A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations

• ClinicalTrials.gov Identifier: NCT01970865
• Recruitment Status: Completed
• First Posted: October 28, 2013
• Results First Posted: May 29, 2018
• Last Update Posted: June 7, 2023
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: October 16, 2013
• First Posted Date: October 28, 2013
• Results First Submitted Date: March 5, 2018
• Results First Posted Date: May 29, 2018
• Last Update Posted Date: June 7, 2023
• Actual Study Start Date: January 8, 2014
• Actual Primary Completion Date: March 15, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 8, 2018)

• Number of Participants With Cycle 1 Dose-Limiting Toxicities (DLTs) in Phase 1 [ Time Frame: Cycle 1 (21 days) ]
  DLT was defined as any of the 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 QTc prolongation, or asymptomatic grade >=3 prolongation that had been confirmed by repeat testing and re-evaluation by a qualified person, and 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 the 21 prescribed daily total doses due to toxicities attributable to study drug; failure to restart dosing after 21 days (1 cycle) delay due to toxicities attributable to study drug.
• Percentage of Participants With Overall and Intracranial Objective Response (Phase 2) [ Time Frame: 3 years ]
  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. Results presented here were based on independent central review.

Original Primary Outcome Measures (submitted: October 22, 2013)

• Number of patients with Dose-limiting toxicities (DLT) [ Time Frame: First Cycle ]
• Percentage of Patients With Overall and Intracranial Objective Response [ Time Frame: Every 6 weeks from the time of patient enrollment up to 4 years ]
  Percentage of patients with OR based assessment of intracranial and overall confirmed complete remission (CR) or confirmed partial remission (PR) according to a modified Response Evaluation Criteria in Solid Tumors (RECIST)v 1.1.

Current Secondary Outcome Measures (submitted: July 2, 2020)

• Percentage of Participants With Overall and Intracranial Objective Response (Phase 1) [ Time Frame: 3 years ]
  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. Results presented here were based on independent central review.
• Time to Tumor Response (TTR) and Intracranial TTR (Phase 1) [ Time Frame: 3 years ]
  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. Results presented here were based on independent central review.
• Duration of Response (DOR) and Intracranial DOR (Phase 1) [ Time Frame: 3 years ]
  Duration of Response (DOR) was defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurred first. DOR was only calculated for the subgroup of participants with a confirmed objective tumor response. Intracranial DOR was only calculated for participants with confirmed intracranial objective response. Results presented here were based on independent central review.
• Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 Weeks (Phase 1) [ Time Frame: 12 weeks ]
  Tumor response was evaluated according to RECIST version 1.1, and disease control was defined as confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD). Intracranial assessment was only performed for participants CNS metastases. Results presented here were based on independent central review.
• Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 1) [ Time Frame: 3 years ]
  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.
• Progression-Free Survival (PFS) (Phase 1) [ Time Frame: 3 years ]
  PFS was defined as the time from the first dose of study treatment to the first documentation of objective disease progression or to death on study due to any cause, whichever came first. Results presented here were based on independent central review.
• Overall Survival (OS) (Phase 1) [ Time Frame: 3 years ]
  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.
• Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Single Oral Doses (Phase 1) [ Time Frame: 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. ]
  Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data.
• Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Multiple Oral Doses (Phase 1) [ Time Frame: 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). ]
  Maximum Observed Plasma Concentration (Cmax) of PF-06463922 was observed directly from data.
• Time for Cmax (Tmax) of PF-06463922 Following Single Oral Doses (Phase 1) [ Time Frame: 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. ]
  Tmax of PF-06463922 was observed directly from data as time of first occurrence.
• Time for Cmax (Tmax) of PF-06463922 Following Multiple Oral Doses (Phase 1) [ Time Frame: 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). ]
  Tmax of PF-06463922 was observed directly from data as time of first occurrence.
• Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Single Oral Doses (Phase 1) [ Time Frame: 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. ]
  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.
• Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Multiple Oral Doses (Phase 1) [ Time Frame: 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) ]
  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.
• Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 Following Single Oral Doses (Phase 1) [ Time Frame: 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. ]
  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.
• Apparent Oral Clearance (CL/F) of PF-06463922 Following Single Oral Doses (Phase 1) [ Time Frame: 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. ]
  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.
• Apparent Oral Clearance (CL/F) of PF-06463922 Following Multiple Oral Doses (Phase 1) [ Time Frame: 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) ]
  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.
• Apparent Volume of Distribution (Vz/F) of PF-06463922 Following Single Oral Doses (Phase 1) [ Time Frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle1 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. ]
  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.
• Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 1) [ Time Frame: 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) ]
  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).
• Terminal Half-Life of PF-06463922 Following Single Oral Doses (Phase 1) [ Time Frame: 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. ]
  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.
• Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 1) [ Time Frame: 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) ]
  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.
• Renal Clearance (CLr) of PF-06463922 (Phase 1) [ Time Frame: 0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15 ]
  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).
• Percent of PF-06463922 Recovered Unchanged in Urine up to Dosing Interval (AEtau%) (Phase 1) [ Time Frame: 0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15 ]
  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.
• Maximum Observed Plasma Concentration (Cmax) of Midazolam (Phase 1) [ Time Frame: 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 ]
  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.
• Time for Cmax (Tmax) of Midazolam (Phase 1) [ Time Frame: 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 ]
  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.
• Area Under the Plasma Concentration-Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Midazolam (Phase 1) [ Time Frame: 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 ]
  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.
• Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Midazolam (Phase 1) [ Time Frame: 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 ]
  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.
• Apparent Oral Clearance (CL/F) of Midazolam (Phase 1) [ Time Frame: 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 ]
  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.
• Apparent Volume of Distribution (Vz/F) of Midazolam (Phase 1) [ Time Frame: 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 ]
  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.
• Terminal Half-Life of Midazolam (Phase 1) [ Time Frame: 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 ]
  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.
• Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 1) [ Time Frame: Screening ]
  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.
• Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 1) [ Time Frame: Screening ]
  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.
• Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 1) [ Time Frame: Baseline, Day 1 of Cycles 2-25, Day 1 of every other cycle after Cycle 25, end of treatment (up to 3 years) ]
  European Organisation for Research and Treatment of Cancer Core Quality of Life Questionaires (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 diarrhoea), 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.
• Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 1) [ Time Frame: Baseline, Day 1 of Cycles 2-25, Day 1 of every other cycle after Cycle 25, end of treatment (up to 3 years) ]
  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.
• Change From Baseline in Mini Mental State Examination (MMSE) Score (Phase 1) [ Time Frame: Baseline, Day 1 of each cycle, and end of treatment (up to 3 years) ]
  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. A score of 23 or lower is indicative of 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.
• Time to Tumor Response (TTR) and Intracranial TTR (Phase 2) [ Time Frame: 3 years ]
  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. Results presented here were based on independent central review.
• Duration of Response (DOR) and Intracranial DOR (Phase 2) [ Time Frame: 3 years ]
  Duration of Response (DOR) was defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurred first. DOR was only calculated for the subgroup of participants with a confirmed objective tumor response. Intracranial DOR was only calculated for participants with confirmed intracranial objective response. Results presented here were based on independent central review.
• Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 Weeks (Phase 2) [ Time Frame: 12 weeks ]
  Tumor response was evaluated according to RECIST version 1.1, and disease control was defined as confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD). Intracranial assessment was only performed for participants CNS metastases. Results presented here were based on independent central review.
• Time to Progression (TTP) on the Last Prior Therapy (Phase 2) [ Time Frame: 3 years ]
  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.
• Time to Tumor Progression （TTP) and Intracranial TTP (Phase 2) [ Time Frame: 3 years ]
  Time to progression (TTP) was defined as the time from the first dose of study treatment to the first documentation of objective disease progression. 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. Results presented here were based on independent central review.
• Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 2) [ Time Frame: 3 years ]
  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.
• Progression-Free Survival (PFS) (Phase 2) [ Time Frame: 3 years ]
  PFS was defined as the time from the first dose of study treatment to the first documentation of objective disease progression or to death on study due to any cause, whichever came first. Results presented here were based on independent central review.
• Overall Survival (Phase 2) [ Time Frame: 3 years ]
  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.
• Maximum Observed Plasma Concentration (Cmax) of PF-06463922 (Phase 2) [ Time Frame: 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 ]
  Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data.
• Time for Cmax (Tmax) of PF-06463922 (Phase 2) [ Time Frame: 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 ]
  Tmax of PF-06463922 was observed directly from data as time of first occurrence.
• Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 (Phase 2) [ Time Frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 ]
  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.
• Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 (Phase 2) [ Time Frame: 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 ]
  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.
• Apparent Oral Clearance (CL/F) of PF-06463922 (Phase 2) [ Time Frame: 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 ]
  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.
• Apparent Volume of Distribution (Vz/F) of PF-06463922 (Phase 2) [ Time Frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 ]
  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.
• Terminal Half-Life of PF-06463922 (Phase 2) [ Time Frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 ]
  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.
• Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 2) [ Time Frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 ]
  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).
• Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 2) [ Time Frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15 ]
  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.
• Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 2) [ Time Frame: Screening ]
  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.
• Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 2) [ Time Frame: Screening ]
  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.
• Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 2) [ Time Frame: 3 years ]
  European Organisation for Research and Treatment of Cancer Core Quality of Life Questionaires (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 diarrhoea), 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.
• Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 2) [ Time Frame: 3 years ]
  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.
• Number of Participants With Treatment-Emergent Adverse Events (Phase 1 and Phase 2) [ Time Frame: 3 years ]
  AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of the causal relationship to study treatment. Treatment-emergent AEs (TEAEs) were defined as AEs which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were defined as 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 the ability to conduction normal life functions). AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator. Severity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
• Number of Participants With Laboratory Abnormalities (Phase 1 and Phase 2) - Hematology [ Time Frame: 3 years ]
  Hematology evaluation included hemoglobin, platelets, white blood cell, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils and absolute basophils.
• Number of Participants With Laboratory Abnormalities (Phase 1 and Phase 2) - Chemistry [ Time Frame: 3 years ]
  Chemistry evaluation included alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, blood urea nitrogen (BUN) or urea, creatinine, uric acid, glucose (non-fasted), albumin, phosphorus or phosphate, serum total amylase and serum lipase.
• Number of Participants With Laboratory Abnormalities (Phase 1 and Phase 2) - Coagulation, Lipids and Urinalysis [ Time Frame: 3 years ]
  Coagulation evaluation included activated partial thromboplastin time, international normalized ratio (INR), and prothrombin time. Lipid evaluation included total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides. Urinalysis included urine protein and urine blood.
• Number of Participants With Vital Signs Data Meeting Pre-defined Criteria (Phase 1 and Phase 2) [ Time Frame: Baseline, Days 1, 8 and 15 of Cycle 1, Day 1 of Cycles 2-25 for Phase 1 (Cycles 2-38 for Phase 2), Day 1 of every other cycle thereafter, end of treatment (up to 3 years) ]
  Blood pressure (BP), including systolic BP (SBP) and diastolic BP (DBP), and pulse rate were recorded in sitting position. Body weight was also measured.
• Number of Participants With Maximum Decrease From Baseline Greater Than or Equal to 20 Percent in Left Ventricular Ejection Fraction (LVEF) (Phase 1 and Phase 2) [ Time Frame: Baseline, Day 1 of Cycles 2-3, Day 1 of every other cycle from Cycle 5 up to 18 months for Phase 1 (up to 30 months for Phase 2), every 4 cycles thereafter, and end of treatment (up to 3 years) ]
  Left Ventricular Ejection Fraction (LVEF) was determined by electrocardiogram (ECG) measurement. Baseline was defined as the measurement prior to the first dose of study treatment.
• Number of Participants With Absolute Values and Change From Baseline in QTcF Meeting Pre-defined Criteria (Phase 1 and Phase 2) [ Time Frame: Phase 1: baseline, Days 1, 8 and 15 of Cycle 1, Day 1 of Cycles 2-25, end of treatment (up to 3 years); Phase 2: baseline, Days 1, 8 and 15 of Cycle 1, Day 1 of Cycles 2-5, end of treatment (up to 3 years) ]
  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.
• Number of Participants With Suicidal Ideation and Suicidal Behavior (Phase 2) [ Time Frame: 3 years ]
  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.
• Change From Baseline in Total Scores for Beck Depression Inventory (BDI)-II (Mood Assessment) (Phase 2) [ Time Frame: Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years) ]
  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). 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.
• Change From Baseline in Total Scores for Detection Test (Cognitive Function Assessment) (Phase 2) [ Time Frame: Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years) ]
  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.
• Change From Baseline in Total Scores for Identification Test (Cognitive Function Assessment) (Phase 2) [ Time Frame: Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years) ]
  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.
• Change From Baseline in Total Scores for One Back Test (Cognitive Function Assessment) (Phase 2) [ Time Frame: Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years) ]
  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.
• Change From Baseline in Total Scores for International Shopping List Test (Cognitive Function Assessment) (Phase 2) [ Time Frame: Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years) ]
  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.
• Change From Baseline in Total Scores for International Shopping List Test-Delayed Recall (Cognitive Function Assessment) (Phase 2) [ Time Frame: Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years) ]
  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.

Original Secondary Outcome Measures (submitted: October 22, 2013)

• Maximum tolerated dose and recommended phase 2 dose [ Time Frame: At end of cycle 1 ]
  Recommended phase 2 dose will be determined after the last patient has been treated for at least one cycle in the Phase 1
• Change from Baseline in Mini Mental State Examination (MMSE) across treatment cycles [ Time Frame: Every 3 weeks from the time of enrollment up to 4 years ]
  MMSE measured general cognitive functioning: orientation, memory, attention, calculation, language, visuospatial functions. Total score derived from sub-scores; total ranges from 0 to 30, higher score indicates better cognitive state. Change: across treatment cycles
• Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) [ Time Frame: 7 days prior to first dose of treatment ]
  Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)
• Volume of Distribution at Steady State (Vss) [ Time Frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose of treatment ]
  Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.
• Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
• Maximum Observed Plasma Concentration (Cmax) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
• Area Under the Curve from Time Zero to end of dosing interval (AUCtau) [ Time Frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose of treatment ]
• Apparent Volume of Distribution (Vz/F) [ Time Frame: 7 days prior to the first dose of treatment ]
  Volume of distribution is 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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
• Plasma Decay Half-Life (t1/2) [ Time Frame: 7 days prior to the first dose of treatment ]
  Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
• Urine clearance of drug (Clr) for subjects in food effect and Midazolam substudy [ Time Frame: Pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
• Urine Ae% for subjects in food effect and Midazolam substudy [ Time Frame: Pre Cycle 1 Day 15 dose of treatment ]
• Maximum Observed Plasma Concentration (Cmax) for subjects in Midazolam substudy [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
• Time to Reach Maximum Observed Plasma Concentration (Tmax) for subjects in Midazolam substudy [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
• Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for subjects in Midazolam substudy [ Time Frame: 7 days prior to first dose and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
  Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) after administration of MDZ
• Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 8)] [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
  AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8).
• Plasma Decay Half-Life (t1/2) for subjects in Midazolam substudy [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
  Plasma decay half-life is the time measured for the plasma concentration to decrease by one half after administration of MDZ
• Apparent Oral Clearance (CL/F) for subjects in Midazolam substudy [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
  Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood after administration of MDZ
• Apparent Oral Clearance (CL/F) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
  Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
• Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) [ Time Frame: 7 days prior to the first dose of treatment ]
  Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)
• Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 8)] [ Time Frame: 7 days prior to the first dose of treamtent ]
  AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8).
• Drug concentration in cerebral spinal fluid (CSF) [ Time Frame: Optional sample, up to 4 years, if patient undergoes a lumbar puncture ]
  Should CSF specimen be taken for suspected tumor infiltration this sample may be used for drug concentration levels
• Selective molecular profiling of circulating nucleic acids (CNA) [ Time Frame: Within 28 days of first dose of treatment and at 28 days after the last dose of treatment ]
  Selective molecular profiling of circulating nucleic acids (CNA) at the end of treatment visit defined as 28 days after the last treatment administration
• Selective molecular profiling of tumor tissue [ Time Frame: Within 28 days prior to first dose of treatment ]
  Blood specimen optimized for plasma preparation for nucleic acid analysis will be collected at screening and at end of treatment
• Circulating tumor cells (CTC) enumeration and molecular characterization [ Time Frame: Prior to treatment start on Cycle 1 Day 1, at the end of Cycle 2 and at 28 days after the last dose of treatment ]
• QTc interval [ Time Frame: Within 28 days prior to first dose of treatment, 7 days prior to the first dose of treatment and Day 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-5 and 28 days after the last dose of treatment ]
  ECGs performed to assess QTc (msec) at baseline and on study treatment and at the end of treatment visit defined as 28 days after the last treatment administration
• Patient reported Outcomes [ Time Frame: Day 1 of every cycle, pre dose, up to 4 years and at 28 days after the last dose of treatment ]
  To assess impact of disease /treatment related symptoms of lung cancer and quality of life at D1 of every cycle and at the end of treatment visit defined as 28 days after the last treatment administration
• Duration of Response (DR) [ Time Frame: Every 6 weeks from the time of enrollment up to 4 years ]
  Time in months from the first documentation of objective tumor response to objective tumor progression or death due to any cancer. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1) divided by 7. DR was calculated for the subgroup of participants with a confirmed objective tumor response.
• Progression-Free Survival (PFS) [ Time Frame: Every 6 weeks from the time of enrollment to the first documented progression or date of death from any cause, assessed up to 4 years ]
  The period from study entry until disease progression, death or date of last contact.
• Overall Survival (OS) [ Time Frame: From the time of enrollment until the date of death from any causes, up to 4 years ]
  Overall survival was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact.
• Disease Control Rate (DCR) [ Time Frame: Every 6 weeks from the time of enrollment up to 4 years ]
  DCR is defined as the percent of patients with a confirmed complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1, at 6 weeks.
• Disease Control Rate (DCR) [ Time Frame: Every 12 weeks from the time of enrollment up to 4 years ]
  DCR is defined as the percent of patients with a confirmed complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1, at 12 weeks
• Left Ventricular Ejection Fraction (LVEF) [ Time Frame: Within 28 days prior to the first dose of treatment, pre dose on Day 1 of Cycle 2, pre dose on Day 1 of Cycle 3, pre dose on Day 1 of Cycle 5 and pre dose on Day 1 of every 2 Cycles thereafter; and at 28 days after the last dose of treatment ]
  Left Ventricular Ejection Fraction percentage change by echocardiogram or by multigated acquisition gated scan (MUGA)
• Apparent Volume of Distribution (Vz/F) for subjects in Midazolam substudy [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
  Volume of distribution is 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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations
• Official 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
• 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 .
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: ALK-positive Non Small Cell Lung Cancer (NSCLC) and ROS1-positive NSCLC

Intervention

• Drug: 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
• Drug: Crizotinib
  Oral, starting dose of 250 mg BID continuous daily dosing every 21 days
  Other Name: Xalkori

Study Arms

• Experimental: PF-06463922
  Intervention: Drug: PF-06463922
• Crizotinib
  ALK+ NSCLC patients who are treatment naïve may be eligible to receive crizotinib following PF-06463922 as a substudy to the main study.
  Intervention: Drug: Crizotinib

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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 29, 2018): 334
• Original Estimated Enrollment (submitted: October 22, 2013): 200
• Actual Study Completion Date: May 24, 2023
• Actual Primary Completion Date: March 15, 2017 (Final data collection date for primary outcome measure)

Eligibility 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 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, France, Germany, Hong Kong, Italy, Japan, Korea, Republic of, Singapore, Spain, Switzerland, Taiwan, United States

Administrative Information

• NCT Number: NCT01970865
• Other Study ID Numbers: B7461001; 2013-002620-17 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: 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.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Current Responsible Party: Pfizer
• Original Responsible Party: Same as current
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: June 2023