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0C-12-1-A Phase 1 Study to Evaluate the Effect of Hepatic Impairment on the Pharmacokinetics and Safety of Crizotinib in Advanced Cancer Patients [A8081012]

Description

This is a research study for advanced cancer with varying degree of liver function (normal, mild impairment, moderate impairment or severe impairment). The main purposes of this research study are to see whether a newly approved drug, crizotinib (Xalkori), can be used in patients with liver function that is not normal and to see whether crizotinib can prevent or slow down your cancer from growing, and to assess any side effects that you may have. Some other purposes of this study are to measure how much crizotinib is in your blood, and to provide dosing recommendations for patients with impaired liver function. Crizotinib is approved in the United States (US) and is available by prescription for non-small cell lung cancer (NSCLC) patients with Anaplastic Lymphoma Kinase (ALK) mutation. However, the use of crizotinib in this study is experimental. Crizotinib is not currently approved to treat other advanced cancer patients with unclear ALK status and/or with liver function that is not normal. . The participants of this study will be in this study until their disease progresses (gets worse), they experience unacceptable side effects or they withdraw consent. There will be about 50 advanced cancer patients enrolled in this study. The study is being done at about 3-5 different research sites in US. About 45 participants will take part at USC. This is a multicenter, open-label, non-randomized, phase 1 study. The endpoints are how the drug behaves in the body when taken (pK), effectiveness and safety of the study drug. There will be 5 groups (Groups A1, A2, B, C and D) involved in this study. Groups A1 and A2 have normal liver functions. Group A1 will match Group B(mild) and Group A2 will match Group C(moderate).The study drug is given by mouth and should be taken at approximately the same time each day on a continuous daily dosing.One-way analysis of variance (ANOVA) will be used for statistical analysis. Individual concentration of the study drug in the blood will be listed and summarized. The safety analysis population will include all enrolled patients who receive at least one does of crizotinib. The safety analysis population will be the primary population for evaluating patient characteristics, treatment administration and safety. Safety data will be reviewed on an ongoing basis during the study.

Phase

Phase 1

Inclusion and Exclusion 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.

  • 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.

Sites

  • California

    • Los Angeles County/University of Southern California Medical Center, Los Angeles, California, 90033
    • USC/Norris Comprehensive Cancer / Investigational Drug Services, Los Angeles, California, 90033
    • Pfizer Investigational Site, Los Angeles, California, 90033
    • USC/Norris Comprehensive Cancer Center, Los Angeles, California, 90033
    • Keck Hospital of the University of Southern California, Los Angeles, California, 90033
  • Colorado

    • Drug Shipment: Anschutz Cancer Pavilion, Room 2224, c/o Melinda Friesleben, Pharm D, Aurora, Colorado, 80045
    • Pfizer Investigational Site, Aurora, Colorado, 80045
    • University of Colorado Denver - Clinical Translational Research Center, Aurora, Colorado, 80045
    • University of Colorado Hospital, Aurora, Colorado, 80045
  • Texas

    • Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229
    • Pfizer Investigational Site, San Antonio, Texas, 78229
    • Cancer Therapy & Research Center at UTHSCSA, San Antonio, Texas, 78229
  • Georgia

    • The Emory Clinic, Atlanta, Georgia, 30322
    • Winship Cancer Institute, Atlanta, Georgia, 30322
    • Pfizer Investigational Site, Atlanta, Georgia, 30322
    • Drug Shipment Address: Investigational Drug Service: The Emory Clinic Bldg A, Atlanta, Georgia, 30322
    • Emory University Hospital, Atlanta, Georgia, 30322
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