Pilot Trial of Sirolimus, Gemcitabine and Cisplatin for Patients With High Risk for Cholangiocarcinoma Recurrence
Pilot Trial of Sirolimus, Gemcitabine and Cisplatin for Patients With High Risk for Cholangiocarcinoma Recurrence
This pilot phase I trial studies the side effects and best way to give sirolimus, gemcitabine hydrochloride, and cisplatin in treating patients at high risk for cholangiocarcinoma recurrence after liver transplant or surgery. Sirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sirolimus with gemcitabine hydrochloride and cisplatin may prevent disease recurrence in patients with a high risk of recurrence after a liver transplant or surgery.
PRIMARY OBJECTIVES:
I. Assessment of the percentage of patients who are able to complete therapy through 4 and 6 months post-registration.
SECONDARY OBJECTIVES:
I. To describe the adverse events, rate of dose reductions, and quality of life in these patients.
II. To summarize timed endpoints of time-to-recurrence, disease-free survival, overall survival, time to treatment failure, and time until treatment related grade 3+ adverse events.
OUTLINE:
Patients receive cisplatin intravenously (IV) over 1 hour and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and sirolimus orally (PO) daily or three times weekly. Treatment repeats every 3 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 5 years.
Inclusion Criteria:
Exclusion Criteria:
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Clinically significant cardiac disease, especially history of myocardial infarction =< 6 months, or congestive heart failure (New York Heart Association [NYHA] classification III or IV) requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
Taking strong inhibitors or strong/moderate inducers of cytochrome P450 (CYP)3A4
Strong inhibitors of CYP3A4/5; > 5-fold increase in the plasma area under the curve (AUC) values or more than 80% decrease in clearance
Use of the following inducers are prohibited =< 7 days prior to registration
Strong inducers of CYP3A4/5; > 80% decrease in AUC
Moderate inducers of CYP3A4/5; 50-80% decrease in AUC
Any of the following prior therapies:
Failure to fully recover from acute, reversible effects of prior surgery or chemotherapy regardless of interval since last treatment
Any of the following because this study involves cytotoxic agents
Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation)
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive with low cluster of differentiation (CD)4 count; Note: previous calcineurin inhibitor or previous sirolimus use allowed
Current active other malignancy, except non-melanoma skin cancer or carcinoma-in-situ of the cervix; if there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer
Current impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sirolimus (e.g., active ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
Current severely impaired lung function (i.e., forced expiratory volume in 1 second [FEV1] < 1 liter)
Received immunization with attenuated live vaccines =< 7 days prior to study entry or during study period; NOTE: Close contact with those who have received attenuated live vaccines should be avoided during treatment with sirolimus; examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guérin (BCG), yellow fever, varicella and typhoid (TY)21a typhoid vaccines
Current severe hepatic impairment; Note: A detailed assessment of hepatitis B/C medical history and risk factors must be done at screening for all patients; hepatitis B virus (HBV) deoxyribonucleic acid (DNA) and hepatitis C virus (HCV) ribonucleic acid (RNA) polymerase chain reaction (PCR) testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection