This phase I trial is studying the side effects and best dose of erlotinib hydrochloride when given together with GDC-0449 with or without gemcitabine hydrochloride in treating patients with metastatic pancreatic cancer or solid tumors that cannot be removed by surgery. Drugs used in chemotherapy, such as GDC-0449 and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving GDC-0449 together with erlotinib hydrochloride with or without gemcitabine hydrochloride may kill more tumor cells.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of erlotinib hydrochloride and Hedgehog antagonist GDC-0449 with or without gemcitabine hydrochloride in patients with unresectable solid tumors. SECONDARY OBJECTIVES: I. To describe the adverse events profile associated with these treatment regimens. II. To describe the responses in patients treated with these regimens. III. To assess the effect of erlotinib hydrochloride and Hedgehog antagonist GDC-0449 on selected biomarkers in circulating tumor cells and tumor biopsy samples from patients with metastatic pancreatic cancer. IV. To assess the effect of erlotinib hydrochloride and Hedgehog antagonist GDC-0449 on fludeoxyglucose F 18 positron emission tomography imaging in patients with metastatic pancreatic cancer. V. To study the association between clinical (toxicity and/or tumor response or activity) and biologic (pharmacodynamic) results associated with erlotinib hydrochloride and Hedgehog antagonist GDC-0449 in patients with metastatic pancreatic cancer. OUTLINE: This is a dose-escalation study of erlotinib hydrochloride. Patients receive Hedgehog antagonist GDC-0449 orally (PO) once daily (QD) and erlotinib hydrochloride PO QD on days 1-28. Some patients also receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients treated at the maximum tolerated dose undergo fludeoxyglucose F 18 positron emission tomography at baseline and on day 28. These patients also undergo tumor tissue and blood sample collection at baseline and periodically during study for correlative laboratory studies. Samples are analyzed for tyrosine phosphorylated or total MAP-K, EGFR, AKT, and other potential biomarkers of activity/response and for levels of genes transcriptionally activated (e.g., BCL-2, GLI, BFL-1/A1, 4-1BB, PTC1) by immunofluorescence, IHC, and quantitative-PCR. After completion of study therapy, patients are followed at 3 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
55
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
Mayo Clinic in Florida
Jacksonville, Florida, United States
Orlando Health Cancer Institute
Orlando, Florida, United States
Mayo Clinic in Rochester
Rochester, Minnesota, United States
Maximum tolerated dose of erlotinib hydrochloride defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients
DLT will be defined as an adverse event, according to CTCAE version 3.0, attributed (definitely, probably, or possibly to the study treatment.
Time frame: 28 days
Adverse events as assessed by NCI CTCAE v3.0
The number and severity of all adverse events (overall, and by dose-level) will be tabulated and summarized.
Time frame: Up to 3 months after completion of study treatment
Toxicity, defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment, graded using the NCI CTCAE version 3.0
Time frame: Up to 3 months after completion of study treatment
Response as assessed by modified RECIST criteria
Summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease.
Time frame: Up to 3 months after completion of study treatment
Time until treatment related grade 3+ toxicity
Time frame: Up to 3 months after completion of study treatment
Time until hematologic nadirs (WBC, ANC, platelets)
Time frame: Up to 3 months after completion of study treatment
Time to progression
Time frame: Up to 3 months after completion of study treatment
Time to treatment failure
Time frame: From registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by the patient, assessed up to 3 months after completion of study treatment
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