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Hepatic Impairment Study For Crizotinib In Advanced Cancer Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01576406
Recruitment Status : Completed
First Posted : April 12, 2012
Results First Posted : October 25, 2018
Last Update Posted : October 25, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:
This study is designed to evaluate the potential effect of hepatic impairment on the pharmacokinetics and safety of crizotinib in advanced cancer patients. Advanced cancer patients with mild, moderate or severe liver dysfunction as well as patients with normal liver function will be enrolled in this study.

Condition or disease Intervention/treatment Phase
Advanced Cancer Drug: crizotinib Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 88 participants
Allocation: Non-Randomized
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Phase I Study To Evaluate The Effect Of Hepatic Impairment On The Pharmacokinetics And Safety Of Crizotinib In Advanced Cancer Patients
Actual Study Start Date : July 2012
Actual Primary Completion Date : June 2016
Actual Study Completion Date : June 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Crizotinib

Arm Intervention/treatment
Experimental: A1: normal hepatic function Drug: crizotinib
crizotinib 250 mg twice a day

Experimental: A2: normal hepatic function Drug: crizotinib
crizotinib 250 mg once a day

Experimental: B: mild hepatic impairment Drug: crizotinib
crizotinib 250 mg twice a day

Experimental: C: moderate hepatic impairment Drug: crizotinib
crizotinib 250 mg once a day

Experimental: D: severe hepatic impairment Drug: crizotinib
crizotinib 250 mg once a day




Primary Outcome Measures :
  1. Area Under Plasma Concentration Time Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib: Cycle 2 Day 1 [ Time Frame: 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 ]
    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.

  2. Maximum Observed Plasma Concentration (Cmax) of Crizotinib: Cycle 2 Day 1 [ Time Frame: 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 ]

Secondary Outcome Measures :
  1. Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Plasma Concentration (AUClast) of Crizotinib: Cycle 1 Day 1 [ Time Frame: 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 ]
  2. Maximum Observed Plasma Concentration (Cmax) of Crizotinib: Cycle 1 Day 1 [ Time Frame: 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 ]
  3. Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib: Cycle 1 Day 1 [ Time Frame: 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 ]
  4. Minimum Observed Plasma Concentration (Cmin) of Crizotinib: Cycle 2 Day 1 [ Time Frame: 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 ]
  5. Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Plasma Concentration (AUClast) of Crizotinib: Cycle 2 Day 1 [ Time Frame: 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 ]
  6. Plasma Accumulation Ratio (Rac) of Crizotinib [ Time Frame: 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 ]
    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).

  7. Apparent Oral Clearance (CL/F) of Crizotinib: Cycle 2 Day 1 [ Time Frame: 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 ]
    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.

  8. Fraction of Unbound Crizotinib in Plasma: Cycle 2 Day 1 [ Time Frame: 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 ]
    Fraction of unbound Crizotinib concentration in plasma was defined as the ratio of unbound Crizotinib concentration to the total Crizotinib concentration.

  9. Unbound Area Under the Plasma Concentration Time Curve From Time Zero to the Last Quantifiable Plasma Concentration (AUClast) of Crizotinib: Cycle 2 Day 1 [ Time Frame: 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 from time zero to the last quantifiable plasma concentration post-dose of Cycle 2 day 1.

  10. Unbound Area Under Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib: Cycle 2 Day 1 [ Time Frame: 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 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.

  11. Unbound Maximum Observed Plasma Concentration (Cmax) of Crizotinib: Cycle 2 Day 1 [ Time Frame: 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 ]
  12. Area Under Plasma Concentration Time Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06260182: Cycle 2 Day 1 [ Time Frame: 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 ]
    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.

  13. Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Plasma Concentration (AUClast) of PF-06260182: Cycle 1 Day 1 [ Time Frame: 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 ]
    AUClast of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

  14. Maximum Observed Plasma Concentration (Cmax) of PF-06260182: Cycle 1 Day 1 [ Time Frame: 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 ]
    Cmax of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

  15. Maximum Observed Plasma Concentration (Cmax) of PF-06260182: Cycle 2 Day 1 [ Time Frame: 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 ]
    Cmax of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

  16. Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06260182: Cycle 1 Day 1 [ Time Frame: 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 ]
    Tmax of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

  17. Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06260182: Cycle 2 Day 1 [ Time Frame: 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 ]
    Tmax of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

  18. 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 [ Time Frame: 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 ]
    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.

  19. 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 [ Time Frame: 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 ]
    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.

  20. Metabolite Ratio for Maximum Observed Plasma Concentration (Cmax) of PF-06260182: Cycle 1 Day 1 [ Time Frame: 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 ]
    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.

  21. Metabolite Ratio for Maximum Observed Plasma Concentration (Cmax) of PF-06260182: Cycle 2 Day 1 [ Time Frame: 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 ]
    Metabolite ratio for Cmax was defined as the ratio of Cmax of metabolite (PF-06260182) to Cmax of parent drug (Crizotinib), where Cmax was maximum observed plasma concentration post-dose of Cycle 2 Day 1.

  22. Fraction of Unbound PF-06260182 in Plasma: Cycle 2 Day 1 [ Time Frame: 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 ]
    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.

  23. Unbound Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Plasma Concentration (AUClast) of PF-06260182: Cycle 2 Day 1 [ Time Frame: 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 AUClast of PF-06260182 (a metabolite of Crizotinib) is reported in this outcome measure.

  24. Unbound Area Under Plasma Concentration Time Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06260182: Cycle 2 Day 1 [ Time Frame: 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 from time zero to the quantifiable concentration at the end of dosing interval (tau hours post-dose, where tau was 12 hours for twice daily dosing and 24 hours for once daily dosing) of Cycle 2 Day 1. Unbound AUCtau of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

  25. Unbound Maximum Observed Plasma Concentration (Cmax) of PF-06260182: Cycle 2 Day 1 [ Time Frame: 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 Cmax of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.


Other Outcome Measures:
  1. Area Under the Plasma Concentration Time Curve as Daily Exposure (AUCdaily) of Crizotinib: Cycle 2 Day 1 [ Time Frame: 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 ]
  2. Unbound Area Under the Plasma Concentration Time Curve as Daily Exposure (AUCdaily) of Crizotinib: Cycle 2 Day 1 [ Time Frame: 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 ]
  3. Area Under the Plasma Concentration Time Curve as Daily Exposure (AUCdaily) of PF-06260182: Cycle 2 Day 1 [ Time Frame: 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 ]
    AUCdaily of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure.

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

  5. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From initiation of treatment up to follow-up period (up to 4 years) ]
    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.

  6. Number of Participants With Treatment-Emergent Adverse Events, by National Cancer Institute (NCI) Common Terminology Criteria (CTC) for AEs (CTCAE) (Version 4.0) Grade [ Time Frame: From initiation of treatment up to follow-up period (up to 4 years) ]
    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.

  7. Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From initiation of treatment up to follow-up period (up to 4 years) ]
    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.

  8. Number of Participants With Laboratory Test Abnormalities: NCI CTCAE (Version 4.0) Grade 1 to 4 Hematological Test Abnormalities [ Time Frame: Baseline up to end of treatment (up to 728 days) ]
    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.

  9. Number of Participants With Laboratory Test Abnormalities: NCI CTCAE (Version 4.0) Grade 1 to 4 Chemistry Test Abnormalities [ Time Frame: Baseline up to end of treatment (up to 728 days) ]
    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.

  10. Number of Participants With Abnormal Electrocardiogram (ECG) Findings [ Time Frame: Baseline up to end of treatment (up to 728 days) ]
    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.

  11. Number of Participants With Abnormal Fundoscopy Examination Findings [ Time Frame: Baseline up to end of treatment (up to 728 days) ]
    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.

  12. Objective Response Rate (ORR) [ Time Frame: Baseline, every 8 weeks until disease progression or unacceptable toxicity up to end of treatment (up to 728 days) ]
    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.

  13. Duration of Response (DR) [ Time Frame: Baseline, every 8 weeks until disease progression or unacceptable toxicity up to end of treatment (up to 728 days) ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01576406


Locations
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Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01576406    
Other Study ID Numbers: A8081012
First Posted: April 12, 2012    Key Record Dates
Results First Posted: October 25, 2018
Last Update Posted: October 25, 2018
Last Verified: January 2018
Keywords provided by Pfizer:
crizotinib
xalkori
PF-02341066
hepatic impairment
pharmacokinetics
advanced cancer
Additional relevant MeSH terms:
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Neoplasms
Crizotinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action