Non-Small-Cell Lung Carcinoma
Conditions
Brief summary
This open-label, non-randomized, multicenter, Phase 1/2 study will evaluate the safety and efficacy of alectinib in participants with non-small cell lung cancer who have ALK mutation and failed crizotinib treatment. In Part 1, cohorts of participants will receive escalating doses of alectinib orally twice daily. In Part 2, participants will receive the recommended phase 2 dose (RP2D) of alectinib as determined in Part 1. Treatment will continue in Part 1 and Part 2 on the same dose until disease progression. In Part 3, following disease progression, participants without epidermal growth factor receptor (EGFR) mutation will be offered continued treatment with alectinib, participants with EGFR mutations will be offered a combination of alectinib and erlotinib.
Interventions
DRUGErlotinib
Erlotinib will be administered at a dose of 100 mg via tablet, orally, once daily in combination with alectinib to participants who progressed on alectinib alone treatment as per treating physician discretion.
DRUGAlectinib
Alectinib will be administered at a dose of 600 milligrams (mg) via capsule, orally, twice daily.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Locally advanced or metastatic non-small cell lung cancer (stage IIIB or IV by American Joint Committee on Cancer \[AJCC\]) * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Documented ALK rearrangement based on Food and Drug Administration (FDA)-approved test * Prior treatment with crizotinib and progression according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1) criteria. Participants had to have a minimum 1-week wash-out period between the last dose of crizotinib and the first dose of study treatment. Participants can either be chemotherapy-naïve or have received at least one line of platinum-based chemotherapy * Adequate hematologic, hepatic, and renal function * Participants with brain or leptomeningeal metastases are allowed if protocol defined criteria are met * Measurable disease according to RECIST v1.1 prior to administration of first dose of study drug
Exclusion criteria
* Receipt of any other ALK inhibitors in addition to crizotinib * Receipt of any prior cytotoxic chemotherapy for ALK-positive NSCLC within 4 weeks prior to the first dose of study drug * Participants who received crizotinib or any other tyrosine kinase inhibitors need to have a minimum 1-week washout period before the first dose of study drug * Active or uncontrolled infectious diseases requiring treatment * National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03) Grade 3 or higher toxicities due to prior therapy that have not shown improvement and are considered to interfere with current study medication * History of organ transplant * Co-administration of anti-cancer therapies other than those administered in this study * Baseline corrected Q-T interval (QTc) greater than (\>) 470 milliseconds, or baseline symptomatic bradycardia (less than 45 heart beats per minute) * Pregnant or breastfeeding women * Known Human Immunodeficiency Virus (HIV) positivity or Acquired Immunodeficiency Syndrome (AIDS)-related illness * History of hypersensitivity to any of the additives in the alectinib formulation * Any clinically significant concomitant disease or condition that could interfere with, or for which treatment might interfere with, the conduct of the study, or absorption of oral medications, or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase 2 Dose (RP2D) of Alectinib | Cycle 1 (up to 28 days) | RP2D was to be determined based on the safety and tolerability profile of the study treatment. |
| Percentage of Participants With Dose Limiting Toxicities (DLTs) | Cycle 1 (up to 28 days) | DLTs were to be assessed based on the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.3 (NCI-CTCAE v 4.3). DLTs: drug-related toxicities that meet any one of the following criteria: Grade 4 thrombocytopenia; Grade 3 thrombocytopenia with bleeding; Grade 4 neutropenia continuing for greater than or equal to (\>/=) 7 consecutive days or neutropenic fever; Non-hematological toxicity of Grade 3 or higher; Adverse events that require interruption of treatment for a total of \>/=7 days. |
| Percentage of Participants Achieving Objective Response (Complete Response [CR] or Partial Response [PR]) as Assessed by Independent Radiological Review Committee (IRC) in Response Evaluable (RE) Population | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) | Tumor response was assessed by IRC according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to less than (\<) 10 millimeters (mm). PR was defined as \>/=30 percent (%) decrease in the sum of diameters (SoD) of target lesions (taking as reference the baseline SoD). The 95% confidence interval (CI) was computed using Clopper-Pearson method. |
| Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Pretreated Participants | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) | Tumor response was assessed by IRC according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). The 95% CI was computed using Clopper-Pearson method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DoR) as Assessed by IRC in RE Population | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) | DoR was defined as the time from the first observation of an objective tumor response (CR or PR) until first observation of progressive disease (PD) according to RECIST v1.1 or death from any cause. CR: disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR: \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-target lesions. Duration of response was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Participants who did not progress or die after a confirmed objective response were censored at the date of their last tumor assessment. |
| Percentage of Participants With PD as Assessed by IRC According to RECIST v1.1 or Death From Any Cause in Safety Population | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) | According to RECIST v1.1, PD was defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-target lesions. |
| Progression Free Survival (PFS) as Assessed by IRC in Safety Population | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) | PFS was defined as the time interval between the date of the first treatment and the date of PD or death from any cause, whichever occurred first. PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-target lesions. PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Participants who neither progressed nor died at the time of assessment or who were lost to follow-up were censored at the date of the last tumor assessment. Participants with no post-baseline assessments were censored at the date of first dose. |
| Percentage of Participants Who Died of Any Cause | Baseline up to death from any cause (up to approximately 4 years) | Percentage of participants who died of any cause was reported. |
| Overall Survival (OS) | Baseline up to death from any cause (up to approximately 4 years) | OS was defined as the time from the date of first treatment to the date of death, regardless of the cause of death. OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Participants who did not die were censored at the date last known to be alive. |
| Percentage of Participants Achieving CR, PR or Stable Disease (SD) According to RECIST v1.1 in RE Population | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) | The disease control rate (DCR) was defined as the percentage of participants achieving CR, PR, or SD that lasted for at least 16 weeks. Tumor response was assessed by the investigator and IRC according to RECIST v1.1. CR: disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR: \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-target lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SoD while on study. The 95% CI was computed using Clopper-Pearson method. |
| Percentage of Participants Achieving Central Nervous System (CNS) Objective Response as Assessed by IRC According to RECIST v1.1 | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) | CNS response was assessed by IRC according to RECIST v1.1. CNS Objective response was defined as percentage of participants with a CR or PR. CR was defined as disappearance of all CNS lesions. PR was defined as \>/=30% decrease in the SoD of measurable CNS lesions (taking as reference the baseline SoD). The 95% CI was computed using Clopper-Pearson method. |
| Tmax of Alectinib Metabolite | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 | Tmax for alectinib metabolite was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software. |
| Percentage of Participants Achieving CNS Objective Response as Assessed by IRC According to Radiology Assessment in Neuro-Oncology (RANO) Criteria | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up until cutoff 18 August 2014 (up to approximately 53 weeks) | CNS response was assessed by IRC according to RANO criteria. CNS Objective response: percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as complete disappearance of all enhancing measurable, non-measurable disease; stable or improved non-enhancing lesions; no new lesions; no corticosteroids (or only physiologic replacement dose), and clinically stable or improved. PR was defined as \>/=50% decrease compared to screening in the sum of the products of the diameters (SPD) of enhancing measurable lesions; no progression of non-measurable disease (enhancing and non-enhancing lesions); no new lesions; no corticosteroids (or only physiologic replacement dose), and clinically stable or improved. The 95% CI was computed using Clopper-Pearson method. |
| CNS Duration of Response (CDoR) as Assessed by IRC According to RECIST v1.1 | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) | CDoR was defined as the time from the first observation of a CNS objective response (CR or PR) until first observation of CNS progression as assessed by IRC according to RECIST v 1.1 or death from any cause. CR: disappearance of all CNS lesions. PR: \>/=30% decrease in the SoD of measurable CNS lesions (taking as reference the baseline SoD). CNS progression: \>/=20% increase in the SoD of measurable CNS lesions (with an absolute increase of at least 5 mm), taking as reference the baseline SoD; 1 or more new CNS lesion(s); and/or unequivocal progression of non-measurable CNS lesions. CDoR was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. |
| CDoR as Assessed by IRC According to RANO Criteria | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up until cutoff 18 August 2014 (up to approximately 53 weeks) | CDoR: time from the CNS objective response until CNS progression as assessed by IRC according to RANO criteria or death from any cause. CR: complete disappearance of all enhancing measurable, non-measurable disease; stable/improved non-enhancing lesions; no new lesions; no corticosteroids, and clinically stable/improved. PR: \>/=50% decrease compared to screening in SPD of enhancing measurable lesions; no progression of non-measurable disease; no new lesions; no corticosteroids, and clinically stable/improved. Progression: \>/=25% increase in SPD of enhancing measurable lesions compared to best response on study; stable/increasing doses of corticosteroids; significant increase in non-enhancing lesions not caused by co-morbid events; any new lesions; progression of non-measurable disease; or clinical deterioration not attributable to other non-tumor causes. CDoR was estimated by Kaplan-Meier method and 95% CI was assessed using method of Brookmeyer and Crowley. |
| Percentage of Participants With CNS Progression as Assessed by IRC According to RECIST v 1.1 | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up until cutoff 18 August 2014 (up to approximately 53 weeks) | According to RECIST v 1.1, CNS progression was defined as \>/=20% increase in the SoD of measurable CNS lesions (with an absolute increase of at least 5 mm), taking as reference the baseline SoD; 1 or more new CNS lesion(s); and/or unequivocal progression of non-measurable CNS lesions. |
| Maximum Observed Plasma Concentration (Cmax) of Alectinib | Pre-dose (0 hours [hrs]), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 | Cmax for alectinib was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 (Pharsight Corporation) software. |
| Time to Cmax (Tmax) of Alectinib | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 | Tmax for alectinib was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software. |
| Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Naive Participants | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) | Tumor response was assessed by IRC according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). |
| Area Under the Plasma Concentration-Time Curve From Time 0 to 10 Hours Post-dose (AUC[0-10]) of Alectinib | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 | The AUC(0-10) of alectinib was calculated using the linear trapezoidal rule and actual sampling times (with the exception of pre-dose which was set to zero). |
| Area Under the Plasma Concentration-Time Curve From Time 0 to Tlast (AUC[0-last]) of Alectinib | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 | The AUC(0-last) of alectinib was calculated using the linear trapezoidal rule and actual sampling times (with the exception of pre-dose which was set to zero). |
| Cmax of Alectinib Metabolite | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 | Cmax for alectinib metabolite was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software. |
| Tlast of Alectinib Metabolite | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 | Tlast for alectinib metabolite was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software. |
| AUC(0-10) of Alectinib Metabolite | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 | The AUC(0-10) of alectinib metabolite was calculated using the linear trapezoidal rule and actual sampling times (with the exception of pre-dose which was set to zero). |
| AUC(0-last) of Alectinib Metabolite | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 | The AUC(0-last) of alectinib metabolite was calculated using the linear trapezoidal rule and actual sampling times (with the exception of pre-dose which was set to zero). |
| Metabolite to Parent Ratio Based on AUC(0-10) | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 | Metabolite to parent ratio based on AUC(0-10) was computed as AUC(0-10) of metabolite divided by AUC(0-10) of parent drug (alectinib) corrected for the molecular weight of parent divided by the molecular weight of the metabolite. |
| Metabolite to Parent Ratio Based on AUC(0-last) | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 | Metabolite to parent ratio based on AUC(0-last) was computed as AUC(0-last) of metabolite divided by AUC(0-last) of parent drug (alectinib) corrected for the molecular weight of parent divided by the molecular weight of the metabolite. |
| Trough Plasma Concentration (Ctrough) of Alectinib | Pre-dose (0 hrs) on Day 21 of Cycle 1 | — |
| Ctrough of Alectinib Metabolite | Pre-dose (0 hrs) on Day 21 of Cycle 1 | — |
| Peak to Trough Ratio of Alectinib | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Day 21 of Cycle 1 | — |
| Accumulation Ratio of Alectinib | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Day 1 and Day 21 of Cycle 1 | Accumulation ratio after repeat dosing was computed as AUC(0-10) on Day 21 divided by AUC(0-10) on Day 1. |
| Accumulation Ratio of Alectinib Metabolite | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Day 1 and Day 21 of Cycle 1 | Accumulation ratio after repeat dosing was computed as AUC(0-10) on Day 21 divided by AUC(0-10) on Day 1. |
| Time to Last Measurable Plasma Concentration (Tlast) of Alectinib | Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1 | Tlast for alectinib was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software. |
| Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in RE Population | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) | Tumor response was assessed by the investigator according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). The 95% CI was computed using Clopper-Pearson method. |
| Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Pretreated Participants | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) | Tumor response was assessed by the investigator according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). |
| Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Naive Participants | Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years) | Tumor response was assessed by the investigator according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). |
Countries
Australia, Belgium, Denmark, France, Germany, Italy, Luxembourg, Netherlands, Russia, Singapore, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Overall study status was confirmed as completed. Here, 'study terminated by sponsor' in reason for study not completed means participants were transitioned to commercial supply of alectinib (where it was available) or transitioned to a roll-over study BO39694 (NCT03194893) where they continued to receive alectinib treatment.
Pre-assignment details
Part 1 of study was planned to determine recommended Phase 2 dose (RP2D) of alectinib to be used in Part 2. During the conduct of Part 1 for this study, RP2D was confirmed in Study NP28761 (NCT01871805). Hence Part 1 participants were merged into Part 2. Part 3 was post-progression treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Alectinib Participants received alectinib at a dose of 600 mg via capsule, orally, twice daily, continuously starting on Day 1 Cycle 1 (in 28-day cycles) until PD, death, or withdrawal for any other reasons, whichever occurred first. After PD, participants were allowed to continue treatment with alectinib as per the discretion of the treating physician. | 138 |
| Total | 138 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 12 |
| Overall Study | Death | 8 |
| Overall Study | Other | 1 |
| Overall Study | Physician Decision | 5 |
| Overall Study | Progressive Disease | 81 |
| Overall Study | Study Terminated by Sponsor | 27 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Alectinib |
|---|---|
| Age, Continuous | 51.5 years STANDARD_DEVIATION 11.1 |
| Sex: Female, Male Female | 77 Participants |
| Sex: Female, Male Male | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 75 / 138 |
| other Total, other adverse events | 133 / 138 |
| serious Total, serious adverse events | 39 / 138 |
Outcome results
Primary
Percentage of Participants Achieving Objective Response (Complete Response [CR] or Partial Response [PR]) as Assessed by Independent Radiological Review Committee (IRC) in Response Evaluable (RE) Population
Tumor response was assessed by IRC according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to less than (\<) 10 millimeters (mm). PR was defined as \>/=30 percent (%) decrease in the sum of diameters (SoD) of target lesions (taking as reference the baseline SoD). The 95% confidence interval (CI) was computed using Clopper-Pearson method.
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
Population: Analysis was performed on RE population (IRC) which included all participants with measurable disease at baseline according to the IRC, who had baseline tumor assessment and received at least one dose of alectinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alectinib | Percentage of Participants Achieving Objective Response (Complete Response [CR] or Partial Response [PR]) as Assessed by Independent Radiological Review Committee (IRC) in Response Evaluable (RE) Population | 50.8 percentage of participants |
Comparison: Tests null hypothesis that the objective response rate (ORR) is equal to 35% versus the alternative hypothesis that the objective response rate was not equal to 35%.p-value: 0.0005Exact Clopper-Pearson CI
Primary
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Pretreated Participants
Tumor response was assessed by IRC according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). The 95% CI was computed using Clopper-Pearson method.
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
Population: Analysis was performed on RE population (IRC) participants who received prior chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alectinib | Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Pretreated Participants | 44.8 percentage of participants |
Comparison: Tests null hypothesis that the ORR is equal to 35% versus the alternative hypothesis that the objective response rate was not equal to 35%.p-value: 0.0599Exact Clopper-Pearson CI
Primary
Percentage of Participants With Dose Limiting Toxicities (DLTs)
DLTs were to be assessed based on the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.3 (NCI-CTCAE v 4.3). DLTs: drug-related toxicities that meet any one of the following criteria: Grade 4 thrombocytopenia; Grade 3 thrombocytopenia with bleeding; Grade 4 neutropenia continuing for greater than or equal to (\>/=) 7 consecutive days or neutropenic fever; Non-hematological toxicity of Grade 3 or higher; Adverse events that require interruption of treatment for a total of \>/=7 days.
Time frame: Cycle 1 (up to 28 days)
Population: The endpoint was not analyzed in this study as the RP2D was confirmed in study NP28761 (NCT01871805).
Primary
Recommended Phase 2 Dose (RP2D) of Alectinib
RP2D was to be determined based on the safety and tolerability profile of the study treatment.
Time frame: Cycle 1 (up to 28 days)
Population: The endpoint was not analyzed in this study as the RP2D was confirmed in study NP28761 (NCT01871805).
Secondary
Accumulation Ratio of Alectinib
Accumulation ratio after repeat dosing was computed as AUC(0-10) on Day 21 divided by AUC(0-10) on Day 1.
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Overall Number of Participants Analyzed'=number of participant evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alectinib | Accumulation Ratio of Alectinib | 6.95 Ratio | Geometric Coefficient of Variation 42.1 |
Secondary
Accumulation Ratio of Alectinib Metabolite
Accumulation ratio after repeat dosing was computed as AUC(0-10) on Day 21 divided by AUC(0-10) on Day 1.
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Overall Number of Participants Analyzed'=number of participant evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alectinib | Accumulation Ratio of Alectinib Metabolite | 8.68 Ratio | Geometric Coefficient of Variation 64.2 |
Secondary
Area Under the Plasma Concentration-Time Curve From Time 0 to 10 Hours Post-dose (AUC[0-10]) of Alectinib
The AUC(0-10) of alectinib was calculated using the linear trapezoidal rule and actual sampling times (with the exception of pre-dose which was set to zero).
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Number Analyzed'=number of participant evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alectinib | Area Under the Plasma Concentration-Time Curve From Time 0 to 10 Hours Post-dose (AUC[0-10]) of Alectinib | Day 1 | 1140 hrs*nanograms per milliliter (hrs*ng/mL) | Geometric Coefficient of Variation 44.5 |
| Alectinib | Area Under the Plasma Concentration-Time Curve From Time 0 to 10 Hours Post-dose (AUC[0-10]) of Alectinib | Day 21 | 7860 hrs*nanograms per milliliter (hrs*ng/mL) | Geometric Coefficient of Variation 37.2 |
Secondary
Area Under the Plasma Concentration-Time Curve From Time 0 to Tlast (AUC[0-last]) of Alectinib
The AUC(0-last) of alectinib was calculated using the linear trapezoidal rule and actual sampling times (with the exception of pre-dose which was set to zero).
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Number Analyzed'=number of participant evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alectinib | Area Under the Plasma Concentration-Time Curve From Time 0 to Tlast (AUC[0-last]) of Alectinib | Day 1 | 1340 hrs*ng/mL | Geometric Coefficient of Variation 44.9 |
| Alectinib | Area Under the Plasma Concentration-Time Curve From Time 0 to Tlast (AUC[0-last]) of Alectinib | Day 21 | 9090 hrs*ng/mL | Geometric Coefficient of Variation 36.9 |
Secondary
AUC(0-10) of Alectinib Metabolite
The AUC(0-10) of alectinib metabolite was calculated using the linear trapezoidal rule and actual sampling times (with the exception of pre-dose which was set to zero).
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Number Analyzed'=number of participant evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alectinib | AUC(0-10) of Alectinib Metabolite | Day 1 | 300 hrs*ng/mL | Geometric Coefficient of Variation 68.4 |
| Alectinib | AUC(0-10) of Alectinib Metabolite | Day 21 | 2590 hrs*ng/mL | Geometric Coefficient of Variation 35 |
Secondary
AUC(0-last) of Alectinib Metabolite
The AUC(0-last) of alectinib metabolite was calculated using the linear trapezoidal rule and actual sampling times (with the exception of pre-dose which was set to zero).
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Number Analyzed'=number of participant evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alectinib | AUC(0-last) of Alectinib Metabolite | Day 1 | 378 hrs*ng/mL | Geometric Coefficient of Variation 67.5 |
| Alectinib | AUC(0-last) of Alectinib Metabolite | Day 21 | 3040 hrs*ng/mL | Geometric Coefficient of Variation 34.9 |
Secondary
CDoR as Assessed by IRC According to RANO Criteria
CDoR: time from the CNS objective response until CNS progression as assessed by IRC according to RANO criteria or death from any cause. CR: complete disappearance of all enhancing measurable, non-measurable disease; stable/improved non-enhancing lesions; no new lesions; no corticosteroids, and clinically stable/improved. PR: \>/=50% decrease compared to screening in SPD of enhancing measurable lesions; no progression of non-measurable disease; no new lesions; no corticosteroids, and clinically stable/improved. Progression: \>/=25% increase in SPD of enhancing measurable lesions compared to best response on study; stable/increasing doses of corticosteroids; significant increase in non-enhancing lesions not caused by co-morbid events; any new lesions; progression of non-measurable disease; or clinical deterioration not attributable to other non-tumor causes. CDoR was estimated by Kaplan-Meier method and 95% CI was assessed using method of Brookmeyer and Crowley.
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up until cutoff 18 August 2014 (up to approximately 53 weeks)
Population: Analysis was performed on safety population participants with measurable CNS lesions at baseline and who had CNS objective response as assessed by IRC according to RANO criteria.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alectinib | CDoR as Assessed by IRC According to RANO Criteria | 7.6 months |
Secondary
Cmax of Alectinib Metabolite
Cmax for alectinib metabolite was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software.
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Number Analyzed'=number of participant evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alectinib | Cmax of Alectinib Metabolite | Day 1 | 57.2 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 68.6 |
| Alectinib | Cmax of Alectinib Metabolite | Day 21 | 303 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 33.5 |
Secondary
CNS Duration of Response (CDoR) as Assessed by IRC According to RECIST v1.1
CDoR was defined as the time from the first observation of a CNS objective response (CR or PR) until first observation of CNS progression as assessed by IRC according to RECIST v 1.1 or death from any cause. CR: disappearance of all CNS lesions. PR: \>/=30% decrease in the SoD of measurable CNS lesions (taking as reference the baseline SoD). CNS progression: \>/=20% increase in the SoD of measurable CNS lesions (with an absolute increase of at least 5 mm), taking as reference the baseline SoD; 1 or more new CNS lesion(s); and/or unequivocal progression of non-measurable CNS lesions. CDoR was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
Population: Analysis was performed on safety population participants with measurable CNS lesions at baseline and who had CNS objective response as assessed by IRC according to RECIST v1.1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alectinib | CNS Duration of Response (CDoR) as Assessed by IRC According to RECIST v1.1 | 11.1 months |
Secondary
Ctrough of Alectinib Metabolite
Time frame: Pre-dose (0 hrs) on Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Overall Number of Participants Analyzed'=number of participant evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alectinib | Ctrough of Alectinib Metabolite | 244 ng/mL | Geometric Coefficient of Variation 37.8 |
Secondary
Duration of Response (DoR) as Assessed by IRC in RE Population
DoR was defined as the time from the first observation of an objective tumor response (CR or PR) until first observation of progressive disease (PD) according to RECIST v1.1 or death from any cause. CR: disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR: \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-target lesions. Duration of response was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Participants who did not progress or die after a confirmed objective response were censored at the date of their last tumor assessment.
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
Population: Analysis was performed on RE population (IRC) participants with documented objective response as assessed by IRC according to RECIST v1.1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alectinib | Duration of Response (DoR) as Assessed by IRC in RE Population | 15.2 months |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Alectinib
Cmax for alectinib was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 (Pharsight Corporation) software.
Time frame: Pre-dose (0 hours [hrs]), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on Pharmacokinetic (PK) Evaluable Population, which included all participants who received any dose of alectinib and who had at least one post-baseline PK sample available. Here, 'Number Analyzed'=number of participant evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alectinib | Maximum Observed Plasma Concentration (Cmax) of Alectinib | Day 1 | 204 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 47.6 |
| Alectinib | Maximum Observed Plasma Concentration (Cmax) of Alectinib | Day 21 | 933 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 34.8 |
Secondary
Metabolite to Parent Ratio Based on AUC(0-10)
Metabolite to parent ratio based on AUC(0-10) was computed as AUC(0-10) of metabolite divided by AUC(0-10) of parent drug (alectinib) corrected for the molecular weight of parent divided by the molecular weight of the metabolite.
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Number Analyzed'=number of participant evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alectinib | Metabolite to Parent Ratio Based on AUC(0-10) | Day 1 | 0.278 Ratio | Geometric Coefficient of Variation 41 |
| Alectinib | Metabolite to Parent Ratio Based on AUC(0-10) | Day 21 | 0.349 Ratio | Geometric Coefficient of Variation 28.7 |
Secondary
Metabolite to Parent Ratio Based on AUC(0-last)
Metabolite to parent ratio based on AUC(0-last) was computed as AUC(0-last) of metabolite divided by AUC(0-last) of parent drug (alectinib) corrected for the molecular weight of parent divided by the molecular weight of the metabolite.
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Number Analyzed'=number of participant evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alectinib | Metabolite to Parent Ratio Based on AUC(0-last) | Day 1 | 0.298 Ratio | Geometric Coefficient of Variation 41.2 |
| Alectinib | Metabolite to Parent Ratio Based on AUC(0-last) | Day 21 | 0.354 Ratio | Geometric Coefficient of Variation 28.7 |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of first treatment to the date of death, regardless of the cause of death. OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Participants who did not die were censored at the date last known to be alive.
Time frame: Baseline up to death from any cause (up to approximately 4 years)
Population: Analysis was performed on safety population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alectinib | Overall Survival (OS) | 29.2 months |
Secondary
Peak to Trough Ratio of Alectinib
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Overall Number of Participants Analyzed'=number of participant evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alectinib | Peak to Trough Ratio of Alectinib | 1.23 Ratio | Geometric Coefficient of Variation 14.4 |
Secondary
Percentage of Participants Achieving Central Nervous System (CNS) Objective Response as Assessed by IRC According to RECIST v1.1
CNS response was assessed by IRC according to RECIST v1.1. CNS Objective response was defined as percentage of participants with a CR or PR. CR was defined as disappearance of all CNS lesions. PR was defined as \>/=30% decrease in the SoD of measurable CNS lesions (taking as reference the baseline SoD). The 95% CI was computed using Clopper-Pearson method.
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
Population: Analysis was performed on safety population participants with measurable CNS lesions at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alectinib | Percentage of Participants Achieving Central Nervous System (CNS) Objective Response as Assessed by IRC According to RECIST v1.1 | 58.8 percentage of participants |
Secondary
Percentage of Participants Achieving CNS Objective Response as Assessed by IRC According to Radiology Assessment in Neuro-Oncology (RANO) Criteria
CNS response was assessed by IRC according to RANO criteria. CNS Objective response: percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as complete disappearance of all enhancing measurable, non-measurable disease; stable or improved non-enhancing lesions; no new lesions; no corticosteroids (or only physiologic replacement dose), and clinically stable or improved. PR was defined as \>/=50% decrease compared to screening in the sum of the products of the diameters (SPD) of enhancing measurable lesions; no progression of non-measurable disease (enhancing and non-enhancing lesions); no new lesions; no corticosteroids (or only physiologic replacement dose), and clinically stable or improved. The 95% CI was computed using Clopper-Pearson method.
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up until cutoff 18 August 2014 (up to approximately 53 weeks)
Population: Analysis was performed on safety population participants with measurable CNS lesions at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alectinib | Percentage of Participants Achieving CNS Objective Response as Assessed by IRC According to Radiology Assessment in Neuro-Oncology (RANO) Criteria | 44.1 percentage of participants |
Secondary
Percentage of Participants Achieving CR, PR or Stable Disease (SD) According to RECIST v1.1 in RE Population
The disease control rate (DCR) was defined as the percentage of participants achieving CR, PR, or SD that lasted for at least 16 weeks. Tumor response was assessed by the investigator and IRC according to RECIST v1.1. CR: disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR: \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-target lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SoD while on study. The 95% CI was computed using Clopper-Pearson method.
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
Population: Analysis was performed on RE population which included all participants with measurable disease at baseline, who had baseline tumor assessment, and who received at least one dose of alectinib. Here, 'Number Analyzed'=number of participant evaluable for specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alectinib | Percentage of Participants Achieving CR, PR or Stable Disease (SD) According to RECIST v1.1 in RE Population | IRC Assessment | 63.9 percentage of participants |
| Alectinib | Percentage of Participants Achieving CR, PR or Stable Disease (SD) According to RECIST v1.1 in RE Population | Investigator Assessment | 69.6 percentage of participants |
Secondary
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Naive Participants
Tumor response was assessed by the investigator according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD).
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
Population: Analysis was performed on RE population (investigator) participants who did not receive prior chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alectinib | Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Naive Participants | 57.1 percentage of participants |
Secondary
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Pretreated Participants
Tumor response was assessed by the investigator according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD).
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
Population: Analysis was performed on RE population (investigator) participants who received prior chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alectinib | Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Pretreated Participants | 50.0 percentage of participants |
Secondary
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in RE Population
Tumor response was assessed by the investigator according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD). The 95% CI was computed using Clopper-Pearson method.
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
Population: Analysis was performed on RE population (Investigator) which included all participants with measurable disease at baseline according to the investigator, who had baseline tumor assessment and received at least one dose of alectinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alectinib | Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in RE Population | 51.4 percentage of participants |
Comparison: Tests null hypothesis that the ORR is equal to 35% versus the alternative hypothesis that the objective response rate was not equal to 35%.p-value: 0.0001Exact Clopper-Pearson CI
Secondary
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Naive Participants
Tumor response was assessed by IRC according to RECIST v1.1. Objective response was defined as percentage of participants with a CR or PR that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level; and reduction in all lymph nodes size to \<10 mm. PR was defined as \>/=30% decrease in the SoD of target lesions (taking as reference the baseline SoD).
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
Population: Analysis was performed on RE population (IRC) participants who did not receive prior chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alectinib | Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Naive Participants | 73.1 percentage of participants |
Secondary
Percentage of Participants Who Died of Any Cause
Percentage of participants who died of any cause was reported.
Time frame: Baseline up to death from any cause (up to approximately 4 years)
Population: Analysis was performed on safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alectinib | Percentage of Participants Who Died of Any Cause | 54.3 percentage of participants |
Secondary
Percentage of Participants With CNS Progression as Assessed by IRC According to RECIST v 1.1
According to RECIST v 1.1, CNS progression was defined as \>/=20% increase in the SoD of measurable CNS lesions (with an absolute increase of at least 5 mm), taking as reference the baseline SoD; 1 or more new CNS lesion(s); and/or unequivocal progression of non-measurable CNS lesions.
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up until cutoff 18 August 2014 (up to approximately 53 weeks)
Population: Analysis was performed on safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alectinib | Percentage of Participants With CNS Progression as Assessed by IRC According to RECIST v 1.1 | 18.8 percentage of participants |
Secondary
Percentage of Participants With PD as Assessed by IRC According to RECIST v1.1 or Death From Any Cause in Safety Population
According to RECIST v1.1, PD was defined as \>/=20% relative increase and \>/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-target lesions.
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
Population: Analysis was performed on safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alectinib | Percentage of Participants With PD as Assessed by IRC According to RECIST v1.1 or Death From Any Cause in Safety Population | 71.0 percentage of participants |
Secondary
Progression Free Survival (PFS) as Assessed by IRC in Safety Population
PFS was defined as the time interval between the date of the first treatment and the date of PD or death from any cause, whichever occurred first. PD: \>/=20% relative increase and \>/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-target lesions. PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Participants who neither progressed nor died at the time of assessment or who were lost to follow-up were censored at the date of the last tumor assessment. Participants with no post-baseline assessments were censored at the date of first dose.
Time frame: Baseline; assessments every 8 weeks post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator, or last tumor assessment (up to approximately 2.5 years)
Population: Analysis was performed on safety population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alectinib | Progression Free Survival (PFS) as Assessed by IRC in Safety Population | 8.9 months |
Secondary
Time to Cmax (Tmax) of Alectinib
Tmax for alectinib was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software.
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Number Analyzed'=number of participant evaluable for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Alectinib | Time to Cmax (Tmax) of Alectinib | Day 1 | 5.89 hrs |
| Alectinib | Time to Cmax (Tmax) of Alectinib | Day 21 | 4.12 hrs |
Secondary
Time to Last Measurable Plasma Concentration (Tlast) of Alectinib
Tlast for alectinib was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software.
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Number Analyzed'=number of participant evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alectinib | Time to Last Measurable Plasma Concentration (Tlast) of Alectinib | Day 1 | 11.59 hrs | Geometric Coefficient of Variation 3.9 |
| Alectinib | Time to Last Measurable Plasma Concentration (Tlast) of Alectinib | Day 21 | 11.65 hrs | Geometric Coefficient of Variation 3.8 |
Secondary
Tlast of Alectinib Metabolite
Tlast for alectinib metabolite was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software.
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Number Analyzed'=number of participant evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alectinib | Tlast of Alectinib Metabolite | Day 1 | 11.59 hrs | Geometric Coefficient of Variation 3.9 |
| Alectinib | Tlast of Alectinib Metabolite | Day 21 | 11.65 hrs | Geometric Coefficient of Variation 3.8 |
Secondary
Tmax of Alectinib Metabolite
Tmax for alectinib metabolite was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software.
Time frame: Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hrs post-dose on Day 1 and Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Number Analyzed'=number of participant evaluable for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Alectinib | Tmax of Alectinib Metabolite | Day 21 | 7.00 hrs |
| Alectinib | Tmax of Alectinib Metabolite | Day 1 | 8.03 hrs |
Secondary
Trough Plasma Concentration (Ctrough) of Alectinib
Time frame: Pre-dose (0 hrs) on Day 21 of Cycle 1
Population: Analysis was performed on PK Evaluable Population. Here, 'Overall Number of Participants Analyzed'=number of participant evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alectinib | Trough Plasma Concentration (Ctrough) of Alectinib | 761 ng/mL | Geometric Coefficient of Variation 42.9 |