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