Small Cell Lung Cancer
Conditions
Keywords
Drug therapy
Brief summary
This is a two-arm, randomized, double-blind, placebo-controlled, multicenter, phase 2 study designed to is to determine if the combination treatment can improve progression free survival (defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occurs first) when compared with placebo + paclitaxel.
Detailed description
The drug tested in this study is called alisertib. Alisertib is being tested to treat people who have Small Cell Lung Cancer (SCLC). This study determined the safety and efficacy for alisertib when given twice a day along with paclitaxel. This open label study enrolled 178 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there is an urgent medical need) and participants were stratified at baseline as to whether brain mets were present or not; whether they were sensitive to prior therapy or were relapsed/refractory to prior therapy; and by world region: * Alisertib 40 mg + Paclitaxel 60 mg/m\^2 * Paclitaxel 80 mg/m\^2 + Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient All participants received treatment until their disease progressed or they experienced unacceptable alisertib-related toxicity. This multi-center trial was conducted world-wide. The overall time to participate in this study was approximately up to 22 months. Participants made multiple visits to the clinic, and were contacted by telephone every month for 6 months after the end of treatment (EOT) for follow-up assessment of progression free survival and for overall survival every 2 months until death, study closure, or 14 months after randomization of the last participant.
Interventions
DRUGAlisertib
Alisertib tablets
DRUGPlacebo
Placebo matching tablets
DRUGPaclitaxel
Paclitaxel intravenous injection
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Each participant must meet all the following inclusion criteria to be enrolled in the study: 1. Male or female participants ≥ 18 years old. 2. Have a pathologically (histology or cytology) confirmed diagnosis of SCLC. 3. Have received and progressed after a platinum-based standard chemotherapy regimen for first line treatment of SCLC, either limited stage (LS) or extensive stage (ES). 4. Have measurable disease within ≤ 2 weeks before randomization. Clear radiographic evidence of disease progression after initial therapy should have been documented. 5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (PS 0-1). 6. Participants with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed provided the lesions have been stable for at least 2 weeks and the participant is off steroids or is on a stable dose of steroids. Participants should be without neurologic dysfunction that would confound the evaluation of neurological and/or other AEs.
Exclusion criteria
Participants meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) as Determined by Investigator, Analyzed Using FDA Guidelines | Every cycle for first 6 months and then every 2 months until disease progression or death or up to data cut-off: 03 January 2016 (approximately 22 months) | PFS is defined as time in days from start of study treatment to first documentation of objective tumor progression based on Investigator's assessment or up to death due to any cause, whichever occurs first based on Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Progressive disease (PD) was defined as ≥20% increase in sum longest diameter (LD) in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From the first dose through 30 days after the last dose of study medication: data cut-off 03 January 2016 (Up to 10.8 months) | An Adverse Event (AE) is defined as any untoward medical occurrence in clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with treatment. An AE can be any unfavorable and unintended sign (eg, clinically significant abnormal laboratory finding), symptom, or disease temporally associated with use of drug, whether or not it is considered related to drug. A treatment-emergent adverse event (TEAE) is defined as an AE with an onset that occurs after receiving study drug. A Serious Adverse Event (SAE) is any experience that suggests significant hazard, contraindication, side effect or precaution that:results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is congenital anomaly/birth defect or is medically significant per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. |
| Overall Survival (OS) | Contact every 2 months after EOT/disease progression until the sooner of death, study closure, or 14 months after the last participant was randomized up to data cut-off: 3 January 2016 (approximately 22 months) | OS was defined as the time in days from the date of randomization to the date of death due to any cause. |
| Overall Response Rate (ORR) | Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months) | ORR is defined as the percentage of participants who achieved CR or partial response (PR) as best response based on Investigator's assessment according to RECIST v 1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as ≥ 30% decrease in sum of LD of target lesions in reference to Baseline sum LD. |
| Complete Response Rate (CRR) | Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months) | CRR is defined as the percentage of participants who achieved CR as best response and based on Investigator's assessment according to RECIST v 1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. |
| Disease Control Rate (DCR) | Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months) | DCR was defined as the percentage of participants who achieved CR, PR, or SD (when SD was a minimum of 8 weeks in duration). Duration of SD was defined as the time from the date of randomization to the date of first documentation of disease progression for participants who achieved SD as their best overall response. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as ≥ 30% decrease in sum of LD of target lesions in reference to Baseline sum LD. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Duration of Response (DOR) | From first documented response until disease progression until data cut-off 03 January 2016 (approximately 9.8 months) | DOR was defined as the time from the date of first documentation of a PR or better to the date of first documentation of PD for responders. PR was defined as ≥ 30% decrease in sum of longest diameter (LD) of target lesions in reference to Baseline sum LD. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Observed Plasma Concentration for Alisertib | Day 1 pre-dose and 1, 2-4, 3-6, 10-11 hours post-dose; Day 8, 2 hours post-dose; Day 15, 6-9 hours (hrs) post-dose | — |
| Observed Plasma Concentration for Paclitaxel | Day 1 pre-dose and 1, 2-4, 3-6, 10-11 hours post-dose; Day 8, 2 hours post-dose; Day 15, 6-9 hours post-dose | — |
| Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5 | Baseline up to Cycle 5 (approximately 4.6 months) | European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 is 30-item questionnaire with 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (fatigue, nausea, vomiting and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions use 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions use 7-point scale (1=very poor - 7=Excellent). Total Score=0-100 scale; for 5 functional scales and global quality-of-life scale, a higher score=a better level of functioning. For symptoms scale, higher score= higher level of symptoms. EORTC QLQ-LC13 is considered as standard instrument to assess the quality of life (QL) of lung cancer participants. Total Score=0-100. Higher score=increase in level of symptomatology. The change between (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) score collected at Cycle 5 relative to baseline. |
| Percentage of Participants Experiencing Symptom Relief | Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months) | Percentage of participants experiencing symptom relief, including coughing relief, dyspnea relief, and pain relief. Coughing relief is defined as a decrease from baseline ≥ 10 in QLQ-LC13 cough scale/item score. Dyspnea relief is defined as a decrease from baseline ≥ 10 in QLQ-C30 dyspnea scale/item score. Pain relief is defined as a decrease from baseline ≥ 10 in QLQ-C30 pain scale score. EORTC QLQ-C30 is 30-item questionnaire with 5 functional scales, 1 global health status scale, 3 symptom scales, 6 single items. Total Score=0-100 scale; for 5 functional scales and global quality-of-life scale, a higher score=a better level of functioning. For symptoms scale, higher score= higher level of symptoms. EORTC QLQ-LC13 is considered as standard instrument to assess the QL of lung cancer participants. Total Score=0-100. Higher score=increase in level of symptomatology. |
| Time to Symptom Relief | Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months) | Time to symptom (coughing/dyspnea/pain) relief was defined as the time from the date of randomization to the date of first detection of coughing/dyspnea/pain relief, respectively. |
| Time to Symptom Progression | Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months) | Time to coughing/dyspnea/pain progression was defined as time from the date of randomization to date of first detection of progression. Coughing progression was defined as increase from baseline ≥10 in QLQ-LC13 cough scale/item score. Dyspnea progression was defined as increase from baseline ≥10 in QLQ-C30 dyspnea scale/item score. Pain progression was defined as increase from baseline ≥10 in QLQ-C30 pain scale score. EORTC QLQ-C30 is 30-item questionnaire with 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (fatigue, nausea, vomiting and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The QLQ-LC13 is 13-item scale for assessing treatment-specific symptoms in lung cancer. Total Score= 0-100 scale; for 5 functional scales and global quality-of-life scale, higher score=better level of functioning. For symptoms scale, higher score=higher level of symptoms. |
Other
| Measure | Time frame |
|---|---|
| Biomarker Correlative Studies Including Circulating Tumor Cells and Circulating DNA Assessments | Day 1 cycle 1 in a 28-day cycle |
| Health Related Quality of Life (HRQOL ) | Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months) |
Countries
Belgium, Canada, Czechia, France, Germany, Hungary, Italy, Poland, Spain, United States
Participant flow
Recruitment details
Participants took part in the study at 54 investigative sites in the United States, Canada, European Union (Belgium, Czech Republic, France, Germany, Hungary, Italy, Poland and Spain) from 12 May 2014 to 10 July 2017. Data cutoff for the primary analysis was 3 January 2016.
Pre-assignment details
Participants with a diagnosis of Small Cell Lung Cancer (SCLC) were enrolled in 1 of 2 treatment groups: alisertib + paclitaxel or placebo + paclitaxel arm group.
Participants by arm
| Arm | Count |
|---|---|
| Alisertib + Paclitaxel Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles). | 89 |
| Placebo + Paclitaxel Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles). | 89 |
| Total | 178 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 18 | 10 |
| Overall Study | Not Reported | 0 | 1 |
| Overall Study | Ongoing at Datacut | 9 | 10 |
| Overall Study | Progressive Disease | 50 | 59 |
| Overall Study | Symptomatic Deterioration | 7 | 7 |
| Overall Study | Withdrawal by Subject | 5 | 2 |
Baseline characteristics
| Characteristic | Alisertib + Paclitaxel | Placebo + Paclitaxel | Total |
|---|---|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 8.55 | 63.4 years STANDARD_DEVIATION 8.56 | 62.6 years STANDARD_DEVIATION 8.57 |
| Body Surface Area | 1.911 m^2 STANDARD_DEVIATION 0.2829 | 1.872 m^2 STANDARD_DEVIATION 0.2433 | 1.891 m^2 STANDARD_DEVIATION 0.2637 |
| Height | 169.5 cm STANDARD_DEVIATION 10.43 | 168.8 cm STANDARD_DEVIATION 9.52 | 169.2 cm STANDARD_DEVIATION 9.96 |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 3 participants | 2 participants | 5 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 participants | 3 participants | 5 participants |
| Race/Ethnicity, Customized Missing | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 81 participants | 84 participants | 165 participants |
| Race/Ethnicity, Customized Not reported | 2 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized Other | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 6 participants | 1 participants | 7 participants |
| Race/Ethnicity, Customized White | 83 participants | 83 participants | 166 participants |
| Region of Enrollment Belgium | 8 participants | 8 participants | 16 participants |
| Region of Enrollment Canada | 6 participants | 6 participants | 12 participants |
| Region of Enrollment Czech Republic | 6 participants | 5 participants | 11 participants |
| Region of Enrollment France | 7 participants | 5 participants | 12 participants |
| Region of Enrollment Germany | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Hungary | 16 participants | 15 participants | 31 participants |
| Region of Enrollment Italy | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Poland | 1 participants | 3 participants | 4 participants |
| Region of Enrollment Spain | 6 participants | 11 participants | 17 participants |
| Region of Enrollment United States | 35 participants | 35 participants | 70 participants |
| Sex: Female, Male Female | 38 Participants | 39 Participants | 77 Participants |
| Sex: Female, Male Male | 51 Participants | 50 Participants | 101 Participants |
| Weight | 78.47 kg STANDARD_DEVIATION 20.561 | 75.26 kg STANDARD_DEVIATION 17.602 | 76.87 kg STANDARD_DEVIATION 19.153 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 87 | 11 / 89 |
| other Total, other adverse events | 85 / 87 | 80 / 89 |
| serious Total, serious adverse events | 39 / 87 | 30 / 89 |
Outcome results
Primary
Progression-Free Survival (PFS) as Determined by Investigator, Analyzed Using FDA Guidelines
PFS is defined as time in days from start of study treatment to first documentation of objective tumor progression based on Investigator's assessment or up to death due to any cause, whichever occurs first based on Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Progressive disease (PD) was defined as ≥20% increase in sum longest diameter (LD) in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Every cycle for first 6 months and then every 2 months until disease progression or death or up to data cut-off: 03 January 2016 (approximately 22 months)
Population: The intent-to-treat (ITT) population was defined as all participants who were randomized to study treatment. For participants who have not progressed and is last known to be alive, PFS was censored at the last response assessment that is stable disease (SD) or better as determined by Investigator, and analyzed using FDA Guidelines.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib + Paclitaxel | Progression-Free Survival (PFS) as Determined by Investigator, Analyzed Using FDA Guidelines | 101 days |
| Placebo + Paclitaxel | Progression-Free Survival (PFS) as Determined by Investigator, Analyzed Using FDA Guidelines | 66 days |
p-value: 0.11395% CI: [0.557, 1.067]Log Rank
Secondary
Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 is 30-item questionnaire with 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (fatigue, nausea, vomiting and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions use 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions use 7-point scale (1=very poor - 7=Excellent). Total Score=0-100 scale; for 5 functional scales and global quality-of-life scale, a higher score=a better level of functioning. For symptoms scale, higher score= higher level of symptoms. EORTC QLQ-LC13 is considered as standard instrument to assess the quality of life (QL) of lung cancer participants. Total Score=0-100. Higher score=increase in level of symptomatology. The change between (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) score collected at Cycle 5 relative to baseline.
Time frame: Baseline up to Cycle 5 (approximately 4.6 months)
Population: The ITT population was defined as all participants who were randomized to study treatment. Here number of participants analyzed are participants evaluated in this outcome measure at the specific timepoint.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib + Paclitaxel | Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5 | Change at Cycle 5, QLQ-C30 Pain Scale | -4.82 score on a scale | Standard Error 4.86 |
| Alisertib + Paclitaxel | Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5 | Change at Cycle 5, QLQ-LC-13 Cough Scale | -10.94 score on a scale | Standard Error 3.07 |
| Alisertib + Paclitaxel | Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5 | Change at Cycle 5, QLQ-C30 Dyspnea Scale | -3.48 score on a scale | Standard Error 4.25 |
| Placebo + Paclitaxel | Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5 | Change at Cycle 5, QLQ-LC-13 Cough Scale | 8.07 score on a scale | Standard Error 6.04 |
| Placebo + Paclitaxel | Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5 | Change at Cycle 5, QLQ-C30 Dyspnea Scale | -1.09 score on a scale | Standard Error 2.92 |
| Placebo + Paclitaxel | Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5 | Change at Cycle 5, QLQ-C30 Pain Scale | -4.88 score on a scale | Standard Error 5.16 |
Secondary
Complete Response Rate (CRR)
CRR is defined as the percentage of participants who achieved CR as best response and based on Investigator's assessment according to RECIST v 1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm.
Time frame: Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)
Population: The ITT population was defined as all participants who were randomized to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib + Paclitaxel | Complete Response Rate (CRR) | 1 percentage of participants |
| Placebo + Paclitaxel | Complete Response Rate (CRR) | 0 percentage of participants |
p-value: 0.28395% CI: [0.01, 9999.99]Weighted Cochran-Mantel-Haenszel test
Secondary
Disease Control Rate (DCR)
DCR was defined as the percentage of participants who achieved CR, PR, or SD (when SD was a minimum of 8 weeks in duration). Duration of SD was defined as the time from the date of randomization to the date of first documentation of disease progression for participants who achieved SD as their best overall response. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as ≥ 30% decrease in sum of LD of target lesions in reference to Baseline sum LD. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)
Population: The ITT population was defined as all participants who were randomized to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib + Paclitaxel | Disease Control Rate (DCR) | 58 percentage of participants |
| Placebo + Paclitaxel | Disease Control Rate (DCR) | 46 percentage of participants |
p-value: 0.07795% CI: [0.32, 1.08]Weighted Cochran-Mantel-Haenszel test
Secondary
Duration of Response (DOR)
DOR was defined as the time from the date of first documentation of a PR or better to the date of first documentation of PD for responders. PR was defined as ≥ 30% decrease in sum of longest diameter (LD) of target lesions in reference to Baseline sum LD. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: From first documented response until disease progression until data cut-off 03 January 2016 (approximately 9.8 months)
Population: The ITT population was defined as all participants who were randomized to study treatment. Responders were evaluated for this outcome measure. Responders without documentation of PD were censored at their date of last response assessment that was SD or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib + Paclitaxel | Duration of Response (DOR) | 96 days |
| Placebo + Paclitaxel | Duration of Response (DOR) | 85 days |
Secondary
Observed Plasma Concentration for Alisertib
Time frame: Day 1 pre-dose and 1, 2-4, 3-6, 10-11 hours post-dose; Day 8, 2 hours post-dose; Day 15, 6-9 hours (hrs) post-dose
Population: Safety population was defined as all participants who received at least 1 dose of any study drug. Number analyzed is the number of participants with evaluable data at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib + Paclitaxel | Observed Plasma Concentration for Alisertib | Cycle 1, Day 15, 6-9 hrs Post-Dose (1st Sample) | 1102.93 nM | Standard Deviation 612.265 |
| Alisertib + Paclitaxel | Observed Plasma Concentration for Alisertib | Cycle 1, Day 15, 6-9 hrs Post-Dose (2nd Sample) | 976.92 nM | Standard Deviation 572.09 |
| Alisertib + Paclitaxel | Observed Plasma Concentration for Alisertib | Cycle 1, Day 1, Pre-Dose | 0 nM | Standard Deviation 0 |
| Alisertib + Paclitaxel | Observed Plasma Concentration for Alisertib | Cycle 1, Day 1, 1 hr Post-Dose | 495.37 nM | Standard Deviation 663.456 |
| Alisertib + Paclitaxel | Observed Plasma Concentration for Alisertib | Cycle 1, Day 1, 2-4 hrs Post-Dose | 861.18 nM | Standard Deviation 616.951 |
| Alisertib + Paclitaxel | Observed Plasma Concentration for Alisertib | Cycle 1, Day 1, 3-6 hrs Post-Dose | 1048.88 nM | Standard Deviation 716.447 |
| Alisertib + Paclitaxel | Observed Plasma Concentration for Alisertib | Cycle 1, Day 1, 10-11 hrs Post-Dose | 539.15 nM | Standard Deviation 291.17 |
| Alisertib + Paclitaxel | Observed Plasma Concentration for Alisertib | Cycle 1, Day 8, 2 hrs Post-Dose | 897.41 nM | Standard Deviation 816.387 |
Secondary
Observed Plasma Concentration for Paclitaxel
Time frame: Day 1 pre-dose and 1, 2-4, 3-6, 10-11 hours post-dose; Day 8, 2 hours post-dose; Day 15, 6-9 hours post-dose
Population: Due to change in planned analysis, data was only collected and summarized for alisertib not for paclitaxel.
Secondary
Overall Response Rate (ORR)
ORR is defined as the percentage of participants who achieved CR or partial response (PR) as best response based on Investigator's assessment according to RECIST v 1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as ≥ 30% decrease in sum of LD of target lesions in reference to Baseline sum LD.
Time frame: Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)
Population: The ITT population was defined as all participants who were randomized to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib + Paclitaxel | Overall Response Rate (ORR) | 22 percentage of participants |
| Placebo + Paclitaxel | Overall Response Rate (ORR) | 18 percentage of participants |
p-value: 0.40695% CI: [0.35, 1.55]Weighted Cochran-Mantel-Haenszel test
Secondary
Overall Survival (OS)
OS was defined as the time in days from the date of randomization to the date of death due to any cause.
Time frame: Contact every 2 months after EOT/disease progression until the sooner of death, study closure, or 14 months after the last participant was randomized up to data cut-off: 3 January 2016 (approximately 22 months)
Population: The ITT population was defined as all participants who were randomized to study treatment. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib + Paclitaxel | Overall Survival (OS) | 186 days |
| Placebo + Paclitaxel | Overall Survival (OS) | 165 days |
p-value: 0.71495% CI: [0.652, 1.341]Log Rank
Secondary
Percentage of Participants Experiencing Symptom Relief
Percentage of participants experiencing symptom relief, including coughing relief, dyspnea relief, and pain relief. Coughing relief is defined as a decrease from baseline ≥ 10 in QLQ-LC13 cough scale/item score. Dyspnea relief is defined as a decrease from baseline ≥ 10 in QLQ-C30 dyspnea scale/item score. Pain relief is defined as a decrease from baseline ≥ 10 in QLQ-C30 pain scale score. EORTC QLQ-C30 is 30-item questionnaire with 5 functional scales, 1 global health status scale, 3 symptom scales, 6 single items. Total Score=0-100 scale; for 5 functional scales and global quality-of-life scale, a higher score=a better level of functioning. For symptoms scale, higher score= higher level of symptoms. EORTC QLQ-LC13 is considered as standard instrument to assess the QL of lung cancer participants. Total Score=0-100. Higher score=increase in level of symptomatology.
Time frame: Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)
Population: The ITT population was defined as all participants who were randomized to study treatment. Participants without coughing/dyspnea/pain relief were censored at their last assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib + Paclitaxel | Percentage of Participants Experiencing Symptom Relief | Coughing Relief | 28 percentage of participants |
| Alisertib + Paclitaxel | Percentage of Participants Experiencing Symptom Relief | Dyspnea Relief | 31 percentage of participants |
| Alisertib + Paclitaxel | Percentage of Participants Experiencing Symptom Relief | Pain Relief | 39 percentage of participants |
| Placebo + Paclitaxel | Percentage of Participants Experiencing Symptom Relief | Coughing Relief | 24 percentage of participants |
| Placebo + Paclitaxel | Percentage of Participants Experiencing Symptom Relief | Pain Relief | 36 percentage of participants |
| Placebo + Paclitaxel | Percentage of Participants Experiencing Symptom Relief | Dyspnea Relief | 16 percentage of participants |
Secondary
Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An Adverse Event (AE) is defined as any untoward medical occurrence in clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with treatment. An AE can be any unfavorable and unintended sign (eg, clinically significant abnormal laboratory finding), symptom, or disease temporally associated with use of drug, whether or not it is considered related to drug. A treatment-emergent adverse event (TEAE) is defined as an AE with an onset that occurs after receiving study drug. A Serious Adverse Event (SAE) is any experience that suggests significant hazard, contraindication, side effect or precaution that:results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is congenital anomaly/birth defect or is medically significant per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.
Time frame: From the first dose through 30 days after the last dose of study medication: data cut-off 03 January 2016 (Up to 10.8 months)
Population: The safety population was defined as all participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib + Paclitaxel | Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 99 percentage of participants |
| Alisertib + Paclitaxel | Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 44 percentage of participants |
| Placebo + Paclitaxel | Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 96 percentage of participants |
| Placebo + Paclitaxel | Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 31 percentage of participants |
Secondary
Time to Symptom Progression
Time to coughing/dyspnea/pain progression was defined as time from the date of randomization to date of first detection of progression. Coughing progression was defined as increase from baseline ≥10 in QLQ-LC13 cough scale/item score. Dyspnea progression was defined as increase from baseline ≥10 in QLQ-C30 dyspnea scale/item score. Pain progression was defined as increase from baseline ≥10 in QLQ-C30 pain scale score. EORTC QLQ-C30 is 30-item questionnaire with 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (fatigue, nausea, vomiting and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The QLQ-LC13 is 13-item scale for assessing treatment-specific symptoms in lung cancer. Total Score= 0-100 scale; for 5 functional scales and global quality-of-life scale, higher score=better level of functioning. For symptoms scale, higher score=higher level of symptoms.
Time frame: Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)
Population: The ITT population was defined as all participants who were randomized to study treatment. Participant without coughing/dyspnea/pain progression were censored at their last assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Alisertib + Paclitaxel | Time to Symptom Progression | Time to Coughing Progression | NA months |
| Alisertib + Paclitaxel | Time to Symptom Progression | Time to Dyspnea Progression | 3.7 months |
| Alisertib + Paclitaxel | Time to Symptom Progression | Time to Pain Progression | 2.9 months |
| Placebo + Paclitaxel | Time to Symptom Progression | Time to Coughing Progression | 2.8 months |
| Placebo + Paclitaxel | Time to Symptom Progression | Time to Dyspnea Progression | 4.6 months |
| Placebo + Paclitaxel | Time to Symptom Progression | Time to Pain Progression | 2.8 months |
Secondary
Time to Symptom Relief
Time to symptom (coughing/dyspnea/pain) relief was defined as the time from the date of randomization to the date of first detection of coughing/dyspnea/pain relief, respectively.
Time frame: Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)
Population: The ITT population was defined as all participants who were randomized to study treatment. Participants without coughing/dyspnea/pain relief were censored at their last assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Alisertib + Paclitaxel | Time to Symptom Relief | Time to Coughing Relief | NA months |
| Alisertib + Paclitaxel | Time to Symptom Relief | Time to Dyspnea Relief | NA months |
| Alisertib + Paclitaxel | Time to Symptom Relief | Time to Pain Relief | 3.0 months |
| Placebo + Paclitaxel | Time to Symptom Relief | Time to Coughing Relief | NA months |
| Placebo + Paclitaxel | Time to Symptom Relief | Time to Dyspnea Relief | NA months |
| Placebo + Paclitaxel | Time to Symptom Relief | Time to Pain Relief | 3.7 months |
Other Pre-specified
Biomarker Correlative Studies Including Circulating Tumor Cells and Circulating DNA Assessments
Time frame: Day 1 cycle 1 in a 28-day cycle
Population: This is an exploratory endpoint.
Other Pre-specified
Health Related Quality of Life (HRQOL )
Time frame: Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)
Population: This is an exploratory endpoint.