Sirolimus, Gemcitabine Hydrochloride, and Cisplatin in Treating Patients At High Risk for Cholangiocarcinoma Recurrence After 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:

- Histologic proof of presence of residual tumor in liver explants and /or positive
resection margins

- Absolute neutrophil count (ANC) >= 1500/μL obtained =< 7 days prior to registration

- Platelets (PLT) >= 100,000/μL obtained =< 7 days prior to registration

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) obtained =< 7 days
prior to registration

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
obtained =< 7 days prior to registration (=< 5 x ULN in patients with liver
metastases)

- Creatinine =< 1.5 x Institutional ULN obtained =< 7 days prior to registration

- Alkaline phosphatase =< 5 x institutional ULN obtained =< 7 days prior to
registration

- Hemoglobin (Hgb) >= 9.0 g/dL obtained =< 7 days prior to registration

- International normalized ratio (INR) and partial thromboplastin (PTT) =< 3.0 x ULN
(anticoagulation is allowed if target INR =< 3.0 x ULN on a stable dose of warfarin
or on a stable dose of low molecular weight [LMW] heparin for > 2 weeks at time of
registration)

- Fasting serum glucose < 1.5 x ULN obtained =< 7 days prior to registration

- Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =<
2.5 x ULN obtained =< 90 days prior to registration; NOTE: In case one or both of
these thresholds are exceeded, the patient can only be included after initiation of
appropriate lipid lowering medication

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

- Ability to provide informed consent

- Willingness to return to Mayo Clinic for follow up

- Life expectancy >= 12 months

- Women of childbearing potential only: negative serum pregnancy test done =< 7 days
prior to registration

- Four months post liver transplant

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

- Clarithromycin (Biaxin®, Biaxin XL®)

- Conivaptan (Vaprisol®)

- Grapefruit juice

- Itraconazole (Sporanox®)

- Ketoconazole (Nizoral®)

- Mibefradil

- Nefazodone (Serzone®)

- Posaconazole (Noxafil®)

- Telaprevir (Incivek®)

- Telithromycin (Ketek®)

- Use of the following inducers are prohibited =< 7 days prior to registration

- Strong inducers of CYP3A4/5; > 80% decrease in AUC

- Avasimibe

- Carbamazepine (Carbatrol®, Epitol®, Equetro™, Tegretol®, Tegretol-XR®)

- Phenytoin (Dilantin®, Phenytek®)

- Rifampin (Rifadin®)

- St. John's wort

- Moderate inducers of CYP3A4/5; 50-80% decrease in AUC

- Bosentan (Tracleer®)

- Modafinil (Provigil®)

- Nafcillin

- Phenobarbital (Luminal®)

- Rifabutin (Mycobutin®)

- Troglitazone

- Any of the following prior therapies:

- Chemotherapy =< 4 weeks prior to registration

- Mitomycin C/nitrosoureas =< 6 weeks prior to registration

- Immunotherapy =< 4 weeks prior to registration

- Biologic therapy =< 4 weeks prior to registration

- Radiation therapy =< 4 weeks prior to registration

- Radiation to > 25% of bone marrow prior to registration

- 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

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- 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