Everolimus, Gemcitabine Hydrochloride, and Cisplatin in Treating Patients With Unresectable Solid Tumors Refractory to Standard Therapy

OBJECTIVES:

I. To determine the maximally tolerated dose (MTD) of concurrently administered everolimus
and gemcitabine (gemcitabine hydrochloride) in patients with advanced, refractory solid
tumors (two-agent MTD).

II. To determine the maximally tolerated dose of concurrently administered everolimus,
gemcitabine and cisplatin in patients with advanced, refractory solid tumors (three-agent
MTD).

III. To describe the toxicity of the two treatment combinations. IV. To describe any
evidence of the antitumor activity of the two treatment combinations.

V. To obtain pilot data on toxicity and efficacy outcome of everolimus, gemcitabine and
cisplatin in patients with cholangiocarcinoma or gallbladder carcinoma. (Cohort III)

OUTLINE: This is a dose-escalation study of gemcitabine hydrochloride and everolimus.

COHORT I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on
days 1 and 8 and everolimus orally (PO) once daily or 3 times weekly.

COHORT II: Patients receive gemcitabine hydrochloride IV over 30 minutes and cisplatin IV
over 1 hour on days 1 and 8 and everolimus PO once daily or 3 times weekly.

COHORT III: Patients receive treatment as in cohort II.

Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3 months.

Inclusion Criteria:

- Histologic proof of cancer that is now unresectable and refractory to or refused all
standard treatment for the disease; exception: cancers in which gemcitabine is
considered an appropriate initial treatment option

- Cohort III (MTD) Only: Patients with histologic proof of metastatic
cholangiocarcinoma or gallbladder carcinoma who have not had previous treatment for
metastatic disease or who received gemcitabine >= 6 months ago as part of adjuvant
therapy

- Absolute neutrophil count (ANC) >= 1500/uL

- Platelet (PLT) >= 100,000/uL

- Total bilirubin =< 1.5 x Institutional upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper
limit of normal (ULN) (=< 5x ULN in patients with liver metastases)

- Creatinine =< 1.5 x Institutional ULN

- Alkaline phosphatase =< 5 x Institutional ULN

- Hemoglobin (Hgb) >= 9.0 g/dL

- International normalized ratio (INR) and Partial thromboplastin time (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

- Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =<
2.5 x ULN; 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 weeks

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

Exclusion Criteria:

- Known standard therapy for the patient's disease that is potentially curative or
definitely capable of extending life expectancy

- 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

- Patients taking strong inhibitors or inducers of CYP3A4

- Prior therapy with everolimus

- 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

- Biological 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 chemotherapy
regardless of interval since last treatment

- CNS metastases that are not stable for at least 4 weeks prior to registration based
on imaging, clinical assessment, and use of steroids

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

- 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

- Current active other malignancy, except non-melanoma skin cancer or carcinoma-in-situ
of the cervix

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of everolimus (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection)

- Severely impaired lung function (i.e., forced expiratory volume in one 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 everolimus; examples of live
vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG,
yellow fever, varicella and TY21a typhoid vaccines

- Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C);
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