Hepatic Impairment Study For Crizotinib In Advanced Cancer Patients
Condition: Advanced Cancer
MeSH terms: Neoplasms
Intervention: crizotinib; crizotinib; crizotinib; crizotinib; crizotinib
Intervention description: crizotinib 250 mg twice a day; crizotinib 250 mg once a day; crizotinib 250 mg twice a day; crizotinib 250 mg once a day; crizotinib 250 mg once a day
Intervention MeSH terms: Crizotinib
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Non-Randomized
Masking: None (Open Label)
Enrollment: 88.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: crizotinib; xalkori; PF-02341066; hepatic impairment; pharmacokinetics; advanced cancer

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.
    

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.