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Phase I Trial of The Combination of Vismodegib and Sirolimus

Phase 1
18 Years
Open (Enrolling)
Acinar Cell Adenocarcinoma of the Pancreas, Duct Cell Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage IV Pancreatic Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Phase I Trial of The Combination of Vismodegib and Sirolimus


I. To determine the maximally tolerated dose (MTD) of the combination of vismodegib and
sirolimus in unresectable solid tumors. (Cohort I)


I. To describe the adverse event profile associated with this treatment combination.

II. To describe the tumor responses to treatment combination.


I. To assess the effect of the sirolimus and vismodegib combination on selected biomarkers
in tumor biopsies of patients with metastatic pancreatic cancer.

II. To assess the effect of the combination of vismodegib and sirolimus on fludeoxyglucose F
18 (F18-FDG) positron emission tomography (PET) or PET/computed tomography (CT) imaging in
Cohort II (MTD) patients with metastatic pancreatic cancer.

III. To study the association of clinical (toxicity and/or tumor response or activity) with
the biologic (pharmacodynamic) results obtained by examining tissue biopsies and PET or
PET/CT imaging from the same patients.

OUTLINE: This is a dose-escalation study of sirolimus.

Patients receive sirolimus orally (PO) once daily (QD) and vismodegib PO QD on days 1-28.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

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

- 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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD (Cohort I) ) and toxicity profile of combination of vismodegib plus sirolimus every 28 days.

Outcome Description:

MTD is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). DLT will be defined as a course 1 adverse event (Common Terminology Criteria for Adverse Events [CTCAE] v 4.0) attributed (definitely, probably, or possibly) to the study treatment. MTD will be examined in an exploratory and hypothesis generating fashion.

Outcome Time Frame:

120 days

Safety Issue:


Principal Investigator

Charles Erlichman, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

March 2012

Completion Date:

Related Keywords:

  • Acinar Cell Adenocarcinoma of the Pancreas
  • Duct Cell Adenocarcinoma of the Pancreas
  • Recurrent Pancreatic Cancer
  • Stage IV Pancreatic Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Pancreatic Neoplasms
  • Carcinoma, Acinar Cell



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