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Sirolimus and Vismodegib in Treating Patients With Solid Tumors or Pancreatic Cancer That is Metastatic or Cannot Be Removed By Surgery

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01537107
Recruitment Status : Completed
First Posted : February 23, 2012
Last Update Posted : April 8, 2019
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:
This phase I trial studies the side effects and the best dose of sirolimus when given together with vismodegib in treating patients with solid tumors or pancreatic cancer that is metastatic or cannot be removed by surgery. Sirolimus and vismodegib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth

Condition or disease Intervention/treatment Phase
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 Drug: vismodegib Drug: sirolimus Procedure: positron emission tomography Procedure: computed tomography Other: pharmacological study Other: laboratory biomarker analysis Radiation: fludeoxyglucose F 18 Phase 1

Detailed Description:


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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 31 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Trial of The Combination of Vismodegib and Sirolimus
Actual Study Start Date : March 5, 2012
Actual Primary Completion Date : June 27, 2018
Actual Study Completion Date : June 27, 2018

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Treatment (enzyme inhibitor therapy)
Patients receive sirolimus PO QD and vismodegib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: vismodegib
Given PO
Other Name: GDC-0449

Drug: sirolimus
Given PO
Other Names:
  • Rapamune
  • rapamycin
  • RAPA

Procedure: positron emission tomography
Correlative studies
Other Names:
  • PET
  • PET scan
  • tomography, emission computed

Procedure: computed tomography
Correlative studies
Other Name: tomography, computed

Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Other: laboratory biomarker analysis
Correlative studies

Radiation: fludeoxyglucose F 18
Correlative studies
Other Names:
  • 18FDG
  • FDG

Primary Outcome Measures :
  1. MTD (Cohort I) ) and toxicity profile of combination of vismodegib plus sirolimus every 28 days. [ Time Frame: 120 days ]
    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.

Secondary Outcome Measures :
  1. Adverse events (AEs) profile in terms of the number and severity of all adverse events (overall, by dose-level, and by tumor group) at baseline, at each dose level and at 30 days after completion of study treatment [ Time Frame: 120 days ]
  2. Time to treatment failure [ Time Frame: 120 days ]
  3. Antitumor effect of molecularly targeted agents non-invasively by F18-FDG PET or PET/CT (Cohort II) [ Time Frame: 120 days ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01537107

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United States, Arizona
Mayo Clinic Campus in Arizona
Scottsdale, Arizona, United States
United States, Florida
Mayo Clinic Campus in Florida
Jacksonville, Florida, United States, 32224
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
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Principal Investigator: Charles Erlichman, M.D. Mayo Clinic
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Responsible Party: Mayo Clinic Identifier: NCT01537107    
Other Study ID Numbers: MC1111
NCI-2011-03809 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: February 23, 2012    Key Record Dates
Last Update Posted: April 8, 2019
Last Verified: April 2019
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Carcinoma, Acinar Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Fluorodeoxyglucose F18
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Molecular Mechanisms of Pharmacological Action