Hepatic Impairment Study For Crizotinib In Advanced Cancer Patients

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Pfizer
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01576406
First received: March 30, 2012
Last updated: September 8, 2014
Last verified: September 2014
  Purpose

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 Intervention Phase
Advanced Cancer
Drug: crizotinib
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Plasma AUCτ [Area under the plasma concentration-time profile during one dosing interval] for crizotinib at steady-state [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Plasma Cmax [Maximum plasma concentration] of crizotinib at steady-state [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Plasma AUClast [Area under the plasma concentration-time curve to the last measurable concentration]of crizotinib after a single dose if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Plasma Cmax of crizotinib after a single dose if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Plasma Tmax [Time to reach maximum observed plasma concentration] of crizotinib after a single dose if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Plasma Cmin [Minimum plasma concentration] of crizotinib at steady-state if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Plasma accumulation ratio (Rac) of crizotinib at steady-state if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Plasma CL/F [Apparent oral clearance] of crizotinib at steady-state if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Fraction of unbound in plasma (fu) for crizotinib [ Time Frame: predose or 4 hours post dose ] [ Designated as safety issue: No ]
  • Unbound AUClast in plasma for crizotinib if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Unbound Cmax in plasma for crizotinib if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Plasma AUCτ for PF-06260182 if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Plasma AUClast for PF-06260182 if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Plasma Cmax for PF-06260182 if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Plasma Tmax for PF-06260182 if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Metabolite ratio for AUCτ (MRAUCτ) if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Metabolite ratio for AUClast (MRAUClast) if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Metabolite ratio for Cmax (MRCmax) if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Fraction of unbound in plasma (fu) for Pf-06260182 [ Time Frame: predose or 4 hours post dose ] [ Designated as safety issue: No ]
  • Unbound AUClast in plasma for PF-06260182 if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Unbound AUCτ in plasma for PF-06260182 if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Unbound Cmax in plasma for PF-06260182 if possible [ Time Frame: 0 (predose), 1, 2, 4, 6, 8, 12 or 24 hours post dose ] [ Designated as safety issue: No ]
  • Type, incidence, severity, seriousness, and relationship to study medications of adverse events (AE) and any laboratory abnormalities [ Time Frame: 1.5 years ] [ Designated as safety issue: Yes ]
  • Objective response rate (ORR) [ Time Frame: 1.5 years ] [ Designated as safety issue: No ]
  • Duration of response (DR) [ Time Frame: 1.5 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 70
Study Start Date: July 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01576406

Contacts
Contact: Pfizer CT.gov Call Center 1-800-718-1021

Locations
United States, California
Pfizer Investigational Site Recruiting
Los Angeles, California, United States, 90033
United States, Colorado
Pfizer Investigational Site Recruiting
Aurora, Colorado, United States, 80045
United States, Georgia
Pfizer Investigational Site Recruiting
Atlanta, Georgia, United States, 30322
United States, Ohio
Pfizer Investigational Site Recruiting
Columbus, Ohio, United States, 43210
United States, Texas
Pfizer Investigational Site Recruiting
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01576406     History of Changes
Other Study ID Numbers: A8081012
Study First Received: March 30, 2012
Last Updated: September 8, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
crizotinib
xalkori
PF-02341066
hepatic impairment
pharmacokinetics
advanced cancer

Additional relevant MeSH terms:
Neoplasms
Liver Diseases
Digestive System Diseases
Crizotinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 01, 2014