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

Tracking Information
First Submitted Date ICMJE	February 14, 2012
First Posted Date ICMJE	February 23, 2012
Last Update Posted Date	February 6, 2018
Actual Study Start Date ICMJE	March 5, 2012
Estimated Primary Completion Date	December 2018 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: February 22, 2012)	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.
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT01537107 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: February 22, 2012)	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 ]; Time to treatment failure [ Time Frame: 120 days ]; Antitumor effect of molecularly targeted agents non-invasively by F18-FDG PET or PET/CT (Cohort II) [ Time Frame: 120 days ]
Original Secondary Outcome Measures ICMJE	Same as current
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Sirolimus and Vismodegib in Treating Patients With Solid Tumors or Pancreatic Cancer That is Metastatic or Cannot Be Removed By Surgery
Official Title ICMJE	Phase I Trial of The Combination of Vismodegib and Sirolimus
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
Detailed Description	PRIMARY OBJECTIVES: I. To determine the maximally tolerated dose (MTD) of the combination of vismodegib and sirolimus in unresectable solid tumors. (Cohort I) SECONDARY OBJECTIVES: I. To describe the adverse event profile associated with this treatment combination. II. To describe the tumor responses to treatment combination. CORRELATIVE OBJECTIVES: 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.
Study Type ICMJE	Interventional
Study Phase	Phase 1
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	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
Intervention ICMJE	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: FDG-PET 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
Study Arms	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.; Interventions: Drug: vismodegib; Drug: sirolimus; Procedure: positron emission tomography; Procedure: computed tomography; Other: pharmacological study; Other: laboratory biomarker analysis; Radiation: fludeoxyglucose F 18
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Suspended
Estimated Enrollment ICMJE; (submitted: February 22, 2012)	32
Original Estimated Enrollment ICMJE	Same as current
Estimated Study Completion Date	December 2018
Estimated Primary Completion Date	December 2018 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01537107
Other Study ID Numbers ICMJE	MC1111; NCI-2011-03809 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Mayo Clinic
Study Sponsor ICMJE	Mayo Clinic
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Charles Erlichman, M.D. Mayo Clinic
PRS Account	Mayo Clinic
Verification Date	March 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP