A Phase II Trial of Neoadjuvant MK-2206 in Combination With Either Anastrozole if Postmenopausal or Anastrozole and Goserelin if Premenopausal in Women With Clinical Stage 2 or 3 PIK3CA Mutant Estrogen Receptor Positive and HER2 Negative Invasive Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 16
- 试验地点
- 8
- 主要终点
- Pathological Complete Response Rate
研究概览
简要总结
This phase II trial studies how well Akt inhibitor MK-2206 (MK-2206) and anastrozole with or without goserelin acetate works in treating patients with stage II-III breast cancer. MK-2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using anastrozole and goserelin acetate may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving MK-2206, anastrozole, and goserelin acetate together may kill more tumor cells.
详细描述
PRIMARY OBJECTIVES:
I. To determine the pathologic complete response (pCR) rate of neoadjuvant MK-2206 (Akt inhibitor MK-2206) in combination with anastrozole (goserelin [goserelin acetate] is added if premenopausal) in women with clinical stage II or III phosphatidlinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutated estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- breast cancer.
SECONDARY OBJECTIVES:
I. To determine the safety profile of neoadjuvant MK-2206 in combination with anastrozole (goserelin is added if premenopausal) in women with clinical stage II or III PIK3CA mutated ER+/HER2- breast cancer.
II. To estimate the rate of clinical response and radiologic response using the World Health Organization (WHO) criteria.
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
- Female
- 接受健康志愿者
- 否
入选标准
- •Clinical T2-T4c, any N, M0 invasive ER+ (Allred score of 6-8) and HER2 negative (0 or 1+ by immunohistochemistry [IHC] or fluorescence in situ hybridization [FISH] negative for amplification) breast cancer, by American Joint Committee on Cancer (AJCC) 7th edition clinical staging, with the goal being surgery to completely excise the tumor in the breast and the lymph node;
- •Note: if the patient has invasive or ductal carcinoma in situ (DCIS) in the contralateral breast the patient is not eligible for this study
- •>= 1 measurable lesion that is palpable, its size can be measured by bi-dimensional tape, ruler or caliper technique, and the minimum size of the largest tumor diameter is greater than 2.0 cm by imaging or physical examination
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
- •Life expectancy > 4 months
- •Leukocytes >= 3,000/mcL
- •Absolute neutrophil count >= 1,500/mcL
- •Platelets >= 100,000/mcL
- •Total bilirubin =< upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
- •Creatinine =< ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine above institutional normal
- •Patient with diabetes mellitus: fasting glucose =< 120 mg/dL and hemoglobin A1c (HbA1c) =< 8%
- •Negative serum pregnancy test =< 7 days prior to pre-registration for women of childbearing potential
- •Ability to understand and the willingness to sign a written informed consent document
- •Patient is postmenopausal or premenopausal
- •NOTE: postmenopausal women, verified by
- •Bilateral surgical oophorectomy, or
- •No spontaneous menses >= 1 year or
- •No menses for < 1 year with follicle stimulating hormone (FSH) and estradiol levels in postmenopausal range, according to institutional standards or
- •Premenopausal women, verified by:
- •Regular menses or
- •FSH and estradiol levels in premenopausal range, according to institutional standards
- •Willingness to provide biologic samples for PIK3CA sequencing and correlative studies
- •Positive for PIK3CA mutation based on central laboratory testing
- •In premenopausal women, serum estradiol level in postmenopausal range =< 7 days prior to registration
排除标准
- •Any of the following for treatment of this cancer including:
- •Radiation therapy
- •Chemotherapy
- •Biotherapy
- •Hormonal therapy
- •Investigational agent prior to study entry
- •Receiving any other investigational agents
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206 or other agents used in this study
- •Prior axillary lymph node sampling (sentinel lymph node biopsy or axillary lymph node dissection); NOTE: fine needle aspiration (FNA) of axillary lymph node is acceptable
- •Invasive cancer or DCIS in the contralateral breast
- •Receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP450 3A4);
- •NOTE: oxidative metabolism of MK-2206 in human liver microsomes is catalyzed primarily by CYP3A4, although direct glucuronidation also occurs; at least 7 days washout period is required in patients who were previously taking strong inhibitors or inducers of CYP.450 3A4; patients who are currently taking moderate inhibitors or inducers of CYP450 3A4 are encouraged to switch to other medications that do not interact with CYP450 3A4
- •Corrected QT interval (QTc) prolongation (defined as a QTc interval > 480 msec) or other significant electrocardiogram (ECG) abnormalities
- •Receiving any medications or substances with risk of torsades de pointes; Note: medications or substances on the list "Drugs with Risk of Torsades de Pointes" are prohibited; medications or substances on the list "Drugs with Possible or Conditional Risk of Torsades de Pointes" may be used while on study with extreme caution and careful monitoring
- •Uncontrolled intercurrent illness including, but not limited to:
- •Ongoing or active infection
- •Symptomatic congestive heart failure
- •Unstable angina pectoris
- •Uncontrolled symptomatic cardiac arrhythmia
- •Psychiatric illness/social situations that would limit compliance with study requirements
- •Any of the following:
- •Pregnant women
- •Nursing women
- •Women of childbearing potential who are unwilling to employ adequate contraception
- •NOTE: breastfeeding should be discontinued if the mother is treated with MK-2206; women of childbearing potential must use two forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
- •Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy; NOTE: HIV-positive patients on combination antiretroviral therapy are ineligible; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
- •Evidence of inflammatory cancer (clinical presentation of skin erythema involving more than one third of the breast or pathological evidence of dermal lymphatic involvement)
- •Patients with known metastatic disease are excluded
- •Current use of therapeutic anticoagulation therapy
- •Previous excisional biopsy of the breast cancer
- •Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous [IV] alimentation, prior surgical procedures affecting absorption) that impairs patients ability to swallow MK-2206 tablets
研究组 & 干预措施
Treatment (MK2206, anastrozole, goserelin acetate)
Patients receive Akt inhibitor MK-2206 PO on days 2, 9, 16, and 23; anastrozole PO daily on days 1-28; and goserelin acetate SC on day 1 (premenopausal patients only). Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Akt Inhibitor MK2206 (Drug)
Treatment (MK2206, anastrozole, goserelin acetate)
Patients receive Akt inhibitor MK-2206 PO on days 2, 9, 16, and 23; anastrozole PO daily on days 1-28; and goserelin acetate SC on day 1 (premenopausal patients only). Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Anastrozole (Drug)
Treatment (MK2206, anastrozole, goserelin acetate)
Patients receive Akt inhibitor MK-2206 PO on days 2, 9, 16, and 23; anastrozole PO daily on days 1-28; and goserelin acetate SC on day 1 (premenopausal patients only). Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Goserelin Acetate (Drug)
Treatment (MK2206, anastrozole, goserelin acetate)
Patients receive Akt inhibitor MK-2206 PO on days 2, 9, 16, and 23; anastrozole PO daily on days 1-28; and goserelin acetate SC on day 1 (premenopausal patients only). Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (MK2206, anastrozole, goserelin acetate)
Patients receive Akt inhibitor MK-2206 PO on days 2, 9, 16, and 23; anastrozole PO daily on days 1-28; and goserelin acetate SC on day 1 (premenopausal patients only). Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Neoadjuvant Therapy (Procedure)
Treatment (MK2206, anastrozole, goserelin acetate)
Patients receive Akt inhibitor MK-2206 PO on days 2, 9, 16, and 23; anastrozole PO daily on days 1-28; and goserelin acetate SC on day 1 (premenopausal patients only). Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Treatment (MK2206, anastrozole, goserelin acetate)
Patients receive Akt inhibitor MK-2206 PO on days 2, 9, 16, and 23; anastrozole PO daily on days 1-28; and goserelin acetate SC on day 1 (premenopausal patients only). Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Therapeutic Conventional Surgery (Procedure)
结局指标
主要结局
Pathological Complete Response Rate
时间窗: At time of surgery (up to 3 weeks after 4, 28-day cycles)
Any woman whose Ki67 value ≤10% on cycle 1 day 17 of combination treatment who does not receive alternative treatment prior to surgery and has no histologic evidence of invasive tumor cells in the surgical breast specimen and the axillary lymph nodes is considered to have a pathological complete response (pCR). A ninety percent confidence interval for the true pathologic complete response rate will be calculated using the Duffy-Santer approach.
次要结局
- Radiological Response Rate(Baseline and completion of cycle 4 (28 day cycles))
- Clinical Response Rate(Baseline to end of Cycle 4 (28 day cycles))
- Incidence of Adverse Events, Based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0(Baseline to end of Cycle 4 (28 day cycles))