Phase I Trial of The Combination of Vismodegib and Sirolimus

Inclusion Criteria:

- COHORT I (DOSE ESCALATION): histologic proof of cancer that is now unresectable, not
amenable to any other standard therapies, or patient refuses standard therapy

- COHORT II (MTD): metastatic adenocarcinoma of the pancreas and tumor amenable to
biopsies; prior systemic treatment for metastatic disease is allowed

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

- Platelet >= 100,000/uL

- Total bilirubin =< upper limit of normal (ULN) Aspartate aminotransferase (AST)
(serum glutamic oxaloacetic transaminase [SGOT]) =< 3 x ULN

- Creatinine =< 1.5 x ULN

- Hemoglobin >= 9.0 g/dL

- Prothrombin time (PT)/international normalized ratio (INR) < 1.25 x ULN (Cohort II
[MTD] only)

- Cholesterol < Common Terminology Criteria for Adverse Events (CTCAE) grade 3

- Triglycerides < CTCAE grade 2

- Magnesium >= lower limit of normal (LLN) and =< ULN

- Ability to provide informed consent

- Willing to return to Mayo Clinic for follow up

- Life expectancy >= 12 weeks

- Cohort II (MTD) only - Translational Research: Willing to provide the biologic
specimens as required by the protocol; Note: this is part of the mandatory
translational research component

- Women of childbearing potential only: Negative serum pregnancy test done =< 7 days
prior to registration; NOTE: female subjects who are pregnant or nursing are excluded
from this study; there is no specific mitigation strategy for vismodegib toxicity;
however, male patients should be made aware of it during the consent process;
although this effect is expected to be reversible with discontinuation of dosing,
long-term effects on male fertility cannot be excluded at this time

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

- Able to swallow or have medication administered through a G-tube and absorb the
medication

- Participant agrees to use acceptable form of contraception during the study and for
up to 7 months after last study drug dose

- Acceptable forms of contraception:

- Latex condom (always used with spermicide)

- Diaphragm (always used with spermicide)

- Cervical cap (always used with spermicide)

- Acceptable forms of secondary contraception, when used along with a barrier method:

- Hormonal contraception methods, including pills, patches, rings, or injections
except progestin-only containing pills (i.e. "Mini-pill")

- Tubal ligation

- Partner's vasectomy

- Intrauterine device (non-progesterone T)

- Vaginal sponge (containing spermicide)

- Other acceptable forms:

- 100% commitment to abstinence

- Unacceptable forms of contraception for women of childbearing potential:

- Oral contraception containing progestins only

- Intrauterine device (IUD) progesterone T

- Female condom

- Natural family planning (rhythm method) or breastfeeding

- Fertility awareness

- Withdrawal

- Cervical shield

- Willing not to smoke

- Willing to complete a pill diary each day

Exclusion Criteria:

- COHORT I (DOSE ESCALATION): 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, diabetes mellitus or psychiatric illness/social situations that would
limit compliance with study requirements

- 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

- Failure to fully recover from acute, reversible effects of prior chemotherapy
regardless of interval since last treatment

- New York Heart Association classification III or IV

- Uncontrolled Seizure Disorder

- Central nervous system (CNS) metastases if not stable for at least 2-3 months based
on imaging, clinical assessment, use of steroids, or seizure disorder

- Any of the following:

- Pregnant women

- Nursing women

- This study involves an investigational agent whose genotoxic, mutagenic and
teratogenic effects on the developing fetus and newborn are unknown

- Other concurrent chemotherapy, immunotherapy, radiotherapy, any ancillary therapy
considered investigational (utilized for a non-Food and Drug Administration
[FDA]-approved indication and in the context of a research investigation) or
receiving any other investigational agent which would be considered as a treatment
for the primary neoplasm

- Receiving any medications or substances that are strong or moderate inhibitors of
cytochrome P450 3A4 (CPY450 3A4); use of the following strong or moderate inhibitors
are prohibited:

- Strong Inhibitors of CYP3A4: Indinavir, Nelfinavir, Ritonavir, Clarithromycin,
Itraconazole, Ketoconazole, Nefazodone, Saquinavir, Telithromycin

- Moderate Inhibitors of CYP3A4: Aprepitant, Erythromycin, Fluconazole, Grapefruit
juice, Verapamil, Diltiazem

- Receiving any medications or substances that are inducers of CYP450 3A4

- Inducers of CYP3A4: Efavirenz, Nevirapine, Carbamazepine, Modafinil,
Phenobarbital, Phenytoin, Pioglitazone, Rifabutin, Rifampin, St. John's wort

- Receiving any medications or substances that are strong or moderate inhibitors of
CYP450 CYP2C8

- Strong or Moderate Inhibitors of CYP2C8: Gemfibrozil, Trimethoprim

- Receiving any medications or substances that are inducers of CYP450 2C8

- Inducer of CYP2C8: Rifampin

- Receiving any medications or substances that are strong or moderate inhibitors of
CYP450 CYP2C9

- Strong or Moderate Inhibitors of CYP2C9: Fluconazole, Amiodarone

- Receiving any medications or substances that are inducers of CYP450 2C9

- Inducers of CYP2C9: Rifampin, Secobarbital

- Immunocompromised patients (other than that related to the use of corticosteroids)
including patients receiving highly active antiretroviral therapy (HAART) treatment

- Active other malignancy, excepting non-melanotic skin cancer or carcinoma-in situ
(e.g. of cervix, breast prostate); if there is a history of prior malignancy, they
must not be receiving other specific treatment (other than hormonal therapy) for
their cancer

- History of myocardial infarction =< 6 months, or congestive heart failure requiring
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

- Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's
syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp
examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal
corneal sensitivity test (Schirmer test or similar tear production test)

- Prior therapy with a hedgehog inhibitor