Hepatic Impairment Study For Crizotinib In Advanced Cance... | NCT01576406

Label	Type	Intervention Names
A1: normal hepatic function	Experimental	Drug: crizotinib
A2: normal hepatic function	Experimental	Drug: crizotinib
B: mild hepatic impairment	Experimental	Drug: crizotinib
C: moderate hepatic impairment	Experimental	Drug: crizotinib
D: severe hepatic impairment	Experimental	Drug: crizotinib

Name	Type	Description	Arm Group Labels	Other Names
crizotinib	Drug	crizotinib 250 mg twice a day	A1: normal hepatic function

Measure	Description	Time Frame
Area Under Plasma Concentration Time Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib: 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 post-dose, where tau was 12 hours for twice daily dosing and 24 hours for once daily dosing) of Cycle 2 Day 1.	Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose
Maximum Observed Plasma Concentration (Cmax) of Crizotinib: Cycle 2 Day 1		Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

Measure	Description	Time Frame
Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Plasma Concentration (AUClast) of Crizotinib: Cycle 1 Day 1		Cycle 1 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose
Maximum Observed Plasma Concentration (Cmax) of Crizotinib: Cycle 1 Day 1

Measure	Description	Time Frame
Area Under the Plasma Concentration Time Curve as Daily Exposure (AUCdaily) of Crizotinib: Cycle 2 Day 1		Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose
Unbound Area Under the Plasma Concentration Time Curve as Daily Exposure (AUCdaily) of Crizotinib: Cycle 2 Day 1

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Histologically or cytologically confirmed solid malignancy or lymphoma that is metastatic or unresectable, and for which standard curative or palliative measures do not exist, or are no longer effective. In case of hepatocellular carcinoma, the diagnosis should be based on at least one of the following:
1. The presence of at least one lesion, measuring ≥ 2 cm, with characteristic arterial enhancement and venous washout in the setting of liver cirrhosis and/or hepatitis B or C infection.
2. The presence of liver lesion(s) (as defined in a.) with AFP ≥ 400 ng/mL.
3. Tissue confirmation.
Biliary obstruction for whom a biliary drain or stent has been placed are eligible, provided that the drain or stent have been in place for at least 10 days prior to the first dose of crizotinib, and the liver function has stabilized as defined by 2 measurements at least 5 days apart that put the patient in the same hepatic dysfunction stratum as defined in Section 3.
Presence of gliomas and brain metastases only if neurologically stable and treated without ongoing requirement for corticosteroids for at least 2 weeks.
Any prior systemic therapy (e.g., chemotherapy, molecularly targeted agent, immunotherapy, etc.) or major surgery must have been completed at least 30 days (or as determined by the local requirement, whichever is longer), or at least 5 half lives for drugs with half lives of 6 days or longer prior to initiation of crizotinib treatment. Any prior radiation (except palliative) or minor surgeries/procedures must have been completed at least 2 weeks prior to the initiation of crizotinib treatment. Palliative radiation (≤ 10 fractions) must have been completed 48 hours prior to the initiation of crizotinib treatment. Any acute toxicity must have recovered to Grade ≤1 (except alopecia).
Eastern Cooperative Oncology Group [ECOG] performance status 0-2.
Adequate organ function for patients receiving crizotinib therapy as defined by the following criteria:

Bone marrow function

Absolute neutrophil count (ANC) ≥ 750/uL
Platelets ≥ 30,000/uL
Hemoglobin ≥ 8.0 g/dL (≥ 7.0 g/dL for hematologic malignancy) Renal function
Creatinine ≤ 1.5 x ULN or CrCl > 60 mL/min/1.73 m2 for patients with serum creatinine levels above institutional 1.5 x ULN
- Male and female patients of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.

Exclusion Criteria:

Untreated esophageal varices observed on EGD or imaging study; however, patients with known portal hypertension and evidence of varices on EGD or imaging study who have undergone appropriate therapy as indicated within the last 6 months (if applicable) are eligible for enrollment.
Uncontrolled ascites that is not stable with medical management (i.e., on diuretics and salt restriction) as defined by requiring therapeutic paracentesis more than once every 4 weeks.
Episodes of hepatic encephalopathy within the last 4 weeks. Patients with prior episodes of hepatic encephalopathy who are clinically stable on lactulose, neomycin, and/or xifaxan therapy are allowed.
Prior therapy with crizotinib.
Spinal cord compression.
Carcinomatous meningitis or leptomeningeal disease
Any of the following within the 6 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, or cerebrovascular accident including transient ischemic attack.
Symptomatic congestive heart failure.
Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥ 2, uncontrolled atrial fibrillation of any grade, or an average of triplicate QTc interval >470 msec.
History of extensive disseminated/bilateral or known presence of interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis, but not history of prior radiation pneumonitis.
Active hemolysis or evidence of biliary sepsis.
Pregnant females; breastfeeding females; males and females of childbearing potential; males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 28 days after last dose of investigational product; males and females of childbearing potential not using two (2) methods of highly effective contraception or not agreeing to continue two (2) methods of highly effective contraception for at least 28 days after last dose of investigational product.
Use of drugs or foods that are known strong CYP3A4 inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit or grapefruit juice.
Use of drugs that are known strong CYP3A4 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.
Use of drugs that are CYP3A4 substrates with narrow therapeutic indices, including but not limited to dihydroergotamine, ergotamine, and pimozide.
Other severe acute or chronic medical (may include severe gastrointestinal conditions such as chronic diarrhea or ulcer disease) or psychiatric conditions, or laboratory abnormalities that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of the study results and, in the judgment of the investigator, would make the patient inappropriate for study entry.
Patients who had prior major gastrointestinal surgery removing part of gastrointestinal tract and/or gall bladder.

Name	Affiliation	Role
Pfizer CT.gov Call Center	Pfizer	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Keck Hospital of USC		Los Angeles	California	90033	United States
LAC&USC Medical Center

PubMed Identifier	Type	Citation	Retractions
29468455	Derived	El-Khoueiry AB, Sarantopoulos J, O'Bryant CL, Ciombor KK, Xu H, O'Gorman M, Chakrabarti J, Usari T, El-Rayes BF. Evaluation of hepatic impairment on pharmacokinetics and safety of crizotinib in patients with advanced cancer. Cancer Chemother Pharmacol. 2018 Apr;81(4):659-670. doi: 10.1007/s00280-018-3517-8. Epub 2018 Feb 21.

Label	URL
To obtain contact information for a study center near you, click here.	View source

ID	Title	Description
FG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Area Under Plasma Concentration Time Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib: 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 post-dose, where tau was 12 hours for twice daily dosing and 24 hours for once daily dosing) of Cycle 2 Day 1.

PK evaluable set:Cycle 2 Day 1(C2D1)full PK collected;no dose change;atleast 14 days of constant dosing before C2D1 or>80% of Crizotinib during 14 days prior to C2D1;not vomited Crizotinib on same day of PK collection on C2D1;no prior major GI surgery;11 days of constant dosing instead of 14 days before C2D1 but met all other PK evaluable criteria.

Posted

Geometric Mean

Geometric Coefficient of Variation

nanogram*hour per milliliter (ng*hr/mL)

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.
OG002	Mild Hepatic Impairment: Crizotinib 250 mg Twice Daily	Participants with mild hepatic impairment received Crizotinib 250 mg capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Mild hepatic impairment was defined as total bilirubin level <=ULN and AST levels greater than (>) ULN or total bilirubin level > 1.0 to 1.5*ULN.
OG003	Moderate Hepatic Impairment: Crizotinib 250 mg Once Daily	Participants with moderate hepatic impairment received Crizotinib 250 mg capsules, orally, once daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Moderate hepatic impairment was defined as total bilirubin level >1.5 to 3*ULN
OG004	Moderate Hepatic Impairment Crizotinib 200 mg Twice Daily	Participants with moderate hepatic impairment received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Moderate hepatic impairment was defined as total bilirubin level >1.5 to 3*ULN
OG005	Severe Hepatic Impairment Crizotinib 250 mg Once Daily	Participants with severe hepatic impairment received Crizotinib 250 mg capsules, orally, once daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Severe hepatic Impairment was defined as total bilirubin level >3*ULN.

Units	Counts
Participants	OG0008 OG0019 OG00210 OG003

Title

Denominators

Categories

Title	Measurements
	OG0003552± 48 OG0012712± 66 OG0023238± 73 OG003

Primary

Maximum Observed Plasma Concentration (Cmax) of Crizotinib: Cycle 2 Day 1

PK evaluable set: C2D1 full PK collected;no dose change;atleast 14 days of constant dosing before C2D1 or>80% of Crizotinib during 14 days prior to C2D1;not vomited Crizotinib on same day of PK collection on C2D1;no prior major GI surgery;11 days of constant dosing instead of 14 days before C2D1 but met all other PK evaluable criteria.

Posted

Geometric Mean

Geometric Coefficient of Variation

nanogram per milliliter (ng/mL)

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Plasma Concentration (AUClast) of Crizotinib: Cycle 1 Day 1

PK evaluable set. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*hr/mL

Cycle 1 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Maximum Observed Plasma Concentration (Cmax) of Crizotinib: Cycle 1 Day 1

PK evaluable set. Here, 'N' signifies those participants who were evaluable for this measure.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Cycle 1 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.
OG002

Secondary

Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib: Cycle 1 Day 1

PK evaluable set. Here, 'N' signifies those participants who were evaluable for this measure.

Posted

Median

Full Range

hour

Cycle 1 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.
OG002

Secondary

Minimum Observed Plasma Concentration (Cmin) of Crizotinib: Cycle 2 Day 1

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Plasma Concentration (AUClast) of Crizotinib: Cycle 2 Day 1

Data for this outcome measure was not estimated, since few secondary PK parameters listed in the protocol and/or SAP were not estimated, due to change in planned analysis. However, it did not affect the interpretation of the final PK data.

Posted

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Plasma Accumulation Ratio (Rac) of Crizotinib

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).

Posted

Cycle 1 Day 1 and Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Apparent Oral Clearance (CL/F) of Crizotinib: Cycle 2 Day 1

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

Liter/hour

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001

Secondary

Fraction of Unbound Crizotinib in Plasma: 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.

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Unbound Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Plasma Concentration (AUClast) of Crizotinib: Cycle 2 Day 1

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

Posted

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Unbound Area Under Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib: 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.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*hr/mL

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily

Secondary

Unbound Maximum Observed Plasma Concentration (Cmax) of Crizotinib: Cycle 2 Day 1

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Area Under Plasma Concentration Time Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06260182: 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.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*hr/mL

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily

Secondary

Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Plasma Concentration (AUClast) of PF-06260182: Cycle 1 Day 1

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

PK evaluable set. Here, 'N' signifies those participants who were evaluable for this measure.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*hr/mL

Cycle 1 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Maximum Observed Plasma Concentration (Cmax) of PF-06260182: Cycle 1 Day 1

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

PK evaluable set. Here, 'N' signifies those participants who were evaluable for this measure.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Cycle 1 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Maximum Observed Plasma Concentration (Cmax) of PF-06260182: Cycle 2 Day 1

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

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06260182: Cycle 1 Day 1

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

PK evaluable set. Here, 'N' signifies those participants who were evaluable for this measure.

Posted

Median

Full Range

hour

Cycle 1 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06260182: Cycle 2 Day 1

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

Posted

Median

Full Range

hour

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Metabolite Ratio for Area Under Plasma Concentration Time Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06260182: Cycle 2 Day 1

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001

Secondary

Metabolite Ratio for Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Plasma Concentration (AUClast) of PF-06260182: Cycle 1 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.

PK evaluable set. Here, 'N' signifies those participants who were evaluable for this measure.

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Cycle 1 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Metabolite Ratio for Maximum Observed Plasma Concentration (Cmax) of PF-06260182: 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.

PK evaluable set. Here, 'N' signifies those participants who were evaluable for this measure.

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Cycle 1 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Metabolite Ratio for Maximum Observed Plasma Concentration (Cmax) of PF-06260182: Cycle 2 Day 1

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Fraction of Unbound PF-06260182 in Plasma: 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.

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Unbound Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Plasma Concentration (AUClast) of PF-06260182: Cycle 2 Day 1

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

Posted

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Secondary

Unbound Area Under Plasma Concentration Time Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06260182: Cycle 2 Day 1

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*hr/mL

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily

Secondary

Unbound Maximum Observed Plasma Concentration (Cmax) of PF-06260182: Cycle 2 Day 1

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

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Other Pre-specified

Area Under the Plasma Concentration Time Curve as Daily Exposure (AUCdaily) of Crizotinib: Cycle 2 Day 1

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*hr/mL

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Other Pre-specified

Unbound Area Under the Plasma Concentration Time Curve as Daily Exposure (AUCdaily) of Crizotinib: Cycle 2 Day 1

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*hr/mL

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Other Pre-specified

Area Under the Plasma Concentration Time Curve as Daily Exposure (AUCdaily) of PF-06260182: Cycle 2 Day 1

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

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*hr/mL

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Other Pre-specified

Unbound Area Under the Plasma Concentration Time Curve as Daily Exposure (AUCdaily) of PF-06260182: Cycle 2 Day 1

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*hr/mL

Cycle 2 Day 1- Twice daily dosing: pre-dose and 1, 2, 4, 6, 8, 12 hours post-dose; Once daily dosing: pre-dose and 1, 2, 4, 6, 8, 24 hours post-dose

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Other Pre-specified

Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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.

Safety analysis population included all enrolled participants who received at least 1 dose of Crizotinib on Cycle 1, Day 1.

Posted

Number

participants

From initiation of treatment up to follow-up period (up to 4 years)

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily

Other Pre-specified

Number of Participants With Treatment-Emergent Adverse Events, by National Cancer Institute (NCI) Common Terminology Criteria (CTC) for AEs (CTCAE) (Version 4.0) Grade

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.

Safety analysis population included all enrolled participants who received at least 1 dose of Crizotinib on Cycle 1, Day 1.

Posted

Number

participants

From initiation of treatment up to follow-up period (up to 4 years)

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).

Other Pre-specified

Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

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.

Safety analysis population included all enrolled participants who received at least 1 dose of Crizotinib on Cycle 1, Day 1.

Posted

Number

participants

From initiation of treatment up to follow-up period (up to 4 years)

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Other Pre-specified

Number of Participants With Laboratory Test Abnormalities: NCI CTCAE (Version 4.0) Grade 1 to 4 Hematological Test Abnormalities

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.

Safety analysis population included all enrolled participants who received at least 1 dose of Crizotinib on Cycle 1, Day 1.

Posted

Number

participants

Baseline up to end of treatment (up to 728 days)

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).

Other Pre-specified

Number of Participants With Laboratory Test Abnormalities: NCI CTCAE (Version 4.0) Grade 1 to 4 Chemistry Test Abnormalities

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.

Safety analysis population included all enrolled participants who received at least 1 dose of Crizotinib on Cycle 1, Day 1.

Posted

Number

participants

Baseline up to end of treatment (up to 728 days)

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).

Other Pre-specified

Number of Participants With Abnormal Electrocardiogram (ECG) Findings

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.

Safety analysis population included all enrolled participants who received at least 1 dose of Crizotinib on Cycle 1, Day 1.

Posted

Number

participants

Baseline up to end of treatment (up to 728 days)

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily

Other Pre-specified

Number of Participants With Abnormal Fundoscopy Examination Findings

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.

Safety analysis population included all enrolled participants who received at least 1 dose of Crizotinib on Cycle 1, Day 1.

Posted

Number

participants

Baseline up to end of treatment (up to 728 days)

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
OG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.

Other Pre-specified

Objective Response Rate (ORR)

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.

Response-evaluable population was defined as all participants in the safety analysis population who had an adequate baseline tumor assessment.

Posted

Number

95% Confidence Interval

percentage of participants

Baseline, every 8 weeks until disease progression or unacceptable toxicity up to end of treatment (up to 728 days)

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).

Other Pre-specified

Duration of Response (DR)

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.

Response evaluable population. Here, 'N' signifies participants who were evaluable for this outcome measure. Data for normal hepatic function (200 mg), moderate (250 mg) and severe (250 mg) hepatic impairment arms was not estimable since no participants had achieved CR or PR in these reporting arms.

Posted

Median

95% Confidence Interval

week

Baseline, every 8 weeks until disease progression or unacceptable toxicity up to end of treatment (up to 728 days)

ID	Title	Description
OG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG0030 affected10 at risk EG0040 affected16 at risk EG0050 affected16 at risk
Atrial fibrillation	Cardiac disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Anal fistula	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Ascites	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Oesophagitis	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Proctalgia	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Small intestinal obstruction	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Asthenia	General disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Disease progression	General disorders	MedDRA v19.0	Non-systematic Assessment	EG0002 affected11 at risk EG0012 affected15 at risk EG0024 affected20 at risk EG003
Oedema	General disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Oedema peripheral	General disorders	MedDRA v19.0	Non-systematic Assessment	EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Pyrexia	General disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Cholecystitis	Hepatobiliary disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Hepatic failure	Hepatobiliary disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Hyperbilirubinaemia	Hepatobiliary disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Atypical pneumonia	Infections and infestations	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Gastroenteritis	Infections and infestations	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Meningitis bacterial	Infections and infestations	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Peritonitis	Infections and infestations	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Pneumonia	Infections and infestations	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0011 affected15 at risk EG0021 affected20 at risk EG003
Sepsis	Infections and infestations	MedDRA v19.0	Non-systematic Assessment	EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Septic shock	Infections and infestations	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Humerus fracture	Injury, poisoning and procedural complications	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Pelvic fracture	Injury, poisoning and procedural complications	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Fluid overload	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Hyperammonaemia	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Hyperuricaemia	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Aphasia	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment	EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Encephalopathy	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Generalised tonic-clonic seizure	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Haemorrhagic stroke	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Hepatic encephalopathy	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Confusional state	Psychiatric disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Mental status changes	Psychiatric disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Acute kidney injury	Renal and urinary disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0022 affected20 at risk EG003
Renal failure	Renal and urinary disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0022 affected20 at risk EG003
Urinary retention	Renal and urinary disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0022 affected20 at risk EG003
Dyspnoea exertional	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0012 affected15 at risk EG0020 affected20 at risk EG003
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0011 affected15 at risk EG0021 affected20 at risk EG003
Wound drainage	Surgical and medical procedures	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Deep vein thrombosis	Vascular disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Hypotension	Vascular disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Intra-abdominal haemorrhage	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment	EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA v19.0	Non-systematic Assessment		EG0003 affected11 at risk EG0015 affected15 at risk EG0026 affected20 at risk EG0032 affected10 at risk EG0045 affected16 at risk EG0053 affected16 at risk
Coagulopathy	Blood and lymphatic system disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Neutropenia	Blood and lymphatic system disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Bradycardia	Cardiac disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0012 affected15 at risk EG0020 affected20 at risk EG003
Right ventricular failure	Cardiac disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Sinus bradycardia	Cardiac disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Halo vision	Eye disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Photophobia	Eye disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0012 affected15 at risk EG0020 affected20 at risk EG003
Photopsia	Eye disorders	MedDRA v19.0	Non-systematic Assessment		EG0002 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Vision blurred	Eye disorders	MedDRA v19.0	Non-systematic Assessment		EG0004 affected11 at risk EG0011 affected15 at risk EG0022 affected20 at risk EG003
Visual impairment	Eye disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Vitreous floaters	Eye disorders	MedDRA v19.0	Non-systematic Assessment		EG0002 affected11 at risk EG0010 affected15 at risk EG0022 affected20 at risk EG003
Abdominal distension	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0003 affected11 at risk EG0010 affected15 at risk EG0022 affected20 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0025 affected20 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0006 affected11 at risk EG0012 affected15 at risk EG0024 affected20 at risk EG003
Ascites	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0007 affected11 at risk EG0014 affected15 at risk EG0025 affected20 at risk EG003
Dry mouth	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0003 affected11 at risk EG0012 affected15 at risk EG0020 affected20 at risk EG003
Dysphagia	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0002 affected11 at risk EG0011 affected15 at risk EG0021 affected20 at risk EG003
Eructation	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0012 affected15 at risk EG0020 affected20 at risk EG003
Haematochezia	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0007 affected11 at risk EG0018 affected15 at risk EG00211 affected20 at risk EG003
Odynophagia	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Oesophagitis	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Proctalgia	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Rectal haemorrhage	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0004 affected11 at risk EG0018 affected15 at risk EG0026 affected20 at risk EG003
Asthenia	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Chest discomfort	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Chest pain	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Chills	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Disease progression	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Face oedema	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Fatigue	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0004 affected11 at risk EG0016 affected15 at risk EG0024 affected20 at risk EG003
General physical health deterioration	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Malaise	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Mucosal inflammation	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0021 affected20 at risk EG003
Oedema	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Pain	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Pyrexia	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0013 affected15 at risk EG0020 affected20 at risk EG003
Hyperbilirubinaemia	Hepatobiliary disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0024 affected20 at risk EG003
Body tinea	Infections and infestations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Candida infection	Infections and infestations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Conjunctivitis	Infections and infestations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Influenza	Infections and infestations	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Pneumonia	Infections and infestations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Respiratory tract infection	Infections and infestations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0011 affected15 at risk EG0023 affected20 at risk EG003
Oedema peripheral	General disorders	MedDRA v19.0	Non-systematic Assessment		EG0004 affected11 at risk EG0012 affected15 at risk EG0023 affected20 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA v19.0	Non-systematic Assessment		EG0003 affected11 at risk EG0013 affected15 at risk EG0021 affected20 at risk EG003
Road traffic accident	Injury, poisoning and procedural complications	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Activated partial thromboplastin time prolonged	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0003 affected11 at risk EG0011 affected15 at risk EG0026 affected20 at risk EG003
Ammonia increased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Aspartate aminotransferase increased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0003 affected11 at risk EG0014 affected15 at risk EG0027 affected20 at risk EG003
Blood albumin decreased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Blood alkaline phosphatase increased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0002 affected11 at risk EG0012 affected15 at risk EG0022 affected20 at risk EG003
Blood bilirubin increased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0022 affected20 at risk EG003
Blood creatinine increased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0005 affected11 at risk EG0014 affected15 at risk EG0025 affected20 at risk EG003
Blood lactate dehydrogenase increased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0021 affected20 at risk EG003
Blood phosphorus decreased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Heart rate decreased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
International normalised ratio increased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Neutrophil count decreased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Platelet count decreased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Transaminases increased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Weight decreased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0021 affected20 at risk EG003
Weight increased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
White blood cell count decreased	Investigations	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Abnormal loss of weight	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Cachexia	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0004 affected11 at risk EG0014 affected15 at risk EG0025 affected20 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0013 affected15 at risk EG0021 affected20 at risk EG003
Food intolerance	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0012 affected15 at risk EG0020 affected20 at risk EG003
Hypocalcaemia	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0011 affected15 at risk EG0021 affected20 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0022 affected20 at risk EG003
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0016 affected15 at risk EG0025 affected20 at risk EG003
Hypophagia	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Hypophosphataemia	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0012 affected15 at risk EG0021 affected20 at risk EG003
Metabolic acidosis	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0022 affected20 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0003 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Arthritis	Musculoskeletal and connective tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0012 affected15 at risk EG0021 affected20 at risk EG003
Flank pain	Musculoskeletal and connective tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Joint effusion	Musculoskeletal and connective tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Joint swelling	Musculoskeletal and connective tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0002 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0002 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Aphasia	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Dizziness	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0012 affected15 at risk EG0021 affected20 at risk EG003
Dysgeusia	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment		EG0003 affected11 at risk EG0012 affected15 at risk EG0024 affected20 at risk EG003
Encephalopathy	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Headache	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment		EG0002 affected11 at risk EG0011 affected15 at risk EG0021 affected20 at risk EG003
Hepatic encephalopathy	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Memory impairment	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Migraine	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Myoclonus	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Neuropathy peripheral	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Visual perseveration	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Aphthous ulcer	Gastrointestinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Anxiety	Psychiatric disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0022 affected20 at risk EG003
Confusional state	Psychiatric disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Insomnia	Psychiatric disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0023 affected20 at risk EG003
Libido decreased	Psychiatric disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Mental status changes	Psychiatric disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Acute kidney injury	Renal and urinary disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Haematuria	Renal and urinary disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Hydronephrosis	Renal and urinary disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Proteinuria	Renal and urinary disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Erectile dysfunction	Reproductive system and breast disorders	MedDRA v19.0	Non-systematic Assessment	This AE was gender specific.	EG0000 affected7 at risk EG0010 affected9 at risk EG0020 affected13 at risk EG003
Gynaecomastia	Reproductive system and breast disorders	MedDRA v19.0	Non-systematic Assessment	This AE was gender specific.	EG0000 affected7 at risk EG0010 affected9 at risk EG0020 affected13 at risk EG003
Ovarian cyst	Reproductive system and breast disorders	MedDRA v19.0	Non-systematic Assessment	This AE was gender specific.	EG0001 affected4 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Penile swelling	Reproductive system and breast disorders	MedDRA v19.0	Non-systematic Assessment	This AE was gender specific.	EG0000 affected7 at risk EG0010 affected9 at risk EG0020 affected13 at risk EG003
Scrotal oedema	Reproductive system and breast disorders	MedDRA v19.0	Non-systematic Assessment	This AE was gender specific.	EG0001 affected7 at risk EG0010 affected9 at risk EG0020 affected13 at risk EG003
Scrotal pain	Reproductive system and breast disorders	MedDRA v19.0	Non-systematic Assessment	This AE was gender specific.	EG0001 affected7 at risk EG0010 affected9 at risk EG0020 affected13 at risk EG003
Vaginal haemorrhage	Reproductive system and breast disorders	MedDRA v19.0	Non-systematic Assessment	This AE was gender specific.	EG0000 affected4 at risk EG0010 affected6 at risk EG0020 affected7 at risk EG003
Atelectasis	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0012 affected15 at risk EG0022 affected20 at risk EG003
Dry throat	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Dyspnoea exertional	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Pulmonary hypertension	Respiratory, thoracic and mediastinal disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Alopecia	Skin and subcutaneous tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0021 affected20 at risk EG003
Dry skin	Skin and subcutaneous tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Photosensitivity reaction	Skin and subcutaneous tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Rash macular	Skin and subcutaneous tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Skin lesion	Skin and subcutaneous tissue disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Deep vein thrombosis	Vascular disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Flushing	Vascular disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Hypertension	Vascular disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Hypotension	Vascular disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0011 affected15 at risk EG0020 affected20 at risk EG003
Thrombophlebitis superficial	Vascular disorders	MedDRA v19.0	Non-systematic Assessment		EG0001 affected11 at risk EG0010 affected15 at risk EG0020 affected20 at risk EG003
Somnolence	Nervous system disorders	MedDRA v19.0	Non-systematic Assessment		EG0000 affected11 at risk EG0010 affected15 at risk EG0022 affected20 at risk EG003
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA v19.0	Non-systematic Assessment		EG0002 affected11 at risk EG0012 affected15 at risk EG0023 affected20 at risk EG003

ID	Term
D010880	Piperidines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D000631	Aminopyridines
D011725	Pyridines

ID	Title	Description
BG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).
BG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.
BG002	Mild Hepatic Impairment: Crizotinib 250 mg Twice Daily	Participants with mild hepatic impairment received Crizotinib 250 mg capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Mild hepatic impairment was defined as total bilirubin level <=ULN and AST levels greater than (>) ULN or total bilirubin level > 1.0 to 1.5*ULN.
BG003	Moderate Hepatic Impairment: Crizotinib 250 mg Once Daily	Participants with moderate hepatic impairment received Crizotinib 250 mg capsules, orally, once daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Moderate hepatic impairment was defined as total bilirubin level >1.5 to 3*ULN
BG004	Moderate Hepatic Impairment Crizotinib 200 mg Twice Daily	Participants with moderate hepatic impairment received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Moderate hepatic impairment was defined as total bilirubin level >1.5 to 3*ULN
BG005	Severe Hepatic Impairment Crizotinib 250 mg Once Daily	Participants with severe hepatic impairment received Crizotinib 250 mg capsules, orally, once daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Severe hepatic Impairment was defined as total bilirubin level >3*ULN.
BG006	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Normal Hepatic Function: Crizotinib 250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 250 milligram (mg) capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and aspartate aminotransferase (AST) levels less than or equal to (<=) the upper limit of normal (ULN).	3	11	7	11	11	11
EG001	Normal Hepatic Function: Crizotinib 200/250 mg Twice Daily	Participants with normal hepatic function received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles and dose could be increased to 250 mg twice daily after completion of pharmacokinetic (PK) assessment on Cycle 2 Day 1 based on their tolerability. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Normal hepatic function was defined as total bilirubin and AST levels <=ULN.	4	15	8	15	15	15
EG002	Mild Hepatic Impairment: Crizotinib 250 mg Twice Daily	Participants with mild hepatic impairment received Crizotinib 250 mg capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Mild hepatic impairment was defined as total bilirubin level <=ULN and AST levels greater than (>) ULN or total bilirubin level > 1.0 to 1.5*ULN.	8	20	13	20	20	20
EG003	Moderate Hepatic Impairment Crizotinib 200 mg Twice Daily	Participants with moderate hepatic impairment received Crizotinib 200 mg capsules, orally, twice daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Moderate hepatic impairment was defined as total bilirubin level >1.5 to 3*ULN	5	10	6	10	9	10
EG004	Moderate Hepatic Impairment: Crizotinib 250 mg Once Daily	Participants with moderate hepatic impairment received Crizotinib 250 mg capsules, orally, once daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Moderate hepatic impairment was defined as total bilirubin level >1.5 to 3*ULN	7	16	14	16	16	16
EG005	Severe Hepatic Impairment Crizotinib 250 mg Once Daily	Participants with severe hepatic impairment received Crizotinib 250 mg capsules, orally, once daily continuously in 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred. Severe hepatic Impairment was defined as total bilirubin level >3*ULN.	9	16	14	16	16	16