Hepatic Impairment Study For Crizotinib In Advanced Cancer Patients

Area under the plasma concentration-time curve from time zero to the quantifiable concentration at the end of dosing interval (tau hours post-dose, where tau was 12 hours for twice daily dosing and 24 hours for once daily dosing) of Cycle 2 Day 1.

Rac was defined as the ratio of AUCtau of Cycle 2 Day 1 to AUCtau of Cycle 1 Day 1, where AUCtau was area under the plasma concentration-time curve from time zero to the quantifiable concentration at the end of dosing interval (tau hours post-dose, where tau was 12 hours for twice daily dosing and 24 hours for once daily dosing).

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent oral clearance was obtained by dividing study drug dose with AUCtau, where AUCtau was area under the plasma concentration-time curve from time zero to the quantifiable concentration at the end of dosing interval (tau hours post-dose, where tau was 12 hours for twice daily dosing and 24 hours for once daily dosing) of Cycle 2 Day 1.

Fraction of unbound Crizotinib concentration in plasma was defined as the ratio of unbound Crizotinib concentration to the total Crizotinib concentration.

Unbound area under the plasma concentration-time curve from time zero to the last quantifiable plasma concentration post-dose of Cycle 2 day 1.

Unbound area under the plasma concentration-time curve from time zero to the quantifiable concentration at the end of dosing interval (tau hours post-dose, where tau was 12 hours for twice daily dosing and 24 hours for once daily dosing) of Cycle 2 Day 1.

Area under the plasma concentration-time curve from time zero to the quantifiable concentration at the end of dosing interval (tau hours postdose, where tau was 12 hours for twice daily dosing and 24 hours for once daily dosing) of Cycle 2 Day 1. AUCtau of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

AUClast of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

Cmax of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

Cmax of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

Tmax of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

Tmax of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

Metabolite ratio for AUCtau was defined as the ratio of AUCtau of metabolite (PF-06260182) to AUCtau of parent drug (Crizotinib), where AUCtau was the area under the plasma concentration-time curve from time zero to the quantifiable concentration at the end of dosing interval (tau was 12 hours for twice daily dosing and 24 hours for once daily dosing) of Cycle 2 Day 1.

Metabolite ratio for AUClast was defined as the ratio of AUClast of metabolite (PF-06260182) to AUClast of parent drug (Crizotinib), where AUClast was area under the plasma concentration-time curve from time zero to the last quantifiable plasma concentration post-dose of Cycle 1 Day 1.

Metabolite ratio for Cmax was defined as the ratio of Cmax of metabolite (PF-06260182) to Cmax of parent drug (Crizotinib), where Cmax was maximum observed plasma concentration post-dose of Cycle 1 Day 1.

Metabolite ratio for Cmax was defined as the ratio of Cmax of metabolite (PF-06260182) to Cmax of parent drug (Crizotinib), where Cmax was maximum observed plasma concentration post-dose of Cycle 2 Day 1.

Fraction of unbound PF-06260182 (a metabolite of Crizotinib) in plasma was defined as the ratio of unbound PF-06260182 concentration in plasma to the total PF-06260182 concentration.

Unbound AUClast of PF-06260182 (a metabolite of Crizotinib) is reported in this outcome measure.

Unbound area under the plasma concentration-time curve from time zero to the quantifiable concentration at the end of dosing interval (tau hours post-dose, where tau was 12 hours for twice daily dosing and 24 hours for once daily dosing) of Cycle 2 Day 1. Unbound AUCtau of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

Unbound Cmax of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

AUCdaily of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

Unbound AUCdaily of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure, where AUCdaily was area under the plasma concentration time curve as daily exposure post-dose.

An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 4 years that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to severity grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events [CTCAE] Version 4.0. Grade 1 =mild; Grade 2 =moderate; Grade 3 =severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4 =life-threatening or disabling, urgent intervention indicated; Grade 5 =death. Treatment-emergent events were events between first dose of study drug and up to 4 years that were absent before treatment that worsened relative to pretreatment state. If the same participant in a given treatment had more than 1 adverse event, only the maximum CTCAE was reported.

Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both serious and non-serious adverse events.

Anemia(grade[g]1:Less than[<] Lower limit of normal[LLN] to 10gram per[/] deciliter[g/dL],g2:<10 to 8g/dL,g3:<8g/dL,g4:lifethreatening);platelet (g1:<LLN to 75*10^3/millimeter[mm]^3,g2:<75*10^3/mm^3 to 50*10^3/mm^3,g3:<50*10^3/mm^3 to 25*10^3/mm^3,g4:<25*10^3/mm^3);lymphopenia(g1:<LLN to 8*10^2/mm^3,g2:<8*10^2 to 5*10^2/mm^3,g3:<5*10^2 to 2*10^2/mm^3,g4:<2*10^2/mm^3);neutrophil (Absolute)(g1:<LLN to 15*10^2/mm^3,g2:<15*10^2 to 10*10^2/mm^3,g3:<10*10^2 to 5*10^2/mm^3,g4:<5*10^2/mm^3);white blood cell count(g1:<LLN to 3*10^3/mm^3,g2:<3*10^3 to 2*10^3/mm^3,g3:<2*10^3 to 1*10^3/mm^3,g4:<1*10^3/mm^3);hemoglobin(g1:increase in hemoglobin level>0 to 2 g/dL above ULN or above baseline if baseline is above ULN,g2:increase in hemoglobin level>2 to 4g/dL above ULN or above baseline if baseline is above ULN,g3:increase in hemoglobin level>4 g/dL above ULN or above baseline if baseline is above ULN). Only categories with atleast 1 participant with abnormality are reported in this outcome measure.

ALT/AST(grade[g]1:>ULN-3*ULN,g2:>3-5*ULN,g3:>5-20*ULN,g4:>20*ULN);AP(g1:>ULN-2.5*ULN,g2:>2.5-5*ULN,g3:>5-20*ULN,g4:>20*ULN);CR(g1:>ULN-1.5*ULN,g2:>1.5-3*ULN,g3:>3-6*ULN,g4:>6*ULN);hyperglycemia(g1:>ULN-160mg/dL,g2:>160-250mg/dL,g3:>250-500mg/dL,g4:>500mg/dL);bilirubin(total)(g1:>ULN-1.5*ULN,g2:>1.5-3*ULN,g3:>3-10*ULN,g4:>10*ULN);hypoglycemia(g1:<LLN-55mg/dL,g2:<55-40mg/dL,g3:<40-30mg/dL,g4:<30mg/dL);hyperkalemia(g1:>ULN-5.5mmol/L,g2:>5.5-6mmol/L,g3:>6-7mmol/L,g4:>7mmol/L);hypokalemia(g1:<LLN-3mmol/L,g2:<LLN-3mmol/L,g3:<3-2.5mmol/L,g4:<2.5mmol/L);hypermagnesemia(g1:>ULN-3mg/dL,g3:>3-8mg/dL,g4:>8mg/dL);hypocalcemia(g1:<LLN-8mg/dL,g2:<8-7mg/dL,g3:<7-6mg/dL,g4:<6mg/dL);hypomagnesemia(g1:<LLN-1.2mg/dL,g2:<1.2-0.9mg/dL,g3:<0.9-0.7mg/dL,g4:<0.7mg/dL);hyponatremia(g1:<LLN-130mmol/L,g3:<130-120mmol/L,g4:<120mmol/L);hypoalbuminemia(g1:<LLN-3g/dL,g2:<3-2g/dL,g3:<2g/dL,g4:lifethreatening);hypophosphatemia(g1:<LLN-2.5mg/dL,g2:<2.5-2mg/dL,g3:<2-1mg/dL,g4:<1mg/dL).Participant>=1abnormality given.

Criteria for abnormal value of ECG parameters: maximum increase from baseline (IFB) in QT interval using Fridericia's correction (QTcF)/QT interval using Bazett's correction (QTcB) range from less than (<)30 millisecond (msec), 30 to <60, greater than or equal to (>=)60 msec; maximum post-dose QTcF/QTcB ranges from <450 msec, 450 to <480 msec, 480 to <500, and >=500 msec; PR interval: >=50 percent (%) increase when baseline <200 msec; or increase >=25% when baseline less than or equal to (<=)200 msec; QRS interval: >=50% increase when baseline <100 msec; >=25% increase when baseline >=100 msec. Only categories which included atleast 1 participant with abnormality are reported in this outcome measure.

Fundoscopy examination included an examination of the vitreous body, retina macula, retina non-macula, optic nerve head, optic disc notching and fundus using the category of the examination status (normal, mild, moderate, or severe). In this outcome measure, number of participants with abnormal fundoscopy values identified by investigator were reported.

ORR was defined as percentage of participants with confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumors (RECIST) version 1.1. In case of target lesions CR was defined as the disappearance of all target lesions and in case nodal disease included in the sum of target lesions. The nodes decreased to normal size (<10 mm). In case of non-target lesions disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Confirmed responses were those who persisted on repeat imaging study at least 4 weeks after the initial documentation of response.

DR was defined as the time from date of first documentation of CR or PR to first documentation of objective tumor progression or death due to any cause, whichever occurred first. In case of target lesions CR was defined as the disappearance of all target lesions and in case nodal disease included in the sum of target lesions. The nodes decreased to normal size (<10 mm). In case of non-target lesions disappearance of all non-target lesions and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Objective tumor progression as per RECIST version 1.1 was defined as >=20% increase in sum of diameters of target lesions taking as a reference smallest sum of diameters recorded since treatment started, or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. DR was estimated using Kaplan-Meier method.