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

简要总结

主要结局

次要结局

• Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Single Oral Doses (Phase 1)(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.)
• Time for Cmax (Tmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)(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).)
• Renal Clearance (CLr) of PF-06463922 (Phase 1)(0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15)
• Time for Cmax (Tmax) of Midazolam (Phase 1)(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)
• Time to Tumor Response (TTR) and Intracranial TTR (Phase 1)(From start of study treatment to the first documentation of objective tumor response (CR or PR) (maximum of 8 years approximately))
• Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 and 24 Weeks (Phase 1)(12 and 24 weeks)
• Time for Cmax (Tmax) of PF-06463922 Following Single Oral Doses (Phase 1)(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.)
• Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Single Oral Doses (Phase 1)(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.)
• Apparent Oral Clearance (CL/F) of PF-06463922 Following Multiple Oral Doses (Phase 1)(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))
• Percentage of Participants With Overall and Intracranial Objective Response (Phase 1)(From start of study treatment until CR or PR (maximum of 8 years approximately))
• Number of Participants With Duration of Response (DOR) and Intracranial DOR (Phase 1)(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))
• Progression-Free Survival (PFS) (Phase 1)(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))
• Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Multiple Oral Doses (Phase 1)(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))
• Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 1)(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))
• Terminal Half-Life of PF-06463922 Following Single Oral Doses (Phase 1)(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 Following Multiple Oral Doses (Phase 1)(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).)
• Apparent Oral Clearance (CL/F) of PF-06463922 Following Single Oral Doses (Phase 1)(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.)
• Apparent Volume of Distribution (Vz/F) of PF-06463922 Following Single Oral Doses (Phase 1)(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.)
• Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 1)(3 years)
• Overall Survival (OS) (Phase 1)(3 years)
• Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 Following Single Oral Doses (Phase 1)(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.)
• Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 1)(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))
• Apparent Volume of Distribution (Vz/F) of Midazolam (Phase 1)(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 Half-Life of Midazolam (Phase 1)(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)
• Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 1)(Screening (up to 28 days))
• Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 1)(Screening (up to 28 days))
• Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 2)(From first dose of study treatment until first event of CNS progression (maximum of 7.5 years for Phase 2))
• Apparent Volume of Distribution (Vz/F) of PF-06463922 (Phase 2)(Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7)
• Percent of PF-06463922 Recovered Unchanged in Urine up to Dosing Interval (AEtau%) (Phase 1)(0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15)
• Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Midazolam (Phase 1)(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)
• Apparent Oral Clearance (CL/F) of Midazolam (Phase 1)(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)
• Change From Baseline in Mini Mental State Examination (MMSE) Score (Phase 1)(Baseline, Day 1 of Cycle 1-52, and end of treatment (up to 3 years))
• Duration of Response (DOR) and Intracranial DOR (Phase 2 and DDI Substudy)(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))
• Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 (Phase 2)(Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7)
• Maximum Observed Plasma Concentration (Cmax) of Midazolam (Phase 1)(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)
• Time to Tumor Response (TTR) and Intracranial TTR (Phase 2 and DDI Sub-study)(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))
• Time to Progression on the Last Prior Therapy (Phase 2)(From first dose of study treatment to the date of progression (maximum of 7.5 years for Phase 2))
• Time to Tumor Progression (TTP) and Intracranial TTP (Phase 2 and DDI Substudy)(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))
• Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 (Phase 2)(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)
• Apparent Oral Clearance (CL/F) of PF-06463922 (Phase 2)(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)
• Number of Participants With Laboratory Abnormalities (Phase 1, Phase 2 and DDI Sub-study) - Coagulation, Lipids and Urinalysis(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))
• Area Under the Plasma Concentration-Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Midazolam (Phase 1)(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)
• Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 1)(From start of study treatment until end of treatment (maximum of 8 years approximately))
• Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 1)(From start of study treatment until end of treatment (maximum of 8 years approximately))
• Percentage of Participants Achieving Disease Control and Intracranial Disease Control at Week 12 and 24 (Phase 2 and DDI Substudy)(Weeks 12 and 24)
• Time for Cmax (Tmax) of PF-06463922 (Phase 2)(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)
• Terminal Half-Life of PF-06463922 (Phase 2)(Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7)
• Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 2)(Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15)
• Progression-Free Survival (PFS) (Phase 2 and DDI Substudy)(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))
• Overall Survival (Phase 2 and DDI Substudy)(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))
• Maximum Observed Plasma Concentration (Cmax) of PF-06463922 (Phase 2)(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)
• Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 2)(Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15)
• Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 2)(Screening (up to 28 days))
• Number of Participants With Suicidal Ideation and Suicidal Behavior (Phase 2)(From first dose of study treatment to end of treatment (maximum of 7.5 years for Phase 2))
• Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 2 and DDI Sub-study)(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))
• Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 2 and DDI Sub-study)(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))
• Number of Participants With Laboratory Abnormalities (Phase 1, Phase 2 and DDI Sub-study) - Hematology(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))
• Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 2)(Screening (up to 28 days))
• Number of Participants With Treatment-Emergent Adverse Events (Phase 1, Phase 2 and DDI Sub-study)(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))
• Number of Participants With Absolute Values and Change From Baseline in QTcF Meeting Pre-defined Criteria (Phase 1, Phase 2 and DDI Sub-study)(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))
• Number of Participants With Laboratory Abnormalities (Phase 1, Phase 2 and DDI Sub-study) - Chemistry(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))
• Change From Baseline in Total Scores for Identification Test (Cognitive Function Assessment) (Phase 2)(Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years))
• Change From Baseline in Total Scores for One Back Test (Cognitive Function Assessment) (Phase 2)(Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years))
• Number of Participants With Vital Signs Data Meeting Pre-defined Criteria (Phase 1, Phase 2 and DDI Sub-study)(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))
• 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)(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))
• Change From Baseline in Total Scores for Beck Depression Inventory (BDI)-II (Mood Assessment) (Phase 2)(Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years))
• Change From Baseline in Total Scores for International Shopping List Test (Cognitive Function Assessment) (Phase 2)(Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years))
• Change From Baseline in Total Scores for Detection Test (Cognitive Function Assessment) (Phase 2)(Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years))
• Number of Participants With Absolute Values and Change From Baseline in PR Interval Meeting Pre-defined Criteria (Phase 2 and DDI Substudy)(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))
• Change From Baseline in Total Scores for International Shopping List Test-Delayed Recall (Cognitive Function Assessment) (Phase 2)(Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years))