Hepatic Impairment Study For Crizotinib In Advanced Cancer Patients

NCT01576406 | Completed Phase 1 Results

• 1 other identifier: A8081012
• Study Type: interventional
• Target: 88
• Locations: 1 country
• Sites: 20

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.

Conditions

Advanced Cancer

Keywords

crizotinib; xalkori; PF-02341066; hepatic impairment; pharmacokinetics; advanced cancer

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (25)

• 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

Other Outcomes (13)

• 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

  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 as Daily Exposure (AUCdaily) of PF-06260182: 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

Study Arms (5)

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

Interventions

crizotinib DRUG

crizotinib 250 mg twice a day

A1: normal hepatic function

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Pfizer: lead

Study Sites (20)

Keck Hospital of USC

Los Angeles, California, 90033, United States

Location

LAC&USC Medical Center

Los Angeles, California, 90033, United States

Location

USC/Norris Comprehensive Cancer Center / Investigational Drug Services

Los Angeles, California, 90033, United States

Location

USC/Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

Anschutz Cancer Pavilion, Room 2224, c/o Melinda Friesleben, Pharm D

Aurora, Colorado, 80045, United States

Location

University of Colorado Denver - Clinical Translational Research Center

Aurora, Colorado, 80045, United States

Location

University of Colorado Denver, Anschutz Cancer Pavilion

Aurora, Colorado, 80045, United States

Location

University of Colorado Denver, Anschutz Inpatient Pavillion

Aurora, Colorado, 80045, United States

Location

Emory University Hospital Midtown Laboratory

Atlanta, Georgia, 30308, United States

Location

Emory University Hospital

Atlanta, Georgia, 30322, United States

Location

Investigational Drug Service: The Emory Clinic Bldg A

Atlanta, Georgia, 30322, United States

Location

The Emory Clinic

Atlanta, Georgia, 30322, United States

Location

Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

University Hospital East

Columbus, Ohio, 43205, United States

Location

Investigational Drug Services

Columbus, Ohio, 43210, United States

Location

James Cancer Hospital

Columbus, Ohio, 43210, United States

Location

The Ohio State University, Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

Martha Morehouse Medical Plaza

Columbus, Ohio, 43221, United States

Location

Cancer Therapy & Research Center at UTHSCSA

San Antonio, Texas, 78229, United States

Location

Medical Arts and Research Center-MARC

San Antonio, Texas, 78229, United States

Location

Related Publications (1)

• 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.

  PMID: 29468455 DERIVED

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Interventions

Crizotinib

Intervention Hierarchy (Ancestors)

Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Aminopyridines; Pyridines

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 30, 2012
• First Posted: April 12, 2012
• Study Start: July 1, 2012
• Primary Completion: June 1, 2016
• Study Completion: June 1, 2016
• Last Updated: October 25, 2018
• Results First Posted: October 25, 2018

Record last verified: 2018-01

Locations

US (20)