Phase I Trial of The Combination of Vismodegib and Sirolimus
Overview
- Phase
- Phase 1
- Intervention
- vismodegib
- Conditions
- Acinar Cell Adenocarcinoma of the Pancreas
- Sponsor
- Mayo Clinic
- Enrollment
- 31
- Locations
- 3
- Primary Endpoint
- MTD (Cohort I) ) and toxicity profile of combination of vismodegib plus sirolimus every 28 days.
- Status
- Completed
- Last Updated
- 7 years ago
Overview
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
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.
Intervention: vismodegib
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.
Intervention: sirolimus
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.
Intervention: positron emission tomography
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.
Intervention: computed tomography
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.
Intervention: pharmacological study
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.
Intervention: laboratory biomarker analysis
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.
Intervention: fludeoxyglucose F 18
Outcomes
Primary Outcomes
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 Outcomes
- 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(120 days)
- Time to treatment failure(120 days)
- Antitumor effect of molecularly targeted agents non-invasively by F18-FDG PET or PET/CT (Cohort II)(120 days)