Clinical Trial Results:
An Open-Label, Non-Randomized, Multicenter Phase I/II Trial of RO5424802 Given Orally to Non-Small Cell Lung Cancer Patients Who have ALK Mutation and Who have Failed Crizotinib Treatment
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Summary
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EudraCT number |
2012-004455-36 |
Trial protocol |
SE GB DE IT ES NL BE FR DK LU |
Global end of trial date |
27 Oct 2017
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Results information
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Results version number |
v2(current) |
This version publication date |
17 Oct 2018
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First version publication date |
16 Mar 2016
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
NP28673
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01801111 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
F. Hoffmann-La Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland, CH-4070
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Public contact |
Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
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Scientific contact |
Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Oct 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Oct 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objectives for Part 1 of the study were:
To determine the recommended Phase 2 dose (RP2D) of alectinib (RO5424802) to be used in Part 2 of the study; To evaluate the safety and tolerability of 600 milligrams (mg) and 900-mg doses of alectinib administered twice daily to participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have anaplastic lymphoma kinase (ALK) rearrangement and in whom prior crizotinib therapy has failed; To characterize dose-limiting toxicities (DLTs), if any, associated with alectinib after 21 days of treatment; and To characterize the pharmacokinetics (PK) of alectinib and metabolite(s).
The primary objective for Part 2 of the study was: To evaluate efficacy of alectinib by objective response rate (ORR) as per independent radiological review committee (IRC) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) criteria in the overall population.
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Protection of trial subjects |
The study was conducted in accordance with the principles of the “Declaration of Helsinki” and International Council for Harmonisation (ICH) guideline for Good Clinical Practice (GCP). Approval from the Independent Ethics Committee (IEC)/Institutional Review Board (IRB) was obtained before study start and was documented in a letter to the investigator specifying the date on which the committee met and granted the approval. No modifications were made to the protocol after receipt of the IEC/IRB approval.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
20 Jun 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 7
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Country: Number of subjects enrolled |
Belgium: 1
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Country: Number of subjects enrolled |
Germany: 6
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Country: Number of subjects enrolled |
Denmark: 2
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Country: Number of subjects enrolled |
Spain: 7
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Country: Number of subjects enrolled |
France: 32
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
Italy: 19
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Country: Number of subjects enrolled |
Korea, Republic of: 17
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Country: Number of subjects enrolled |
Luxembourg: 2
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Country: Number of subjects enrolled |
Netherlands: 2
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Country: Number of subjects enrolled |
Russian Federation: 1
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Country: Number of subjects enrolled |
Singapore: 2
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Country: Number of subjects enrolled |
Sweden: 5
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Country: Number of subjects enrolled |
Taiwan: 10
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Country: Number of subjects enrolled |
United States: 23
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Worldwide total number of subjects |
138
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EEA total number of subjects |
78
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
124
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From 65 to 84 years |
14
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85 years and over |
0
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Recruitment
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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. | ||||||||||||||||||||||
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Pre-assignment
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Screening details |
Part 1 of study was planned to determine the 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. | ||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||
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Arms
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Arm title
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Alectinib | ||||||||||||||||||||||
Arm description |
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 disease progression (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. | ||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||
Investigational medicinal product name |
Alectinib
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Investigational medicinal product code |
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Other name |
RO5424802
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Alectinib was administered at a dose of 600 mg via capsule, orally, twice daily.
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Baseline characteristics reporting groups
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Reporting group title |
Alectinib
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Reporting group description |
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 disease progression (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. | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Alectinib
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Reporting group description |
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 disease progression (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. | ||
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End point title |
RP2D of Alectinib [1] | ||||||||
End point description |
RP2D was to be determined based on the safety and tolerability profile of the study treatment.
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End point type |
Primary
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End point timeframe |
Cycle 1 (up to 28 days)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to EudraCT database limitations it is not possible to add statistical analysis in a single arm study. |
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| Notes [2] - The endpoint was not analyzed in this study as the RP2D was confirmed in study NP28761 (NCT01871805) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with DLTs [3] | ||||||||
End point description |
DLTs were to be assessed based on the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.3 (NCI-CTCAE v4.3). 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.
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End point type |
Primary
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End point timeframe |
Cycle 1 (up to 28 days)
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to EudraCT database limitations it is not possible to add statistical analysis in a single arm study. |
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| Notes [4] - The endpoint was not analyzed in this study as the RP2D was confirmed in study NP28761 (NCT01871805) |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Achieving Objective Response (Complete Response [CR] or Partial Response [PR]) as Assessed by IRC in Response Evaluable (RE) Population [5] | ||||||||
End point description |
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 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. 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.
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End point type |
Primary
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End point timeframe |
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)
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to EudraCT database limitations it is not possible to add statistical analysis in a single arm study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Pretreated Participants [6] | ||||||||
End point description |
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. Analysis was performed on RE population (IRC) participants who received prior chemotherapy.
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End point type |
Primary
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End point timeframe |
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)
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to EudraCT database limitations it is not possible to add statistical analysis in a single arm study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Naive Participants | ||||||||
End point description |
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). Analysis was performed on RE population (IRC) participants who did not receive prior chemotherapy.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in RE Population | ||||||||
End point description |
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. 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.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Pretreated Participants | ||||||||
End point description |
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). Analysis was performed on RE population (investigator) participants who received prior chemotherapy.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Naive Participants | ||||||||
End point description |
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). Analysis was performed on RE population (investigator) participants who did not receive prior chemotherapy.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of Response (DoR) as Assessed by IRC in RE Population | ||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
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)
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| Notes [7] - Analysis was performed on RE population (IRC) participants with documented objective response. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with PD as Assessed by IRC According to RECIST v1.1 or Death from Any Cause in Safety Population | ||||||||
End point description |
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. Analysis was performed on safety population, which included all participants who received at least one dose of alectinib.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression Free Survival (PFS) as Assessed by IRC in Safety Population | ||||||||
End point description |
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. Analysis was performed on safety population.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Died of Any Cause | ||||||||
End point description |
Percentage of participants who died of any cause was reported. Analysis was performed on safety population.
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End point type |
Secondary
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End point timeframe |
Baseline up to death from any cause (up to approximately 4 years)
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival (OS) | ||||||||
End point description |
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. Analysis was performed on safety population.
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End point type |
Secondary
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End point timeframe |
Baseline up to death from any cause (up to approximately 4 years)
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Achieving CR, PR or Stable Disease (SD) According to RECIST v1.1 in RE Population | ||||||||||||
End point description |
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. RE population: All participants who had baseline tumor assessment and received at least one dose of alectinib.
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End point type |
Secondary
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End point timeframe |
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)
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| Notes [8] - Here, ‘n’=number of participant evaluable for specified category. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Participants Achieving Central Nervous System (CNS) Objective Response as Assessed by IRC According to RECIST v1.1 | ||||||||
End point description |
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. Analysis was performed on safety population participants with measurable CNS lesions at baseline.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Achieving CNS Objective Response as Assessed by IRC According to Radiology Assessment in Neuro-Oncology (RANO) Criteria | ||||||||
End point description |
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. Analysis was performed on safety population participants with measurable CNS lesions at baseline.
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End point type |
Secondary
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End point timeframe |
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)
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| No statistical analyses for this end point | |||||||||
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End point title |
CNS Duration of Response (CDoR) as Assessed by IRC According to RECIST v1.1 | ||||||||
End point description |
CDoR was defined as the time from 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 method of Brookmeyer and Crowley. 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. Data ‘99999’ in results signifies that upper limit of 95% CI could not be calculated due to high number of censored participants.
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End point type |
Secondary
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End point timeframe |
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)
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|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
CDoR as Assessed by IRC According to RANO Criteria | ||||||||
End point description |
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.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
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)
|
||||||||
|
|||||||||
| Notes [9] - Safety population participants with measurable CNS lesions at baseline and CNS objective response. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Percentage of Participants with CNS Progression as Assessed by IRC According to RECIST v 1.1 | ||||||||
End point description |
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. Analysis was performed on safety population.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
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)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||
End point title |
Maximum Observed Plasma Concentration (Cmax) of Alectinib | ||||||||||||
End point description |
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. Analysis was performed on 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, ‘n’=number of participant evaluable for specified category.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Time to Cmax (Tmax) of Alectinib | ||||||||||||
End point description |
Tmax for alectinib was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software. Analysis was performed on PK Evaluable Population. Here, ‘n’=number of participant evaluable for specified category.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Time to Last Measurable Plasma Concentration (Tlast) of Alectinib | ||||||||||||
End point description |
Tlast for alectinib was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Area Under the Plasma Concentration-Time Curve From Time 0 to 10 Hours Post-dose (AUC[0-10]) of Alectinib | ||||||||||||
End point description |
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).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Area Under the Plasma Concentration-Time Curve From Time 0 to Tlast (AUC[0-last]) of Alectinib | ||||||||||||
End point description |
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).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Cmax of Alectinib Metabolite | ||||||||||||
End point description |
Cmax for alectinib metabolite was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Tmax of Alectinib Metabolite | ||||||||||||
End point description |
Tmax for alectinib metabolite was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Tlast of Alectinib Metabolite | ||||||||||||
End point description |
Tlast for alectinib metabolite was estimated from plasma concentration versus time data by non-compartmental methods of analysis using Phoenix WinNonlin v6.2 software. Analysis was performed on PK Evaluable Population. Here, ‘n’=number of participant evaluable for specified category.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
AUC(0-10) of Alectinib Metabolite | ||||||||||||
End point description |
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). Analysis was performed on PK Evaluable Population. Here, ‘n’=number of participant evaluable for specified category.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
AUC(0-last) of Alectinib Metabolite | ||||||||||||
End point description |
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). Analysis was performed on PK Evaluable Population. Here, ‘n’=number of participant evaluable for specified category.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Metabolite to Parent Ratio Based on AUC(0-10) | ||||||||||||
End point description |
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. Analysis was performed on PK Evaluable Population. Here, ‘n’=number of participant evaluable for specified category.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Metabolite to Parent Ratio Based on AUC(0-last) | ||||||||||||
End point description |
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. Analysis was performed on PK Evaluable Population. Here, ‘n’=number of participant evaluable for specified category.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||
End point title |
Trough Plasma Concentration (Ctrough) of Alectinib | ||||||||
End point description |
Analysis was performed on PK Evaluable Population. Here, ‘Number of Subjects Analysed’=participants evaluable for this outcome measure.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Pre-dose (0 hrs) on Day 21 of Cycle 1
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Ctrough of Alectinib Metabolite | ||||||||
End point description |
Analysis was performed on PK Evaluable Population. Here, ‘Number of Subjects Analysed’=participants evaluable for this outcome measure.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Pre-dose (0 hrs) on Day 21 of Cycle 1
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Peak to Trough Ratio of Alectinib | ||||||||
End point description |
Analysis was performed on PK Evaluable Population. Here, ‘Number of Subjects Analysed’=participants evaluable for this outcome measure.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Pre-dose (0 hrs), and 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Day 21 of Cycle 1
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Accumulation Ratio of Alectinib | ||||||||
End point description |
Accumulation ratio after repeat dosing was computed as AUC(0-10) on Day 21 divided by AUC(0-10) on Day 1. Analysis was performed on PK Evaluable Population. Here, ‘Number of Subjects Analysed’=participants evaluable for this outcome measure.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
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
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Accumulation Ratio of Alectinib Metabolite | ||||||||
End point description |
Accumulation ratio after repeat dosing was computed as AUC(0-10) on Day 21 divided by AUC(0-10) on Day 1. Analysis was performed on PK Evaluable Population. Here, ‘Number of Subjects Analysed’=participants evaluable for this outcome measure.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
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
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From Baseline until 28 days after the last dose of study drug (overall up to approximately 4 years)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Analysis was performed on safety population.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Alectinib
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
21 Dec 2012 |
Exclusion criterion regarding use of anticoagulation or thrombolytic agent within 2 weeks prior to Day 1 was removed and timing for “archived primary tissue” was updated in the schedule of assessments. |
||
28 May 2013 |
Serial PK sampling was included in Cycle 1 for the first 12 participants enrolled in Part 2 of the study; Dose reduction of 1-dose level was included for Grade 4 hematologic toxicity; Electrocardiograms were included to PK schedule, 2 hours after alectinib administration on Day 1 and Day 21 of Cycle 1; Action taken to detect an eventual QT/QTc prolongation were included; Description of potential phototoxicity and interstitial lung disease class effects and oxygen saturation were included to vital signs collection; It was clarified that the pregnancy test could be done any time during the study; The safety and efficacy data were updated; Total testosterone, free testosterone, follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH) testing was added; Collection of sample for the Roche Clinical Repository was removed; Completion/early termination sample collection was added; The reportable adverse events of special interest were updated; The schedule of assessments was updated for the PK/electrocardiogram schedule. |
||
30 Jan 2014 |
A midazolam drug-drug interaction (DDI) sub-study was incorporated to be conducted in approximately 14 additional participants with ALK-positive NSCLC to gain critical information to support use of alectinib in combination with cytochrome P450 3A (CYP3A) substrates; Inclusion of Stage 3b NSCLC study participants was clarified; Post-progression combination treatment (alectinib and erlotinib) in Part 3 of the study was limited to participants with EGFR mutations and where local health authorities and ethic committees permitted it; The restriction for the last dose of crizotinib to be within 60 days from the first dose of alectinib was removed; The permitted and prohibited medications based on the available DDI information for alectinib was updated; The PK data was updated for study NP28761(NCT01871805); Eligibility for participants with brain or leptomeningeal metastases was clarified; The objectives and endpoints to assess alectinib efficacy on CNS lesions were clarified; tumor assessments during the long term follow-up visits were added; RANO criteria for IRC review of CNS lesions was included; The safety outcome measures with the addition of QTc assessment and the QTc analysis description were included; The safety section was updated with detailed guidance on management of selected adverse events. |
||
14 Apr 2016 |
The summary of safety information for alectinib was updated to include newly available information; Recommendations for CYP3A and cytochrome P450 2C8 (CYP2C8) substrates and P-glycoprotein inhibitors were modified to reflect updated data; List of substrates, inhibitors, and inducers of drug metabolizing enzymes and transporters was updated; End of study was clarified. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Part 1 analysis was not conducted as during the conduct of the study the RP2D was confirmed in study NP28761 (NCT01871805). | |||
