Hepatic Impairment Study For Crizotinib In Advanced Cancer Patients

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I Study To Evaluate The Effect Of Hepatic Impairment On The Pharmacokinetics And Safety Of Crizotinib In Advanced Cancer Patients

Conditions
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Advanced Cancer

Intervention / Treatment
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* Drug: crizotinib
* Drug: crizotinib
* Drug: crizotinib
* Drug: crizotinib
* Drug: crizotinib


Participation Criteria
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Eligibility Criteria
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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: 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. The presence of liver lesion(s) (as defined in a.) with AFP ≥ 400 ng/mL. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A1: normal hepatic function<br> | Drug: crizotinib<br>* crizotinib 250 mg twice a day<br>|
| Experimental: A2: normal hepatic function<br> | Drug: crizotinib<br>* crizotinib 250 mg once a day<br>|
| Experimental: B: mild hepatic impairment<br> | Drug: crizotinib<br>* crizotinib 250 mg twice a day<br>|
| Experimental: C: moderate hepatic impairment<br> | Drug: crizotinib<br>* crizotinib 250 mg once a day<br>|
| Experimental: D: severe hepatic impairment<br> | Drug: crizotinib<br>* crizotinib 250 mg once a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 |  | 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 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) 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 | 
| Minimum Observed Plasma Concentration (Cmin) 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 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Plasma Concentration (AUClast) 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 | 
| 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). | 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 | 
| 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. | 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 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. | 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 (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. | 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 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. | 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 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 | 
| 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. | 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 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. | 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 PF-06260182: Cycle 1 Day 1 | Cmax of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure. | 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 PF-06260182: Cycle 2 Day 1 | Cmax of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure. | 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 | 
| 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. | 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 | 
| 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. | 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 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. | 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 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. | 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 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. | 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 Maximum Observed Plasma Concentration (Cmax) of PF-06260182: Cycle 2 Day 1 | Metabolite ratio for Cmax was defined as the ratio of Cmax of metabolite (PF-06260182) to Cmax of parent drug (Crizotinib), where Cmax was maximum observed plasma concentration post-dose of Cycle 2 Day 1. | 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 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. | 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 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. | 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 Plasma Concentration Time Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06260182: 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. Unbound AUCtau of PF-06260182, (a metabolite of Crizotinib) is reported in this outcome measure. | 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 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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crizotinib, xalkori, PF-02341066, hepatic impairment, pharmacokinetics, advanced cancer