Randomized Phase II Trial of Capecitabine and Lapatinib With or Without IMC-A12 in Patients With HER2 Positive Breast Cancer Previously Treated With Trastuzumab and an Anthracycline and/or a Taxane
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 64
- 试验地点
- 388
- 主要终点
- Progression-free Survival (PFS)
研究概览
简要总结
This phase II trial studies capecitabine and lapatinib ditosylate to see how well they work compared with capecitabine, lapatinib ditosylate, and cixutumumab in treating patients with previously treated HER2-positive stage IIIB-IV breast cancer. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with cixutumumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether capecitabine and lapatinib ditosylate are more effective when given with or without cixutumumab in treating breast cancer that has spread nearby or to other areas of the body.
详细描述
PRIMARY OBJECTIVE:
I. To compare progression-free survival of HER2+ breast cancer patients randomized to receive lapatinib ditosylate (lapatinib) and capecitabine +/- cixutumumab (IMC-A12).
SECONDARY OBJECTIVES:
I. To assess the safety and tolerability of lapatinib and capecitabine +/- IMC-A12 in HER2+ breast cancer patients.
II. To compare the overall survival time, time to treatment failure, confirmed tumor response rate, and duration of response of lapatinib and capecitabine +/- IMC-A12 in HER2+ breast cancer patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Histologically confirmed, locally advanced: (a T4 primary tumor and stage IIIB or IIIC disease) or metastatic breast cancer that has progressed after treatment with regimens that included trastuzumab and either an anthracycline or a taxane or both
- •NOTE: Agents need not have been given concurrently, nor in the same regimen
- •NOTE: Prior treatment with trastuzumab is required unless there is a contraindication for trastuzumab treatment
- •Pre-treatment requirements:
- •Prior treatment with trastuzumab in the neo-adjuvant, adjuvant or metastatic setting is required
- •NOTE: Prior treatment with trastuzumab is required unless there is a contraindication for trastuzumab treatment
- •NOTE: Concomitant use of trastuzumab is not allowed in this study
- •Prior chemotherapy allowed in the neo-adjuvant, adjuvant, or metastatic setting; unlimited prior chemotherapy is allowed
- •Prior hormonal therapy allowed in the neo-adjuvant, adjuvant, or metastatic setting; unlimited prior hormonal therapy is allowed
- •HER2 positive, defined as:
- •Validated immunohistochemistry (IHC) assay score of 3+ (defined as uniform, intense staining of > 30% of invasive tumor cells)
- •-OR- Average HER2 gene copy number of > 6
- •-OR- Gene amplified (HER2:D17Z1 ratio > 2.20)
- •Must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria
- •Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
- •Hemoglobin > 9.0 g/dL (obtained =< 7 days prior to registration)
- •White blood cells (WBC) >= 3,000/mL (obtained =< 7 days prior to registration)
- •Absolute neutrophil count (ANC) >= 1500/mL (obtained =< 7 days prior to registration)
- •Platelet count >= 75,000/mL (obtained =< 7 days prior to registration)
- •Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 7 days prior to registration)
- •Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x ULN or SGOT (AST) and SGPT (ALT) =< 5 x ULN if elevations are due to liver metastases (obtained =< 7 days prior to registration)
- •Serum creatinine =< 1.5 x ULN (obtained =< 7 days prior to registration)
- •Creatinine clearance >= 30 mL/min (calculated according to Cockcroft and Gault) (obtained =< 7 days prior to registration)
- •NOTE: In patients with moderate renal impairment (calculated creatinine clearance 30-50 mL/min) at baseline, a dose reduction of the capecitabine starting dose is required
- •Fasting glucose < 120 mg/dL (obtained =< 7 days prior to registration)
- •NOTE: Patients with diabetes are allowed to participate, provided that their blood glucose is within the guidelines above upon enrollment
- •International normalization ratio (INR) =< 1.5 x ULN (obtained =< 7 days prior to registration)
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2
- •Adequate cardiac function defined as an ejection fraction >= 50% as determined by multi gated acquisition scan (MUGA) or echocardiogram
- •Life expectancy > 3 months
- •Has written informed consent been obtained?
- •Willingness to return to a North Central Cancer Treatment Group (NCCTG) or other participating cooperative group institution for treatment and follow-up
- •Patient willing to provide tissue and blood samples for research purposes
- •Availability of diagnostic material (i.e., diagnostic slides confirming locally advanced/metastatic disease and HER2 stained slides) and operative and pathology reports from diagnosis of locally advanced or metastatic breast cancer
- •NOTE: Biopsy of recurrent disease and submission of these materials is not required if materials available from initial diagnosis of locally advanced/metastatic disease
- •Ability to complete questionnaire(s) by themselves or with assistance
排除标准
- •Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
- •Pregnant women
- •Nursing women
- •Men or women of childbearing potential who are unwilling to employ adequate contraception (as determined by the treating physician)
- •Stage III or IV invasive cancer, other than breast cancer, in =< 5 years prior to registration
- •Actively being treated for other malignancy, excepting non-melanotic skin cancer or carcinoma-in-situ of the cervix; if there is a history of prior malignancy, patient must not be receiving other specific treatment for their cancer
- •New York Heart Association class III or IV cardiovascular disease
- •Current, active hepatic or biliary disease except Gilbert's syndrome or asymptomatic gallstones
- •Evidence of active brain metastasis including leptomeningeal involvement; central nervous system (CNS) metastasis controlled by prior surgery and/or radiotherapy is allowed
- •NOTE: To be considered controlled, there must be at least 2 months of no symptoms or evidence of progression prior to study entry and corticosteroid therapy must have been discontinued
- •Major surgery, chemotherapy, or immunologic therapy =< 4 weeks prior to registration
- •Radiotherapy =< 4 weeks prior to registration, except if to a non-target lesion only; prior radiation to a target lesion is permitted only if there has been clear progression of the lesion since radiation was completed; if patient receives single dose radiation for palliation or radiation to non-target lesion, they may immediately proceed to registration without waiting; acute adverse events from radiation must have resolved to =< Common Terminology Criteria for Adverse Events (CTCAE) version (v) 3.0 grade 1
- •Prior treatment with any therapy targeting IGF-I, IGF-II or its receptors (either monoclonal antibody or tyrosine kinase inhibitor), including but not limited to any of the following (which would have been received on a previous clinical trial):
- •IMC-A12 (cixutumumab)
- •CP-751,871 (figitumumab)
- •MK0646 (h7C10)
- •SCH717454 (19D12, robatumumab)
- •BMS-754807
- •NVP-AEW541
- •Prior therapy with any therapy targeting HER1 (EGFR) and/or HER2 (either monoclonal antibody or tyrosine kinase) other than trastuzumab, including but not limited to any of the following:
- •Lapatinib (Tykerb)
- •Gefitinib (Iressa)
- •Erlotinib (Tarceva)
- •Cetuximab (Erbitux)
- •Panitumumab (Vectibix)
- •Currently receiving treatment with any agents that are contraindicated by study therapies:
- •IMC-A12 - none identified to date
- •Lapatinib - CYP3A4 inhibitors and inducers, including grapefruit and grapefruit juice
- •Capecitabine - warfarin (Coumadin), cimetidine (Tagamet), allopurinol (Lopurin), sorivudine (Usevir) or brivudine (Brivex), ketoconazole (Nizoral), itraconazole (Sporanox), ritonavir (Norvir), amprenavir (Agenerase) or indinavir (Crixivan)
- •Uncontrolled intercurrent illness including, but not limited to:
- •Poorly controlled diabetes
- •Ongoing or active infection
- •Symptomatic congestive heart failure
- •Unstable angina pectoris
- •Cardiac arrhythmia
- •Psychiatric illness/social situations that would limit compliance with study requirements
- •Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of the safety of the prescribed regimens
- •Currently receiving treatment in a different clinical study in which investigational procedures are performed or investigational therapies are administered
- •Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive with an acquired immune deficiency syndrome (AIDS)-defining illness; HIV positive patients with cluster of differentiation (CD) 4 count within institutional normal range and no history of an AIDS-defining illness are eligible; however, some antiviral/antiretroviral medications which have CYP3A4 interactions are prohibited on this study
研究组 & 干预措施
Arm A (lapatinib ditosylate, capecitabine)
Patients receive capecitabine PO BID on days 1-14 and lapatinib ditosylate PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: Capecitabine (Drug)
Arm A (lapatinib ditosylate, capecitabine)
Patients receive capecitabine PO BID on days 1-14 and lapatinib ditosylate PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: Lapatinib Ditosylate (Drug)
Arm A (lapatinib ditosylate, capecitabine)
Patients receive capecitabine PO BID on days 1-14 and lapatinib ditosylate PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: Quality-of-Life Assessment (Other)
Arm B (cixutumumab, lapatinib ditosylate, capecitabine)
Patients receive capecitabine and lapatinib ditosylate as in Arm A. Patients also receive cixutumumab IV over 1 hour on days 1, 8, and 15. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: Capecitabine (Drug)
Arm B (cixutumumab, lapatinib ditosylate, capecitabine)
Patients receive capecitabine and lapatinib ditosylate as in Arm A. Patients also receive cixutumumab IV over 1 hour on days 1, 8, and 15. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: Cixutumumab (Biological)
Arm B (cixutumumab, lapatinib ditosylate, capecitabine)
Patients receive capecitabine and lapatinib ditosylate as in Arm A. Patients also receive cixutumumab IV over 1 hour on days 1, 8, and 15. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: Lapatinib Ditosylate (Drug)
Arm B (cixutumumab, lapatinib ditosylate, capecitabine)
Patients receive capecitabine and lapatinib ditosylate as in Arm A. Patients also receive cixutumumab IV over 1 hour on days 1, 8, and 15. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
干预措施: Quality-of-Life Assessment (Other)
结局指标
主要结局
Progression-free Survival (PFS)
时间窗: From randomization to the earliest date of documentation of disease progression, up to 5 years
Analysis of the primary endpoint, PFS, will be performed using Cox regression with treatment group as a single covariate.
次要结局
- Confirmed Tumor Response, Defined as Either a Complete Response (CR) or Partial Response (PR) Noted as the Objective Status on 2 Consecutive Evaluations at Least 6 Weeks Apart, Assessed by Response Evaluation Criteria for Solid Tumors (RECIST)(Up to 5 years)
- Adverse Event Profile of Capecitabine and Lapatinib With and Without IMC-A12 (Using NCI CTCAE v3.0)(Baseline to 30 days past end of treatment)
- Time to Treatment Failure(From the date of randomization to the date at which the patient is removed from treatment due to progression, adverse events, or refusal, up to 5 years)
- Overall Survival(From randomization to death due to any cause, up to 5 years)
- Duration of Response(Up to 5 years)