participants |
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Percentage of Participants With a Dose Delay During the Entire Study | Carboplatin | 52.9 Percentage of Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Percentage of Participants With a Dose Delay During the Entire Study | nab-Paclitaxel | 48.6 Percentage of Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Percentage of Participants With a Dose Delay During the Entire Study | Carboplatin | 44.3 Percentage of Participants |
Secondary
Percentage of Participants With at Least 1 Treatment Emergent Adverse Event With Action Taken as Study Drug Withdrawn
The percentage of participants with at least 1 TEAE with action taken as studydrug withdrawn during the treatment period of the trial was assessed throughout the conduct of the study. Study drug withdrawn (treatment permanently discontinued) was attributed to the part in which the onset of the adverse event took place.
Time frame: From the date of the first dose of IP until 28 days after the last dose of IP; up to a later data cut-off date of 14 July 2017 the maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively
Population: Safety Population included all participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Percentage of Participants With at Least 1 Treatment Emergent Adverse Event With Action Taken as Study Drug Withdrawn | 25.0 Percentage of Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Percentage of Participants With at Least 1 Treatment Emergent Adverse Event With Action Taken as Study Drug Withdrawn | 20.0 Percentage of Participants |
Secondary
Percentage of Participants With Dose Reductions During the Entire Study
A dose reduction occurred when the dose assigned at a visit was lower than the dose assigned at the previous visit. Dose reductions were typically caused by clinically significant laboratory abnormalities and/or TEAEs or toxicities.
Time frame: From the first dose of study treatment to discontinuation date of study treatment; up to date cut off date of 20 November 2016; the maximum treatment duration for Arms A and B was 16.6 months and 20.1 months respectively
Population: The treated population consisted of all participants who received at least 1 dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Percentage of Participants With Dose Reductions During the Entire Study | nab-Paclitaxel | 64.7 Percentage of Participants |
| Arm A: Nab-Paclitaxel and Carboplatin (21-day Treatment Cylce) | Percentage of Participants With Dose Reductions During the Entire Study | Carboplatin | 57.4 Percentage of Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Percentage of Participants With Dose Reductions During the Entire Study | nab-Paclitaxel | 58.6 Percentage of Participants |
| Arm B: Nab-Paclitaxel and Carboplatin (28-day Treatment Cycle) | Percentage of Participants With Dose Reductions During the Entire Study | Carboplatin | 58.6 Percentage of Participants |