Phase I Trial of the Combination of Vismodegib GDC-0449 and Erlotinib +/- Gemcitabine
概览
- 阶段
- 1 期
- 干预措施
- Diagnostic Laboratory Biomarker Analysis
- 疾病 / 适应症
- Adult Solid Neoplasm
- 发起方
- National Cancer Institute (NCI)
- 入组人数
- 55
- 试验地点
- 4
- 主要终点
- 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
- 状态
- 进行中（未招募）
- 最后更新
- 19天前
概览
简要总结
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.
详细描述
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.
研究者
入排标准
入选标准
- •Histologic proof of a solid tumor that is now unresectable, not amenable to any other standard therapies, or patient refuses standard therapy
- •Metastatic adenocarcinoma of the pancreas amenable to biopsies (cohort II MTD only)
- •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
排除标准
- •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:
- •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 therapy regardless of interval since last treatment
研究组 & 干预措施
Treatment (vismodegib, erlotinib hydrochloride, gemcitabine)
Patients receive Hedgehog antagonist GDC-0449 PO 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.
干预措施: Diagnostic Laboratory Biomarker Analysis
Treatment (vismodegib, erlotinib hydrochloride, gemcitabine)
Patients receive Hedgehog antagonist GDC-0449 PO 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.
干预措施: Erlotinib Hydrochloride
Treatment (vismodegib, erlotinib hydrochloride, gemcitabine)
Patients receive Hedgehog antagonist GDC-0449 PO 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.
干预措施: Gemcitabine Hydrochloride
Treatment (vismodegib, erlotinib hydrochloride, gemcitabine)
Patients receive Hedgehog antagonist GDC-0449 PO 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.
干预措施: Vismodegib
结局指标
主要结局
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
时间窗: 28 days
DLT will be defined as an adverse event, according to CTCAE version 3.0, attributed (definitely, probably, or possibly to the study treatment.
次要结局
- Adverse events as assessed by NCI CTCAE v3.0(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(Up to 3 months after completion of study treatment)
- Time to progression(Up to 3 months after completion of study treatment)
- Response as assessed by modified RECIST criteria(Up to 3 months after completion of study treatment)
- Time until treatment related grade 3+ toxicity(Up to 3 months after completion of study treatment)
- Time until hematologic nadirs (WBC, ANC, platelets)(Up to 3 months after completion of study treatment)
- Time to treatment failure(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)