A Phase I/II Study of Preoperative (Neoadjuvant) Combination of Letrozole (Femara), Everolimus (Afinitor), and TRC105 in Postmenopausal Women With Newly Diagnosed Local or Locally Advanced Potentially Resectable Hormone-Receptor Positive and Her2 Negative Breast Cancer
概览
- 阶段
- 1 期
- 干预措施
- Letrozole
- 疾病 / 适应症
- Breast Cancer
- 发起方
- University of Alabama at Birmingham
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Number of Participants Who Experienced Dose-limiting Toxicities
- 状态
- 已完成
- 最后更新
- 2个月前
概览
简要总结
This study will test how well a new combination of three drugs (Letrozole, Everolimus, and TRC105) is tolerated and how well it works in Stage 2 and 3 breast cancer when given prior to definitive surgery. Letrozole blocks the estrogen receptor expressed by many breast cancers while everolimus blocks signals that drive cancer cells to grow. TRC105 is an investigational drug that blocks the formation and growth of blood vessels that feed the cancer and promote its growth. The goal of this study is to investigate the safety and efficacy of this multitargeted approach in breast cancer.
详细描述
In postmenopausal women with hormone receptor-positive and Her2 negative non-metastatic breast cancer, downstaging or the achievement of a complete pathologic remission before definitive surgery has been associated with the lowest risk of recurrence of breast cancer. In order to achieve a better response in these patients in the preoperative setting, this study combines 3 potentially synergistic agents. Letrozole blocks the synthesis of estrogens and, in doing so, deprives the tumor from hormones which drive its growth. Everolimus is a drug that blocks growth factor signaling which is essential for tumor cells to maintain their growth and proliferation. Everolimus has already been shown to work very well in this subtype of breast cancer in the recurrent and metastatic setting. TRC105 is an investigational agent that prevents the formation and growth of new blood vessels that support tumors by providing oxygen and nutrients. The study has 2 components. First the investigators will determine the ideal in terms of tolerance combination of doses of the 3 agents. Once the ideal regimen is determined, more patients will be treated with the investigational combination. During this second stage, the investigators will get a preliminary idea of how effective the investigational therapy is. Further studies will need to be done to confirm the efficacy of the investigational combination.
研究者
Christos Vaklavas, MD
Associate Professor
University of Utah
入排标准
入选标准
- •Recent diagnosis of hormone receptor positive and HER2 negative breast cancer.
- •Stage 2 and 3 hormone receptor positive and HER2 negative breast cancer (stage T2-4 but not inflammatory, N0-2, M0).
- •Histological grade I, II or III according to the modified Bloom Richardson scale.
- •No prior treatment specific for breast cancer.
- •Postmenopausal status as defined by the National Comprehensive Cancer Network.
- •ECOG performance status \< 2 (Karnofsky \> 60%).
- •Must have signed study-specific informed consent.
- •Liver Function Tests \< 2.5 times the upper normal limit (UNL).
- •ANC ≥ 1,500/mm3, platelets ≥ 100,000/mm3, Hemoglobin ≥ 10g%.
- •Renal function: serum creatinine \< 1.5 institutional UNL or creatinine clearance \> 40 cc/min.
排除标准
- •Inflammatory breast cancer.
- •Pre- and peri-menopausal state.
- •Pregnancy.
- •Metastatic disease.
- •HER2 positive breast cancer by immunohistochemistry or FISH.
- •Triple negative breast cancer (hormone receptor and Her2 negative).
- •Disease that cannot be followed by imaging studies.
研究组 & 干预措施
Phase I Cohort 1
Letrozole 2.5 mg PO daily until surgery, everolimus 5 mg PO daily for 24 weeks, and TRC105 15 mg/kg IV q 2 weeks for 24 weeks
干预措施: Letrozole
Phase I Cohort 1
Letrozole 2.5 mg PO daily until surgery, everolimus 5 mg PO daily for 24 weeks, and TRC105 15 mg/kg IV q 2 weeks for 24 weeks
干预措施: Everolimus
Phase I Cohort 1
Letrozole 2.5 mg PO daily until surgery, everolimus 5 mg PO daily for 24 weeks, and TRC105 15 mg/kg IV q 2 weeks for 24 weeks
干预措施: TRC105
Phase I Cohort 2
Letrozole 2.5 mg PO daily until surgery, everolimus 10 mg PO daily for 24 weeks, and TRC105 15 mg/kg IV q 2 weeks for 24 weeks
干预措施: Letrozole
Phase I Cohort 2
Letrozole 2.5 mg PO daily until surgery, everolimus 10 mg PO daily for 24 weeks, and TRC105 15 mg/kg IV q 2 weeks for 24 weeks
干预措施: Everolimus
Phase I Cohort 2
Letrozole 2.5 mg PO daily until surgery, everolimus 10 mg PO daily for 24 weeks, and TRC105 15 mg/kg IV q 2 weeks for 24 weeks
干预措施: TRC105
Phase I Cohort -1
Letrozole 2.5 mg PO daily until surgery, everolimus 5 mg PO daily for 24 weeks, and TRC105 10 mg/kg IV q 2 weeks for 24 weeks
干预措施: Letrozole
Phase I Cohort -1
Letrozole 2.5 mg PO daily until surgery, everolimus 5 mg PO daily for 24 weeks, and TRC105 10 mg/kg IV q 2 weeks for 24 weeks
干预措施: Everolimus
Phase I Cohort -1
Letrozole 2.5 mg PO daily until surgery, everolimus 5 mg PO daily for 24 weeks, and TRC105 10 mg/kg IV q 2 weeks for 24 weeks
干预措施: TRC105
Phase II
Letrozole 2.5 mg PO daily until surgery, everolimus 5 or 10 mg PO daily for 24 weeks, and TRC105 15 or 10 mg/kg IV q 2 weeks for 24 weeks. Dose and regimen to be determined based on data from the phase I component.
干预措施: Letrozole
Phase II
Letrozole 2.5 mg PO daily until surgery, everolimus 5 or 10 mg PO daily for 24 weeks, and TRC105 15 or 10 mg/kg IV q 2 weeks for 24 weeks. Dose and regimen to be determined based on data from the phase I component.
干预措施: Everolimus
Phase II
Letrozole 2.5 mg PO daily until surgery, everolimus 5 or 10 mg PO daily for 24 weeks, and TRC105 15 or 10 mg/kg IV q 2 weeks for 24 weeks. Dose and regimen to be determined based on data from the phase I component.
干预措施: TRC105
结局指标
主要结局
Number of Participants Who Experienced Dose-limiting Toxicities
时间窗: 4 weeks
This outcome will report the number of patients who experienced a dose-limiting Toxicity (DLT) in Phase I Cohort 1, Phase I Cohort 2, and Phase I Cohort -1. A DLT was defined as: 1. A grade 3 or 4 non-hematologic toxicity except anorexia, alopecia, nausea (which is not refractory to antiemetics), fatigue, and fever without neutropenia; 2. Failure to recover to baseline (except alopecia) after delaying the next dose by more than 14 days; 3. Grade 3 or 4 neutropenia complicated by fever \>38.5°C or infection, or grade 4 neutropenia of ≥7 days duration; or 4. Grade 4 thrombocytopenia, or grade 3 thrombocytopenia complicated by hemorrhage. The maximum tolerated dose (MTD) is defined as the highest dose at which 0 out of the first 3 or 1 out of a total of 6 patients experience DLT during the first cycle of therapy; this dose level will be the recommended phase 2 dose (RP2D) in the Phase II Group.
次要结局
- Rates of Pathologic Complete Remission (pCR)(24 weeks up to time of surgery)
- C Max - Letrozole(Day 1 and Day 29)
- Tumor Proliferation Changes(24 weeks (pretreatment to time of definitive surgery))
- T Max - Letrozole(Day 1)
- AUC - Letrozole(Day 1 and Day 29)
- T 1/2 - Letrozole(Day 1)
- C Max - Everolimus(Day 1 and Day 29)
- T Max Everolimus(Day 1)
- AUC - Everolimus(Day 1 and Day 29)
- T 1/2 - Everolimus(day 1)