Phase I Trial of the Combination of Vismodegib GDC-0449 and Erlotinib +/- Gemcitabine
Phase I Trial of the Combination of Vismodegib GDC-0449 and Erlotinib +/- Gemcitabine
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.
Inclusion Criteria:
Histologic proof of a solid tumor that is now unresectable, not amenable to any other standard therapies, or patient refuses standard therapy
Absolute neutrophil count (ANC) >= 1,500/μL
Platelets >= 100,000/μL
Total bilirubin =< upper limit of normal (ULN)
Aspartate aminotransferase (AST) =< 3 times upper limit of normal (ULN)
Creatinine =< 1.5 times ULN
Hemoglobin >= 9.0 g/dL
International Normalized Ratio (INR) within normal limits (for patients treated at the MTD)
Ability to provide informed consent
Willingness to return to Mayo Clinic for follow up
Life expectancy >= 12 weeks
Willingness to provide the biologic specimens as required by the protocol
Negative serum pregnancy test done =< 7 days prior to registration
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
Able to swallow or have medication administered through a G-tube and absorb the medication
Participant agrees to use an acceptable form of contraception; acceptable forms of contraception:
Acceptable forms of secondary contraceptions, when used along with a barrier method:
Unacceptable forms of contraception for women of childbearing potential:
Oral contraception containing progestins only
IUD progesterone T
Female condom
Natural family planning (rhythm method) or breastfeeding
Fertility awareness
Withdrawal
Cervical shield
Exclusion Criteria:
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, or psychiatric illness/social situations that would limit compliance with study requirements
Any of the following prior therapies:
Failure to fully recover from acute, reversible effects of prior therapy regardless of interval since last treatment
New York Heart Association classification III or IV
Seizure disorder
Central nervous system (CNS) metastases if not stable for at least 2-3 months based on imaging, clinical assessment, and use of steroids, or seizure disorder
Pregnant women
Nursing women
Men or women of childbearing potential who are unwilling to employ adequate contraception until 12 months after last study drug dose
Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation)
Current therapy with a CYP3A4 inhibitor or inducer
Immunocompromised patients (other than that related to the use of corticosteroids) including patients receiving highly active antiretroviral therapy (HAART) treatment
Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
Active other malignancy, excepting non-melanotic skin cancer or carcinoma-in-situ of the cervix; 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)
More than 2 prior chemotherapy regimens for the current metastatic malignancy; full dose chemotherapy used in conjunction with concurrent radiation therapy will be included as prior therapy; Note: prior hormonal therapy (e.g. leuprolide, aromatase inhibitors, tamoxifen) will be allowed and not included as a prior chemotherapy
Previous therapy with a hedgehog inhibitor