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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT01970865
Registration number
NCT01970865
Ethics application status
Date submitted
16/10/2013
Date registered
28/10/2013
Titles & IDs
Public title
A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations
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Scientific title
PHASE 1/2 STUDY OF PF-06463922 (AN ALK/ROS1 TYROSINE KINASE INHIBITOR) IN PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER HARBORING SPECIFIC MOLECULAR ALTERATIONS
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Secondary ID [1]
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2013-002620-17
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Secondary ID [2]
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B7461001
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
ALK-positive Non Small Cell Lung Cancer (NSCLC) and ROS1-positive NSCLC
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Condition category
Condition code
Cancer
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Lung - Mesothelioma
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Cancer
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Lung - Non small cell
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Cancer
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Lung - Small cell
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Intervention/exposure
Study type
Interventional(has expanded access)
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Description of intervention(s) / exposure
Treatment: Drugs - PF-06463922
Treatment: Drugs - Crizotinib
Experimental: PF-06463922 -
Other: Crizotinib - ALK+ NSCLC patients who are treatment naïve may be eligible to receive crizotinib following PF-06463922 as a substudy to the main study.
Treatment: Drugs: PF-06463922
Oral, starting dose 10mg once a day, dose escalation in Phase 1 until recommended Phase 2 dose determined, continuous daily dosing, cycles lasting 21 days
Treatment: Drugs: Crizotinib
Oral, starting dose of 250 mg BID continuous daily dosing every 21 days
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Participants With Cycle 1 Dose-Limiting Toxicities (DLTs) in Phase 1
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Assessment method [1]
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DLT: any of following adverse events (AEs) attributable to PF-06463922: (1) hematologic: grade 4 neutropenia for \>7 days; febrile neutropenia; grade\>=3 neutropenic infection; grade\>=3 thrombocytopenia with bleeding; grade 4 thrombocytopenia; (2) non-hematologic: grade\>=3 pancreatitis; grade\>=3 toxicities (excluding grade \>=3 laboratory abnormalities not requiring dose modifications) persisting after optimal treatment with standard medical therapy; symptomatic grade \>=3 QT interval corrected for heart rate (QTc) prolongation, or asymptomatic grade \>=3 prolongation that had been confirmed by repeat testing, re-evaluation by qualified person, persisted after correction of reversible causes; \>=20% decrease from baseline in left ventricular ejection fraction (LVEF); (3) other: failure to deliver at least 16 out of 21 prescribed daily total dose due to toxicities attributable to study drug; failure to restart dosing after 21 days (1 cycle) delay due to toxicity attributable to study drug.
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Timepoint [1]
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Cycle 1 (21 days)
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Primary outcome [2]
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Percentage of Participants With Overall and Intracranial Objective Response (Phase 2)
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Assessment method [2]
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Objective response (OR) refers to confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Intracranial OR refers to confirmed CR or PR considering only lesions within brain. CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 milliliter (mm) on Target Lesions electronic case report form (eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 percent (%) or more decrease in sum of lesion dimensions (SLD) of target lesions, taking as reference the baseline SLD. Results presented here were based on independent central review.
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Timepoint [2]
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3 years
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Secondary outcome [1]
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Percentage of Participants With Overall and Intracranial Objective Response (Phase 1)
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Assessment method [1]
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Objective response (OR) refers to confirmed CR or PR according to RECIST version 1.1. Intracranial OR refers to confirmed CR or PR considering only lesions within brain. CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. Results presented here were based on independent central review.
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Timepoint [1]
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From start of study treatment until CR or PR (maximum of 8 years approximately)
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Secondary outcome [2]
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Time to Tumor Response (TTR) and Intracranial TTR (Phase 1)
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Assessment method [2]
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Time to tumor response (TTR) was defined as the time from the first dose of study treatment to the first documentation of objective tumor response (CR or PR). For participants whose objective response proceeded from PR to CR, the onset of PR was taken as the onset of response. CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. TTR was only calculated for the subgroup of participants with a confirmed objective tumor response. Intracranial TTR was only calculated for participants with confirmed intracranial objective response. Results presented here were based on independent central review.
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Timepoint [2]
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From start of study treatment to the first documentation of objective tumor response (CR or PR) (maximum of 8 years approximately)
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Secondary outcome [3]
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Number of Participants With Duration of Response (DOR) and Intracranial DOR (Phase 1)
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Assessment method [3]
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Duration of response(DOR): time from first documentation of objective tumor response (CR/PR) to first documentation of disease progression (PD) or to death due to any cause, whichever occurred first. DOR: calculated for subgroup of participants with confirmed objective tumor response. Intracranial DOR: calculated for participants with confirmed intracranial objective response. CR:disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0mm on Target Lesion eCRF). Any pathological lymph node (recorded as target lesion) must have reduction in short axis to \<10mm. PR:30% or more decrease in SLD of target lesion, taking as reference baseline SLD. PD:20% or more increase in the SLD of target lesions relative to baseline or smallest SLD (nadir) recorded since first dose. In addition, also demonstrate absolute increase of at least 5mm (\>=5mm) relative to baseline or smallest SLD (nadir) recorded since first dose.
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Timepoint [3]
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From start of study treatment to first documentation of PD or to death due to any cause, whichever occurred first (maximum of 8 years approximately)
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Secondary outcome [4]
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Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 and 24 Weeks (Phase 1)
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Assessment method [4]
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Tumor response was evaluated according to RECIST version 1.1, and disease control: confirmed CR, confirmed PR, or stable disease (SD). Intracranial assessment was only performed for participants CNS metastases. CR was defined as disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as 30% or more decrease in SLD of target lesions, taking as reference baseline SLD. Progressive disease: 20% or more increase in SLD of target lesions relative to baseline or smallest SLD (nadir) recorded since first dose. In addition to relative increase of 20%, SLD must also demonstrate absolute increase of at least 5mm (\>=5mm) relative to baseline or smallest SLD (nadir) recorded since first dose. Results presented here were based on independent central review.
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Timepoint [4]
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12 and 24 weeks
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Secondary outcome [5]
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Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 1)
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Assessment method [5]
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The probability of the first event being a CNS progression, a non-CNS progression, or death was evaluated with a competing risk approach by estimating cumulative incidence functions (range: 0-1) relative to the analysis set. The time to first event being a Competing Event (either "CNS progression" or "non CNS progression" or "Death") was defined as time from first dose until the date of that specific event. Participants not known to have any of the Competing Events were censored on the date they were last assessed for disease status for PFS. Participants who presented one type of event were counted as a competing cause of failure for the analysis of other type of events. For each type of event, the cumulative incidence function corresponding to the nearest time point preceding 1 year is presented. The results are based on independent central review.
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Timepoint [5]
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3 years
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Secondary outcome [6]
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Progression-Free Survival (PFS) (Phase 1)
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Assessment method [6]
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PFS was defined as the time from the first dose of study treatment to the first documentation of objective PD or to death on study due to any cause, whichever came first. Progressive disease was defined by a 20% or more increase in the SLD of target lesions relative to baseline or the smallest SLD (nadir) recorded since first dose. In addition to the relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm (\>= 5 mm) relative to baseline or the smallest SLD (nadir) recorded since the first dose. Results presented here were based on independent central review.
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Timepoint [6]
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From start of study treatment to first documentation of PD or to death due to any cause, whichever occurred first (maximum of 8 years approximately)
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Secondary outcome [7]
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Overall Survival (OS) (Phase 1)
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Assessment method [7]
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OS was defined as the time from first dose to the date of death due to any cause. For participants still alive at the time of analysis, the OS time was censored on the last date the participants were known to be alive. Estimates of OS and its 95% confidence interval were determined using Kaplan-Meier method.
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Timepoint [7]
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3 years
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Secondary outcome [8]
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Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Single Oral Doses (Phase 1)
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Assessment method [8]
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Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data.
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Timepoint [8]
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Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.
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Secondary outcome [9]
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Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)
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Assessment method [9]
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Maximum Observed Plasma Concentration (Cmax) of PF-06463922 was observed directly from data.
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Timepoint [9]
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Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups).
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Secondary outcome [10]
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Time for Cmax (Tmax) of PF-06463922 Following Single Oral Doses (Phase 1)
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Assessment method [10]
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Tmax of PF-06463922 was observed directly from data as time of first occurrence.
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Timepoint [10]
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Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.
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Secondary outcome [11]
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Time for Cmax (Tmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)
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Assessment method [11]
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Tmax of PF-06463922 was observed directly from data as time of first occurrence.
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Timepoint [11]
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Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups).
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Secondary outcome [12]
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Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Single Oral Doses (Phase 1)
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Assessment method [12]
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Tau refers to the dosing interval, and it equals to 12 or 24 hours for BID or QD dosing, respectively. AUCtau was determined using linear/log trapezoidal method.
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Timepoint [12]
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Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours post-dose on Day -7 for all other groups.
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Secondary outcome [13]
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Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Multiple Oral Doses (Phase 1)
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Assessment method [13]
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Tau refers to the dosing interval, and it equals to 12 or 24 hours for BID or QD dosing, respectively. AUCtau was determined using linear/log trapezoidal method.
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Timepoint [13]
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Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)
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Secondary outcome [14]
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Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 Following Single Oral Doses (Phase 1)
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Assessment method [14]
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AUCinf was calculated as AUClast + (Clast\*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the rate constant for terminal phase.
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Timepoint [14]
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0
Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.
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Secondary outcome [15]
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Apparent Oral Clearance (CL/F) of PF-06463922 Following Single Oral Doses (Phase 1)
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Assessment method [15]
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Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
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Timepoint [15]
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Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.
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Secondary outcome [16]
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Apparent Oral Clearance (CL/F) of PF-06463922 Following Multiple Oral Doses (Phase 1)
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Assessment method [16]
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Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
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Timepoint [16]
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Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)
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Secondary outcome [17]
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Apparent Volume of Distribution (Vz/F) of PF-06463922 Following Single Oral Doses (Phase 1)
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Assessment method [17]
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Vz/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug, and calculated as dose/(AUCinf\*kel), where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time, kel was the rate constant for terminal phase.
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Timepoint [17]
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Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.
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Secondary outcome [18]
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Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 1)
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Assessment method [18]
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Rac was calculated as Day 15 AUCtau/Day -7 AUCtau or Day 1 AUCtau, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (12 and 24 hours for BID and QD dosing regimen, respectively).
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Timepoint [18]
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Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)
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Secondary outcome [19]
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Terminal Half-Life of PF-06463922 Following Single Oral Doses (Phase 1)
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Assessment method [19]
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Terminal plasma half-life was defined as the time measured for the plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was the rate constant for terminal phase.
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Timepoint [19]
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0
Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.
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Secondary outcome [20]
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Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 1)
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Assessment method [20]
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Rss was calculated as Day 15 AUCtau/Day -7 AUCinf, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (12 and 24 hours for BID and QD dosing regimen, respectively), and AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
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Timepoint [20]
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0
Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)
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Secondary outcome [21]
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Renal Clearance (CLr) of PF-06463922 (Phase 1)
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Assessment method [21]
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Renal clearance was calculated as Aetau/AUCtau, where Aetau was the cumulative amount of drug recovered unchanged in urine up to dosing interval tau (24 hours for QD dosing regimen), and AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen).
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Timepoint [21]
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0
0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15
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Secondary outcome [22]
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Percent of PF-06463922 Recovered Unchanged in Urine up to Dosing Interval (AEtau%) (Phase 1)
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Assessment method [22]
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Dosing interval was 24 hours for QD dosing regimen. Aetau% was calculated as 100\*Ae24/dose, where Ae24 was the cumulative amount of drug recovered unchanged in urine up to 24 hours post-dose.
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Timepoint [22]
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0
0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15
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Secondary outcome [23]
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Maximum Observed Plasma Concentration (Cmax) of Midazolam (Phase 1)
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Assessment method [23]
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Cmax of midazolam was observed directly from data. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflected the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflected the PK assessment after multiple doses of PF-06463922 were administered.
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Timepoint [23]
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0
Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
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Secondary outcome [24]
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Time for Cmax (Tmax) of Midazolam (Phase 1)
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Assessment method [24]
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Tmax of midazolam was observed directly from data as time of first occurrence. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
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Timepoint [24]
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0
Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
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Secondary outcome [25]
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Area Under the Plasma Concentration-Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Midazolam (Phase 1)
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Assessment method [25]
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Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) of midazolam was determined using linear/log trapezoidal method. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
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Timepoint [25]
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0
Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
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Secondary outcome [26]
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0
Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Midazolam (Phase 1)
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Assessment method [26]
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0
AUCinf was calculated as AUClast + (Clast\*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
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Timepoint [26]
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0
Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
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Secondary outcome [27]
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0
Apparent Oral Clearance (CL/F) of Midazolam (Phase 1)
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Assessment method [27]
0
0
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
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Timepoint [27]
0
0
Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
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Secondary outcome [28]
0
0
Apparent Volume of Distribution (Vz/F) of Midazolam (Phase 1)
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Assessment method [28]
0
0
Vz/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug, and calculated as dose/(AUCinf\*kel), where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time, kel was the rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
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Timepoint [28]
0
0
Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
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Secondary outcome [29]
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0
Terminal Half-Life of Midazolam (Phase 1)
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Assessment method [29]
0
0
Terminal plasma half-life was defined as the time measured for the plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was the rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
Query!
Timepoint [29]
0
0
Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
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Secondary outcome [30]
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0
Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 1)
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Assessment method [30]
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0
Plasma circulating nucleic acid (CNA) samples were analyzed for ALK kinase domain mutations by digital polymerase chain reaction (PCR) BEAMing technology. Number of participants with one or more ALK mutations is presented.
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Timepoint [30]
0
0
Screening (up to 28 days)
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Secondary outcome [31]
0
0
Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 1)
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Assessment method [31]
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0
Tumor tissues from archived tissue specimens and/or a de novo biopsy were analyzed for ALK kinase domain mutations. Number of participants with one or more ALK mutations is presented.
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Timepoint [31]
0
0
Screening (up to 28 days)
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Secondary outcome [32]
0
0
Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 1)
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Assessment method [32]
0
0
European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ)-C30 (version 3.0) consists of 30 questions assessing 5 functional domains (physical, role, emotional, cognitive and social), global quality of life (QoL), disease/treatment related symptoms (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhea), and the perceived financial impact of disease. Each scale was transformed to a range of 0 to 100 using standard EORTC algorithm. For global QoL and functional scales, higher score indicate better performance, and improvement was defined as an increase of at least 10 points, worsening was defined as a decrease of at least 10 points. For symptom scales, higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.
Query!
Timepoint [32]
0
0
From start of study treatment until end of treatment (maximum of 8 years approximately)
Query!
Secondary outcome [33]
0
0
Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 1)
Query!
Assessment method [33]
0
0
EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.
Query!
Timepoint [33]
0
0
From start of study treatment until end of treatment (maximum of 8 years approximately)
Query!
Secondary outcome [34]
0
0
Change From Baseline in Mini Mental State Examination (MMSE) Score (Phase 1)
Query!
Assessment method [34]
0
0
In Phase 1, the MMSE was collected to assess mental status. The MMSE is a 30 item questionnaire that tests 5 areas of cognitive function: orientation, registration, attention and calculation, recall and language. The maximum score is 30 and minimum score is 0. Highest score indicates no cognitive impairment, lowest score indicates severe cognitive impairment. The MMSE was removed under Amendment 6 of the study protocol, and not required for Phase 2, as the tool was not considered meaningful for assessment of cognitive function.
Query!
Timepoint [34]
0
0
Baseline, Day 1 of Cycle 1-52, and end of treatment (up to 3 years)
Query!
Secondary outcome [35]
0
0
Time to Tumor Response (TTR) and Intracranial TTR (Phase 2 and DDI Sub-study)
Query!
Assessment method [35]
0
0
Time to tumor response (TTR) was defined as the time from the first dose of study treatment to the first documentation of objective tumor response (CR or PR). For participants whose objective response proceeded from PR to CR, the onset of PR was taken as the onset of response. TTR was only calculated for the subgroup of participants with a confirmed objective tumor response. Intracranial TTR was only calculated for participants with confirmed intracranial objective response. CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. Results presented here were based on independent central review.
Query!
Timepoint [35]
0
0
From first dose of study treatment to the first documentation of objective tumor response (CR or PR) (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [36]
0
0
Duration of Response (DOR) and Intracranial DOR (Phase 2 and DDI Substudy)
Query!
Assessment method [36]
0
0
Duration of response(DOR): time from first documentation of objective tumor response (CR/PR) to first documentation of PD or to death due to any cause, whichever occurred first. DOR: calculated for subgroup of participants with confirmed objective tumor response. Intracranial DOR: calculated for participants with confirmed intracranial objective response. CR:disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0mm on Target Lesion eCRF). Any pathological lymph node (recorded as target lesion) must have reduction in short axis to \<10mm. PR:30% or more decrease in SLD of target lesion, taking as reference baseline SLD. PD:20% or more increase in the SLD of target lesions relative to baseline or smallest SLD (nadir) recorded since first dose. In addition, also demonstrate absolute increase of at least 5mm (\>=5mm) relative to baseline or smallest SLD (nadir) recorded since first dose.
Query!
Timepoint [36]
0
0
From first dose of study treatment to first documentation of PD or to death due to any cause, whichever occurred first (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [37]
0
0
Percentage of Participants Achieving Disease Control and Intracranial Disease Control at Week 12 and 24 (Phase 2 and DDI Substudy)
Query!
Assessment method [37]
0
0
Tumor response was evaluated according to RECIST version 1.1, and disease control was defined as confirmed CR, confirmed PR, or stable disease (SD). CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. SD= when neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD is observed, taking as reference the smallest sum diameters while on study. Intracranial assessment was only performed for participants CNS metastases. Results presented here were based on independent central review.
Query!
Timepoint [37]
0
0
Weeks 12 and 24
Query!
Secondary outcome [38]
0
0
Time to Progression on the Last Prior Therapy (Phase 2)
Query!
Assessment method [38]
0
0
TTP on the last prior therapy was defined as time from the first dose date of the last prior treatment regimen to the date of progression. Progressive disease was defined by a 20% or more increase in the SLD of target lesions relative to baseline or the smallest SLD (nadir) recorded since first dose. In addition to the relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm (\>= 5 mm) relative to baseline or the smallest SLD (nadir) recorded since the first dose.
Query!
Timepoint [38]
0
0
From first dose of study treatment to the date of progression (maximum of 7.5 years for Phase 2)
Query!
Secondary outcome [39]
0
0
Time to Tumor Progression (TTP) and Intracranial TTP (Phase 2 and DDI Substudy)
Query!
Assessment method [39]
0
0
Time to progression (TTP) was defined as the time from the first dose of study treatment to the first documentation of objective PD. Intracranial TTP was defined as the time from the first dose of study treatment to the date of the first documentation of objective progression of intracranial disease, based on either new brain metastases or progression of existing brain metastases. Progressive disease was defined by a 20% or more increase in the SLD of target lesions relative to baseline or the smallest SLD (nadir) recorded since first dose. In addition to the relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm (\>= 5 mm) relative to baseline or the smallest SLD (nadir) recorded since the first dose. Results presented here were based on independent central review.
Query!
Timepoint [39]
0
0
From first dose of study treatment to the first documentation of objective PD (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [40]
0
0
Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 2)
Query!
Assessment method [40]
0
0
Probability of first event being CNS progression, non-CNS progression, or death was evaluated with competing risk approach by estimating cumulative incidence functions (range: 0-1) relative to analysis set. Time to first event being Competing Event (either "CNS progression" or "non CNS progression" or "Death") = time from first dose until date of that specific event. Participants not known to have any of Competing Events were censored on date they were last assessed for disease status for PFS. Participants who presented one type of event were counted as competing cause of failure for analysis of other type of events. For each type of event, cumulative incidence function corresponding to nearest time point preceding 1 year is presented. PD:20% or more increase in SLD of target lesion relative to baseline or smallest SLD (nadir) recorded since first dose. SLD must demonstrate absolute increase of atleast 5mm(\>=5 mm) relative to baseline or smallest SLD (nadir) recorded since first dose.
Query!
Timepoint [40]
0
0
From first dose of study treatment until first event of CNS progression (maximum of 7.5 years for Phase 2)
Query!
Secondary outcome [41]
0
0
Progression-Free Survival (PFS) (Phase 2 and DDI Substudy)
Query!
Assessment method [41]
0
0
PFS was defined as the time from the first dose of study treatment to the first documentation of objective PD or to death on study due to any cause, whichever came first. Progressive disease was defined by a 20% or more increase in the SLD of target lesions relative to baseline or the smallest SLD (nadir) recorded since first dose. In addition to the relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm (\>= 5 mm) relative to baseline or the smallest SLD (nadir) recorded since the first dose. Results presented here were based on independent central review.
Query!
Timepoint [41]
0
0
From first dose of study treatment to first documentation of objective PD or death due to any cause, whichever came first (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [42]
0
0
Overall Survival (Phase 2 and DDI Substudy)
Query!
Assessment method [42]
0
0
OS was defined as the time from first dose to the date of death due to any cause. For participants still alive at the time of analysis, the OS time was censored on the last date the participants were known to be alive. Estimates of OS and its 95% confidence interval were determined using Kaplan-Meier method.
Query!
Timepoint [42]
0
0
From first dose of study treatment until date of death (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [43]
0
0
Maximum Observed Plasma Concentration (Cmax) of PF-06463922 (Phase 2)
Query!
Assessment method [43]
0
0
Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data.
Query!
Timepoint [43]
0
0
Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Query!
Secondary outcome [44]
0
0
Time for Cmax (Tmax) of PF-06463922 (Phase 2)
Query!
Assessment method [44]
0
0
Tmax of PF-06463922 was observed directly from data as time of first occurrence.
Query!
Timepoint [44]
0
0
Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Query!
Secondary outcome [45]
0
0
Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 (Phase 2)
Query!
Assessment method [45]
0
0
AUCinf was calculated as AUClast + (Clast\*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the rate constant for terminal phase.
Query!
Timepoint [45]
0
0
Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7
Query!
Secondary outcome [46]
0
0
Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 (Phase 2)
Query!
Assessment method [46]
0
0
Tau refers to the dosing interval, and it equals to 24 hours for QD dosing which was adopted in Phase 2. AUCtau was determined using linear/log trapezoidal method.
Query!
Timepoint [46]
0
0
Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Query!
Secondary outcome [47]
0
0
Apparent Oral Clearance (CL/F) of PF-06463922 (Phase 2)
Query!
Assessment method [47]
0
0
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Query!
Timepoint [47]
0
0
Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Query!
Secondary outcome [48]
0
0
Apparent Volume of Distribution (Vz/F) of PF-06463922 (Phase 2)
Query!
Assessment method [48]
0
0
Vz/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug, and calculated as dose/(AUCinf\*kel), where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time, kel was the rate constant for terminal phase.
Query!
Timepoint [48]
0
0
Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7
Query!
Secondary outcome [49]
0
0
Terminal Half-Life of PF-06463922 (Phase 2)
Query!
Assessment method [49]
0
0
Terminal plasma half-life was defined as the time measured for the plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was the rate constant for terminal phase.
Query!
Timepoint [49]
0
0
Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7
Query!
Secondary outcome [50]
0
0
Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 2)
Query!
Assessment method [50]
0
0
Rac was calculated as Day 15 AUCtau/Day -7 AUCtau, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen which was adopted in Phase 2).
Query!
Timepoint [50]
0
0
Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Query!
Secondary outcome [51]
0
0
Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 2)
Query!
Assessment method [51]
0
0
Rss was calculated as Day 15 AUCtau/Day -7 AUCinf, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen which was adopted in Phase 2), and AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Query!
Timepoint [51]
0
0
Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Query!
Secondary outcome [52]
0
0
Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 2)
Query!
Assessment method [52]
0
0
Plasma CNA samples were analyzed for ALK kinase domain mutations by Next Generation Sequencing (NGS). Number of participants with one or more ALK mutations is presented.
Query!
Timepoint [52]
0
0
Screening (up to 28 days)
Query!
Secondary outcome [53]
0
0
Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 2)
Query!
Assessment method [53]
0
0
Tumor tissues from archived tissue specimens and/or a de novo biopsy were analyzed for ALK kinase domain mutations. Number of participants with one or more ALK mutations is presented.
Query!
Timepoint [53]
0
0
Screening (up to 28 days)
Query!
Secondary outcome [54]
0
0
Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 2 and DDI Sub-study)
Query!
Assessment method [54]
0
0
European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ)-C30 (version 3.0) consists of 30 questions assessing 5 functional domains (physical, role, emotional, cognitive and social), global quality of life (QoL), disease/treatment related symptoms (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhea), and the perceived financial impact of disease. Each scale was transformed to a range of 0 to 100 using standard EORTC algorithm. For global QoL and functional scales, higher score indicate better performance, and improvement was defined as an increase of at least 10 points, worsening was defined as a decrease of at least 10 points. For symptom scales, higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.
Query!
Timepoint [54]
0
0
From first dose of study treatment to end of treatment (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [55]
0
0
Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 2 and DDI Sub-study)
Query!
Assessment method [55]
0
0
EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.
Query!
Timepoint [55]
0
0
From first dose of study treatment to end of treatment (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [56]
0
0
Number of Participants With Treatment-Emergent Adverse Events (Phase 1, Phase 2 and DDI Sub-study)
Query!
Assessment method [56]
0
0
AE: any untoward medical occurrence in clinical investigation participant administered a product or medical device, regardless of causal relationship to study treatment. Treatment-emergent AEs (TEAEs): AEs which occurred for first time during effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs): any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of ability to conduction normal life function). AEs included SAEs and non-serious AEs. Severity was graded as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Grade1: mild, Grade2: moderate, Grade3: severe, Grade4: Life threatening consequences; urgent intervention indicated, Grade 5: death related to AE.
Query!
Timepoint [56]
0
0
From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [57]
0
0
Number of Participants With Laboratory Abnormalities (Phase 1, Phase 2 and DDI Sub-study) - Hematology
Query!
Assessment method [57]
0
0
Hematology evaluation included hemoglobin, platelets, white blood cell, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils and absolute basophils. Hematology parameters with any abnormalities were reported in this outcome measure.
Query!
Timepoint [57]
0
0
From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [58]
0
0
Number of Participants With Laboratory Abnormalities (Phase 1, Phase 2 and DDI Sub-study) - Chemistry
Query!
Assessment method [58]
0
0
Chemistry evaluation included alanine aminotransferase (ALT), alkaline phosphatase, aspartate aminotransferase (AST), blood bilirubin, creatine phosphokinase (CPK), creatinine, gamma-glutamyl transferase (GGT), calcium, sodium, potassium, magnesium, albumin, glucose (non-fasted), albumin, phosphorus or phosphate, serum amylase and lipase.
Query!
Timepoint [58]
0
0
From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [59]
0
0
Number of Participants With Laboratory Abnormalities (Phase 1, Phase 2 and DDI Sub-study) - Coagulation, Lipids and Urinalysis
Query!
Assessment method [59]
0
0
Coagulation evaluation included activated partial thromboplastin time, international normalized ratio (INR), and prothrombin time. Lipid evaluation included Cholesterol and triglycerides.
Query!
Timepoint [59]
0
0
From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [60]
0
0
Number of Participants With Vital Signs Data Meeting Pre-defined Criteria (Phase 1, Phase 2 and DDI Sub-study)
Query!
Assessment method [60]
0
0
Blood pressure (BP), including systolic BP (SBP) and diastolic BP (DBP), and pulse rate were recorded in sitting position. Body weight was also measured.
Query!
Timepoint [60]
0
0
From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [61]
0
0
Number of Participants With Maximum Decrease From Baseline Greater Than or Equal to 20 Percent in Left Ventricular Ejection Fraction (LVEF) (Phase 1, Phase 2 and DDI Sub-study)
Query!
Assessment method [61]
0
0
Left Ventricular Ejection Fraction (LVEF) was determined by echocardiogram. Baseline was defined as the measurement prior to the first dose of study treatment.
Query!
Timepoint [61]
0
0
From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [62]
0
0
Number of Participants With Absolute Values and Change From Baseline in QTcF Meeting Pre-defined Criteria (Phase 1, Phase 2 and DDI Sub-study)
Query!
Assessment method [62]
0
0
Triplicate 12-lead electrocardiograms (ECGs) were performed approximately 2 minutes apart to determine mean QTc interval (QT interval corrected for heart rate). QT interval was corrected for heart rate using Fridericia's formula to provide QTcF. Absolute values and changes from baseline were summarized according to pre-defined criteria. Baseline was defined as the last evaluation on or prior to the first dose of study treatment.
Query!
Timepoint [62]
0
0
From first dose of study treatment to end of treatment (maximum of 8 years for Phase 1, maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
Query!
Secondary outcome [63]
0
0
Number of Participants With Suicidal Ideation and Suicidal Behavior (Phase 2)
Query!
Assessment method [63]
0
0
The Columbia Suicide Severity Rating Scale (C-SSRS) was used to analyze participants' suicidal ideation and behavior, and it is a unique, simple and short method of assessing both behavior and ideation that tracks all suicidal events and provides a summary of suicidality. It assesses the lethality of attempts and other features of ideation (frequency, duration, controllability, reasons for ideation and deterrents), all of which are significantly predictive of completed suicide. Maximum score of 4 or 5 indicates maximum suicidal ideation and minimum score of "0" indicates no suicidal ideation.
Query!
Timepoint [63]
0
0
From first dose of study treatment to end of treatment (maximum of 7.5 years for Phase 2)
Query!
Secondary outcome [64]
0
0
Change From Baseline in Total Scores for Beck Depression Inventory (BDI)-II (Mood Assessment) (Phase 2)
Query!
Assessment method [64]
0
0
The Beck Depression Inventory (BDI)-II is a 21-item self-report scale, with each item rated by participants on a 4-point scale (ranging from 0-3, where 0 indicated lowest depression and 3 indicated severe depression). The scale includes items capturing mood, (loss of pleasure, sadness, and irritability), suicidal ideation, and cognitive signs (punitive thoughts, self-criticism, self-dislike, pessimism, and poor concentration) as well as somatic signs (appetite, sleep, fatigue and libido). Scores were obtained by adding up the total points from the series of answers. Higher total scores indicate more severe depressive symptoms. The standardized cutoffs are as follows: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; 29-63: severe depression.
Query!
Timepoint [64]
0
0
Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)
Query!
Secondary outcome [65]
0
0
Change From Baseline in Total Scores for Detection Test (Cognitive Function Assessment) (Phase 2)
Query!
Assessment method [65]
0
0
The Detection Test is a measure of psychomotor function and uses a well validated simple reaction time paradigm with playing card stimuli. In this test, the on-screen instructions ask: "Has the card turned over?". A playing card is presented face down in the center of the screen. The card flips over so it is face up. As soon as the card flips over the participant must press "Yes". The participant is encouraged to work as quickly as they can and be as accurate as possible. The speed and accuracy of each response are recorded and mean of the log10 transformed reaction times for correct responses is calculated. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
Query!
Timepoint [65]
0
0
Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)
Query!
Secondary outcome [66]
0
0
Change From Baseline in Total Scores for Identification Test (Cognitive Function Assessment) (Phase 2)
Query!
Assessment method [66]
0
0
The Identification Test is a measure of visual attention and uses a well validated choice reaction time paradigm with playing card stimuli. In this task, the playing cards are all red or black jokers. The on-screen instructions ask: "Is the card red?". A playing card is presented face down in the center of the screen. The card flips over so it is face up. As soon as it flips over the participant must decide whether the card is red or not. If it is red the participant should press "Yes", and if it is not red the participant should press "No". The participant is encouraged to work as quickly and accurately as possible. The speed and accuracy of each response are recorded and mean of the log10 transformed reaction times for correct responses is calculated. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
Query!
Timepoint [66]
0
0
Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)
Query!
Secondary outcome [67]
0
0
Change From Baseline in Total Scores for One Back Test (Cognitive Function Assessment) (Phase 2)
Query!
Assessment method [67]
0
0
The One Back Test is a measure of working memory and uses a well validated n back paradigm with playing cards. In this task, the on-screen instructions ask: "Is the previous card the same?". A playing card is presented in the center of the screen. The participant must decide whether the card is the same as the previous card. If it is the same the participant should press "Yes", and if not press "No". The participant is encouraged to work as quickly and accurately as possible. The speed and accuracy of each response are recorded, mean of the log10 transformed reaction times for correct responses is used to demonstrate speed of performance, and the arcsine transformation of the square root of the proportion of correct responses is used to demonstrate accuracy. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
Query!
Timepoint [67]
0
0
Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)
Query!
Secondary outcome [68]
0
0
Change From Baseline in Total Scores for International Shopping List Test (Cognitive Function Assessment) (Phase 2)
Query!
Assessment method [68]
0
0
The International Shopping List task is a measure of verbal learning and uses a well validated list learning paradigm administered using a computer. High frequencies, high imagery, concrete nouns (items from a shopping list) were read to the participant at the rate of one word every 2 seconds. Once all 12 words had been read, the participant was asked to recall as many of the words as quickly as possible. The words recalled by the participant were marked on the computer screen. When the participant could recall no more words, the same list was read again. The words recalled by the participant were recorded. This was then repeated a third time. Total number of correct responses on 3 consecutive trials at a single assessment was recorded. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
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Timepoint [68]
0
0
Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)
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Secondary outcome [69]
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0
Change From Baseline in Total Scores for International Shopping List Test-Delayed Recall (Cognitive Function Assessment) (Phase 2)
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Assessment method [69]
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This test was performed in the same way as the International Shopping List Test, with the exception that, the delayed recall condition required the participant to recall the words from the list 15 30 minutes later without having the list read again. During the recognition condition, the qualified personnel read a shopping list item that may or may not have been on the original list and the participant had to respond either affirmatively (if the item was on the original list) or negatively (if it was not). Total number of correct responses made in remembering the word list after a delay was recorded. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
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Timepoint [69]
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Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)
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Secondary outcome [70]
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Number of Participants With Absolute Values and Change From Baseline in PR Interval Meeting Pre-defined Criteria (Phase 2 and DDI Substudy)
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Assessment method [70]
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PR Interval was determined by ECG measurement. PR interval had following categories: change from baseline\>=25 percent, 40 to \<60 milliseconds (msec), 60 to \<80 msec and \>=80 msec. Baseline was defined as the average of the triplicate measurements prior to the first dose of study drug.
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Timepoint [70]
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0
From first dose of study treatment to end of treatment maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)
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Eligibility
Key inclusion criteria
Inclusion Criteria
* Evidence of histologically or cytologically confirmed diagnosis of metastatic NSCLC (Stage IV, AJCC v7.0) that carries an ALK rearrangement, as determined by the Food and Drug Administration (FDA) approved FISH assay (Abbott Molecular Inc) or by Immunohistochemistry (IHC) (Ventana Inc), or a ROS1 rearrangement as determined by FISH or RT PCR or Next Generation Sequencing (NGS) via a local diagnostic test (LDT). All patients (ALK positive and ROS1 positive) must have archival tissue sample available and collected prior to enrollment.
* Disease Status Requirements:
Phase 1: ALK-positive NSCLC and ROS1-positive patients must either be treatment naïve in the advanced setting or have had disease progression after at least 1 previous ALK/ROS1 inhibitor therapy(ies).
Phase 2:
ALK-positive NSCLC patients must either be or have had:
* Treatment naïve (ie, no prior chemotherapy in the metastatic disease setting and no prior ALK inhibitor therapy allowed).
* Disease progression after crizotinib only. No prior chemotherapy is allowed in the metastatic disease setting.
* Disease progression after crizotinib and 1 or 2 prior regimens of chemotherapy in the metastatic disease setting.
* Disease progression after 1 prior ALK inhibitor therapy other than crizotinib. Patients may have had any number of prior chemotherapy regimens in any disease setting.
* Disease progression after 2 prior ALK inhibitor therapies. Patients may have had any number of prior chemotherapy regimens in any disease setting.
* Disease progression after 3 prior ALK inhibitor therapies. Patients may have had any number of prior chemotherapy regimens in any disease setting.
ROS1-positive NSCLC patients may be:
* Treatment naïve (ie, no prior chemotherapy in the metastatic disease setting and no prior ROS inhibitor therapy).
* Any number of prior therapies (ie, chemotherapy and/or ROS inhibitor therapies).
* Tumor Requirements:
All Patients must have at least one measurable target extracranial lesion according to RECIST v1.1. In addition patients with asymptomatic CNS metastases (including patients asymptomatic by means of stable or decreasing doses of steroids within the last 2 weeks prior to study entry) will be eligible. Patients who have leptomeningeal disease (LM) or carcinomatous meningitis (CM) are eligible.
* Adequate Bone Marrow, Pancreatic Function, Renal Function and Liver Function.
* Negative Serum pregnancy test for females of childbearing potential
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Exclusion Criteria
* Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry. Whole brain radiation must have completed at least 4 weeks prior to study entry.
* Systemic anti cancer therapy completed within a minimum of 5 half lives of study entry.
* Prior therapy with an antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including, but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T lymphocyte associated antigen 4 (anti-CTLA-4) antibody.
* Active and clinically significant bacterial, fungal, or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS) related illness.
* Clinically significant cardiovascular disease (that is, active or <3 months prior to enrollment): cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (New York Heart Association Classification Class = II), second-degree or third-degree AV block (unless paced) or any AV block with PR >220 msec. Ongoing cardiac dysrhythmias of NCI CTCAE Grade =2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as long-distance runners, etc.), machine-read ECG with QTc >470 msec, or congenital long QT syndrome.
* History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis.
* Current use or anticipated need for food or drugs that are known strong or moderate CYP3A4 inhibitors, inducers and substrates; drugs that are CYP2C9 substrates; drugs that are sensitive CYP2B6 substrates; drugs that are strong CYP2C19 inhibitors; drugs that are strong CYP2C8 inhibitors; and drugs that are P-gp substrates.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
8/01/2014
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
24/05/2023
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Sample size
Target
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Accrual to date
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Final
364
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Recruitment in Australia
Recruitment state(s)
NSW,VIC
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Recruitment hospital [1]
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0
Chris O'Brien Lifehouse - Sydney Local Health District [rpa]
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Recruitment hospital [2]
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0
Chris O'Brien Lifehouse - Sydney
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Recruitment hospital [3]
0
0
Royal Prince Alfred Hospital - Sydney
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Recruitment hospital [4]
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Peter MacCallum Cancer Centre - Melbourne
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Recruitment hospital [5]
0
0
Royal Melbourne Hospital - Parkville
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Recruitment postcode(s) [1]
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2050 - Sydney Local Health District [rpa]
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Recruitment postcode(s) [2]
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2050 - Sydney
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Recruitment postcode(s) [3]
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3000 - Melbourne
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Recruitment postcode(s) [4]
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3050 - Parkville
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Recruitment outside Australia
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0
United States of America
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0
Arkansas
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0
United States of America
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California
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0
United States of America
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Colorado
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United States of America
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Connecticut
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United States of America
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District of Columbia
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United States of America
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Massachusetts
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United States of America
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Michigan
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Missouri
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United States of America
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New York
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Ohio
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Pennsylvania
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United States of America
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Tennessee
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Belgium
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Edegem
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Canada
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British Columbia
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Canada
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Ontario
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France
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Grenoble Cedex 9
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France
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Rennes Cedex 9
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France
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Toulouse Cedex 9
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France
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Villejuif Cedex
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France
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Villejuif
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Germany
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Cologne
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Hong Kong
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Shatin
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Italy
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Aviano (PN)
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Italy
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Milano
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Italy
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Perugia
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Japan
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Aichi
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Japan
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Chiba
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Japan
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Ehime
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Japan
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Hokkaido
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Japan
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Hyogo
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Japan
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Osaka
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Japan
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Shizuoka
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Japan
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Tokyo
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Japan
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Fukuoka
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Japan
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Koto-ku, Tokyo
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Korea, Republic of
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Seoul
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Singapore
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Singapore
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Spain
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Madrid
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Spain
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Navarra
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Spain
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Barcelona
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Switzerland
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Lausanne
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Switzerland
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Winterthur
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Taiwan
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Taipei
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Pfizer
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Address
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Ethics approval
Ethics application status
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Summary
Brief summary
Phase 1 and 2 trial to study the safety, pharmacokinetics, pharmacodynamics, patient reported outcomes and efficacy of PF-06463922 in ALK + advanced non-small cell lung cancer patients and ROS1+ advanced non small cell lung cancer patients .
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Trial website
https://clinicaltrials.gov/study/NCT01970865
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Trial related presentations / publications
Soo RA, Huat Tan E, Hayashi H, Seto T, Lin CC, Ou SI, Kim DW, Liu G, Abbattista A, Martini JF, Hooi Wong C, Toffalorio F, Solomon BJ. Efficacy and safety of lorlatinib in Asian and non-Asian patients with ALK-positive advanced non-small cell lung cancer: Subgroup analysis of a global phase 2 trial. Lung Cancer. 2022 Jul;169:67-76. doi: 10.1016/j.lungcan.2022.05.012. Epub 2022 May 23. Ou SI, Solomon BJ, Shaw AT, Gadgeel SM, Besse B, Soo RA, Abbattista A, Toffalorio F, Wiltshire R, Bearz A. Continuation of Lorlatinib in ALK-Positive NSCLC Beyond Progressive Disease. J Thorac Oncol. 2022 Apr;17(4):568-577. doi: 10.1016/j.jtho.2021.12.011. Epub 2022 Jan 10. Chen J, Ruiz-Garcia A, James LP, Peltz G, Thurm H, Clancy J, Hibma J. Lorlatinib Exposure-Response Analyses for Safety and Efficacy in a Phase I/II Trial to Support Benefit-Risk Assessment in Non-Small Cell Lung Cancer. Clin Pharmacol Ther. 2021 Nov;110(5):1273-1281. doi: 10.1002/cpt.2228. Epub 2021 Jun 26. Chen J, O'Gorman MT, James LP, Klamerus KJ, Mugundu G, Pithavala YK. Pharmacokinetics of Lorlatinib After Single and Multiple Dosing in Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: Results from a Global Phase I/II Study. Clin Pharmacokinet. 2021 Oct;60(10):1313-1324. doi: 10.1007/s40262-021-01015-z. Epub 2021 May 3. Peters S, Shaw AT, Besse B, Felip E, Solomon BJ, Soo RA, Bearz A, Gadgeel SM, Lin CC, Kao S, Seto T, Masters ET, Abbattista A, Clancy JS, Thurm H, Reisman A, Peltz G, Ross Camidge D. Impact of lorlatinib on patient-reported outcomes in patients with advanced ALK-positive or ROS1-positive non-small cell lung cancer. Lung Cancer. 2020 Jun;144:10-19. doi: 10.1016/j.lungcan.2020.02.011. Epub 2020 Mar 10. Bauer TM, Shaw AT, Johnson ML, Navarro A, Gainor JF, Thurm H, Pithavala YK, Abbattista A, Peltz G, Felip E. Brain Penetration of Lorlatinib: Cumulative Incidences of CNS and Non-CNS Progression with Lorlatinib in Patients with Previously Treated ALK-Positive Non-Small-Cell Lung Cancer. Target Oncol. 2020 Feb;15(1):55-65. doi: 10.1007/s11523-020-00702-4. Shaw AT, Solomon BJ, Chiari R, Riely GJ, Besse B, Soo RA, Kao S, Lin CC, Bauer TM, Clancy JS, Thurm H, Martini JF, Peltz G, Abbattista A, Li S, Ou SI. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2019 Dec;20(12):1691-1701. doi: 10.1016/S1470-2045(19)30655-2. Epub 2019 Oct 25. Solomon BJ, Besse B, Bauer TM, Felip E, Soo RA, Camidge DR, Chiari R, Bearz A, Lin CC, Gadgeel SM, Riely GJ, Tan EH, Seto T, James LP, Clancy JS, Abbattista A, Martini JF, Chen J, Peltz G, Thurm H, Ou SI, Shaw AT. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018 Dec;19(12):1654-1667. doi: 10.1016/S1470-2045(18)30649-1. Epub 2018 Nov 6. Erratum In: Lancet Oncol. 2019 Jan;20(1):e10. doi: 10.1016/S1470-2045(18)30927-6. Shaw AT, Felip E, Bauer TM, Besse B, Navarro A, Postel-Vinay S, Gainor JF, Johnson M, Dietrich J, James LP, Clancy JS, Chen J, Martini JF, Abbattista A, Solomon BJ. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017 Dec;18(12):1590-1599. doi: 10.1016/S1470-2045(17)30680-0. Epub 2017 Oct 23. Shaw AT, Friboulet L, Leshchiner I, Gainor JF, Bergqvist S, Brooun A, Burke BJ, Deng YL, Liu W, Dardaei L, Frias RL, Schultz KR, Logan J, James LP, Smeal T, Timofeevski S, Katayama R, Iafrate AJ, Le L, McTigue M, Getz G, Johnson TW, Engelman JA. Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F. N Engl J Med. 2016 Jan 7;374(1):54-61. doi: 10.1056/NEJMoa1508887. Epub 2015 Dec 23.
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Public notes
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Contacts
Principal investigator
Name
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Pfizer CT.gov Call Center
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Address
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Pfizer
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Phone
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Email
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Contact person for public queries
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
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When will data be available (start and end dates)?
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Available to whom?
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Available for what types of analyses?
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How or where can data be obtained?
IPD available at link: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests
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What supporting documents are/will be available?
No Supporting Document Provided
Type
Other Details
Attachment
Study protocol
https://cdn.clinicaltrials.gov/large-docs/65/NCT01970865/Prot_002.pdf
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/65/NCT01970865/SAP_003.pdf
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT01970865