Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined With FOLFOX Chemotherapy in Metastatic Colorectal Cancer (CA180048)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 86
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of Dasatinib, Cetuximab and FOLFOX
研究概览
简要总结
The goal of the Phase I part of this clinical research study is to find the highest tolerable dose of a combination of dasatinib, cetuximab, and FOLFOX (5-fluorouracil [5-FU], leucovorin [LV], and Eloxatin [oxaliplatin]) that can be given to patients with metastatic colorectal cancer. The safety of these drugs in combination will also be studied.
The goal of the Phase II part of this clinical research study is to learn if dasatinib given in combination with FOLFOX with or without cetuximab can help to control metastatic colorectal cancer.
详细描述
Cetuximab is a drug designed to block the activity of EGFR, a protein on the surface of some tumor cells that may cause the cells to grow. Blocking EGFR may stop or slow the growth of tumor cells. Dasatinib is a drug that inhibits a protein called c-Src. High levels of c-Src may make it harder for chemotherapy to work against the cancer. If dasatinib can inhibit c-Src, the chemotherapy may be more effective against the cancer. FOLFOX is a drug combination frequently used to treat colon or rectal cancer that has spread to other parts of the body. FOLFOX is designed to kill rapidly dividing cells by preventing DNA (the genetic material of cells) from duplicating.
Kirsten Rat Sarcoma (KRAS) Testing:
Recent studies have found that cetuximab, when given alone or in combination with other chemotherapy drugs, was not effective when given to patients with colorectal cancer that had a KRAS gene mutation.
If you take part in the Phase I part of this study, your tumor tissue from a previous biopsy or surgery will be used to test for KRAS mutation. If you have the KRAS gene mutation, you will not take part in this study.
If you take part in the Phase II part of this study, your tumor tissue from a previous biopsy or surgery will be used to test for KRAS mutation. If you have the KRAS gene mutation, you may take part in the study but you will not receive cetuximab.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient must have histologically or cytologically confirmed colorectal adenocarcinoma with metastatic disease documented on diagnostic imaging studies
- •Phase IB: Patient must have wild type KRAS.
- •Phase IB: For the expansion cohort, only patients with liver metastases >/= 2.0 cm amenable to percutaneous CT or U/S guided biopsy and who agree to having 2 liver biopsies done are eligible.
- •Phase II: Patient must have known KRAS (exon 1, codon 12, 13) or sufficient available tumor tissue from the primary tumor or metastatic site for KRAS mutation analysis [Phase II only].
- •Patient must have previously progressed on systemic therapy for metastatic colorectal cancer, with no limit on the number of prior regimens. For patients in the Phase II cohort, they must have progressed on 5-FU or capecitabine and oxaliplatin [patients with KRAS mutated tumors], and either cetuximab or panitumumab [patients with KRAS wild type tumors].
- •(Continued from # 5) The following criteria must be met for progression. • Baseline imaging was performed 1 month or less prior to starting regimen. • Average treatment intensity (number of cycles received/number of cycles anticipated in absence of delays) of greater than 70%. • Restaging study demonstrating progression 6 weeks or less from last dose of oxaliplatin and EGFR inhibitor (if applicable). • Progression may be by RECIST criteria or, with PI approval, clinical progression.
- •Written informed consent obtained
- •Age >/= 18 years to provide a uniform oncologic phenotype of adult-onset colorectal cancer.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix E)
- •Patients must have adequate organ and marrow function defined as: absolute neutrophil count (ANC) >/= 1,500/mm^3; platelets >/= 100,000/ mm^3; hemoglobin >/= 9 gm/dL (may be transfused to maintain or exceed this level); total bilirubin </= 1.5 mg/dL; AST (SGOT)/ALT(SGPT) </= 2.5 times institution's upper limit of normal (IULN), or </= 5 times IULN if known liver metastases; · Creatinine clearance > 60mL/min using Cockcroft-Gault formula.
- •Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of study medications. Childbearing potential is defined as a woman who is not post-menopausal for 12 months or longer or is not surgically sterile. Patients must agree to practice acceptable contraceptive methods as outlined in the protocol.
排除标准
- •Recent (within 4 weeks of the first infusion of study drugs on this study), or planned participation in another experimental therapeutic drug study. Patients who have had any systemic chemotherapy, radiotherapy, or major surgery within 21 days prior to the first infusion of study drugs.
- •Patients who have not recovered to </= grade 2 for neuropathy or </= grade 1 for other side effects due to prior treatment.
- •Patients with radiographic evidence of pleural effusions in the last 30 days prior to enrollment.
- •Patients with known brain metastases because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
- •Female patients who are pregnant or lactating or men and women of reproductive potential not willing to employ an effective method of birth control during treatment and for 3 weeks after discontinuing study treatment
- •Patients with known dihydropyrimidine dehydrogenase deficiency.
- •Patients with a history of significant bleeding disorder unrelated to cancer, including: Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease); Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
- •Patients currently taking the following drugs that are generally accepted to have a risk of causing Torsades de Pointes:haloperidol, methadone, amiodarone, sotalol, erythromycins, clarithromycin cisapride, chlorpromazine, bepridil, droperidol, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine, quinidine, procainamide, disopyramide, ibutilide, dofetilide. Subjects who have discontinued any of these medications must have a wash-out of at least 5 days (or 14 days for amiodarone) prior to the first dose of dasatinib.
- •Patients with wild type KRAS tumors with a history of allergic reactions attributed to cetuximab, oxaliplatin, 5-FU, capecitabine, or leucovorin that, previously, have not been adequately prevented with premedications.
- •Current use of full-dose warfarin (except as required to maintain patency of preexisting, permanent indwelling IV catheters). For subjects receiving warfarin for catheter patency, international normalized ratio (INR) should be < 1.
- •Current or recent (<2 week) use of aspirin (at a dose greater than 81 mg/day) or clopidogrel.
- •Diagnosed or suspected congenital long QT syndrome
- •Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).
- •Previous allergic reaction to a human monoclonal antibody.
- •Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec) on both the Fridericia [QTc = QT/RR^1/3] and Bazett's [QTc = QT/sqrtRR] correction. Bazett's correction is calculated automatically by institutional EKG machines
- •Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: Uncontrolled high blood pressure (systolic blood pressure >/= 140 and diastolic blood pressure >/= 90), history of labile hypertension, or history of poor compliance with an antihypertensive regimen. Unstable angina or stable angina markedly limiting ordinary physical activity. (Angina occurs on walking one to two blocks on the level and climbing one flight of stairs in normal conditions and at a normal pace) .
- •Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: New York Heart Association (NYHA) >/= grade 2 congestive heart failure; Myocardial infarction within 6 months of study enrollment; History of stroke within 6 months of study enrollment; Unstable symptomatic arrhythmia requiring medication (Patients with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal SVT are eligible); Clinically significant peripheral vascular disease; Uncontrolled diabetes; Serious active or uncontrolled infection
- •History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of a study drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications
- •Inability to take oral medications.
- •Inability to comply with study and/or follow-up procedures.
研究组 & 干预措施
FOLFOX + Dasatinib + Cetuximab
5-FU 2400 mg/m^2 by vein over 46 Hours On Days 1 & 2. Cetuximab initial dose = 400 mg/m^2 by vein, then 250 mg/m^2 Weekly On Days 1 & 8. Dasatinib 100 mg by mouth daily on days 1-14. Leucovorin 400 mg/m^2 by vein on day 1. Oxaliplatin 85 mg/m^2 by vein on day 1.
干预措施: 5-FU (Drug)
FOLFOX + Dasatinib + Cetuximab
5-FU 2400 mg/m^2 by vein over 46 Hours On Days 1 & 2. Cetuximab initial dose = 400 mg/m^2 by vein, then 250 mg/m^2 Weekly On Days 1 & 8. Dasatinib 100 mg by mouth daily on days 1-14. Leucovorin 400 mg/m^2 by vein on day 1. Oxaliplatin 85 mg/m^2 by vein on day 1.
干预措施: Cetuximab (Drug)
FOLFOX + Dasatinib + Cetuximab
5-FU 2400 mg/m^2 by vein over 46 Hours On Days 1 & 2. Cetuximab initial dose = 400 mg/m^2 by vein, then 250 mg/m^2 Weekly On Days 1 & 8. Dasatinib 100 mg by mouth daily on days 1-14. Leucovorin 400 mg/m^2 by vein on day 1. Oxaliplatin 85 mg/m^2 by vein on day 1.
干预措施: Dasatinib (Drug)
FOLFOX + Dasatinib + Cetuximab
5-FU 2400 mg/m^2 by vein over 46 Hours On Days 1 & 2. Cetuximab initial dose = 400 mg/m^2 by vein, then 250 mg/m^2 Weekly On Days 1 & 8. Dasatinib 100 mg by mouth daily on days 1-14. Leucovorin 400 mg/m^2 by vein on day 1. Oxaliplatin 85 mg/m^2 by vein on day 1.
干预措施: Leucovorin (Drug)
FOLFOX + Dasatinib + Cetuximab
5-FU 2400 mg/m^2 by vein over 46 Hours On Days 1 & 2. Cetuximab initial dose = 400 mg/m^2 by vein, then 250 mg/m^2 Weekly On Days 1 & 8. Dasatinib 100 mg by mouth daily on days 1-14. Leucovorin 400 mg/m^2 by vein on day 1. Oxaliplatin 85 mg/m^2 by vein on day 1.
干预措施: Oxaliplatin (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Dasatinib, Cetuximab and FOLFOX
时间窗: 2 Week Cycles
If 2 or more out of the 6 patients in the cohort have dose limiting toxicity (DLT) then the prior dose level is the MTD.
次要结局
- Response-Rate of Dasatinib and Modified FOLFOX6 With or Without Cetuximab(After 4, 14 day cycles)