A Phase Ib Dose Escalation, Open Label, Multicenter Study Evaluating LDE225 (Sonidegib) in Combination With Docetaxel in Triple Negative (TN) Advanced Breast Cancer (ABC) Patients "EDALINE"
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 5
- 主要终点
- Incidence Rate of DLT Within the First Two Cycles of LDE225 (Sonidegib) in Combination With Docetaxel
研究概览
简要总结
This is a single-arm, open-label, phase Ib study. In this trial, patients with Triple Negative (TN) Advanced Breast Cancer (ABC) will be treated with increasing doses of LDE225 (sonidegib) and docetaxel to determine the Maximum Tolerated Dose (MTD), Dose Limiting Toxicity (DLT) and Recommended Phase II Dose (RP2D) of the combination.
Eligible patients with hormonal receptors negative and Human Epidermal Growth Factor Receptor 2 (HER2) negative ABC will be included and treated with docetaxel intravenously in every three weeks cycles. LDE225 will be administered orally at three dose levels 400, 600 and 800mg one a day (QD) (a -1 dose level is included just in case dose de-escalation is needed). Treatment will be repeated on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity or withdraws informed consent.
The investigators propose to develop a phase Ib trial with the combination of docetaxel with LDE225 in TN ABC patients to define the safety, tolerability and RP2D, as well as to have some information about the efficacy of the combination.
详细描述
Primary Objective:
To determine the MTD and RP2D of LDE225 administered orally in combination with docetaxel in TN ABC patients.
Primary End-point:
To determine the incidence rate of DLT within the first two cycles of LDE225 in combination with docetaxel at each dose level.
Secondary Objectives:
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
- •The patient is capable to understand and comply with the protocol and has signed the informed consent document.
- •Females with histologically confirmed advanced breast cancer.
- •TN breast cancer by local laboratory determination. Hormonal Receptor (HR) negative defined as < 1% positive cells by Immunohistochemistry (IHC) for both Estrogen Receptor (ER) and Progesterone Receptor (PgR), and HER2 negative defined as in situ hybridization (ISH) negative or IHC 0 or 1+ in the absence of ISH (Note: patients with IHC 2+ must have an ISH determination in order to confirm the HER2 negativity.
- •Measurable or non-measurable disease according to RECIST 1.1 criteria.
- •Patient is at least 18 years of age.
- •World Health Organization (WHO) Performance Status ≤
- •Life expectancy ≥ 12 weeks.
- •Common laboratory values within normal range (...)
- •A negative serum pregnancy test ≤ 72 hours before starting study treatment for pre-menopausal women and for women < 1 year from the last menstruation date.
排除标准
- •Have received more than 3 prior chemotherapy regimens for ABC.
- •Patients with untreated brain metastases. However, a patient with Central Nervous System (CNS) metastases may participate in this trial if > 4 weeks from therapy completion (incl. radiation and/or surgery), is clinically stable with respect to the tumor at the time of study entry and is not receiving corticosteroid therapy.
- •Patients with acute or chronic liver or renal disease or pancreatitis.
- •Patients with a second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
- •Patients unable to swallow tablets.
- •History of a positive HIV test (HIV testing is not mandatory).
- •History of a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result (Hepatitis B or C testing is not mandatory).
- •Impairment of gastrointestinal (GI) function or GI disease (e.g. ulcerative disease, uncontrolled nausea, vomiting, grade ≥ 2 diarrhea, malabsorption syndrome or small bowel resection).
- •Peripheral vascular disease requiring active therapy or having had surgery < 12 months prior to starting study drug.
- •Impaired cardiac function or clinically significant heart disease (...)
- •A past medical history of clinically significant ECG abnormalities or a family history of prolonged QT-interval syndrome
- •Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
- •Patients who are receiving treatment with medications that are known to be strong inhibitors or inducers of CYP3A4/5 (listed in Protocol Attachment 3) or drugs metabolized by CYP2B6 or CYP2C9 (listed in Protocol Attachment 3) that cannot be discontinued prior to study entry and for the duration of the study. Medications that are strong CYP3A4/5 inhibitors should be discontinued for at least 2 days, and strong CYP3A4/5 inducers for at least 1 week prior to initiating LDE225 dosing.
- •Patients who have received chemotherapy within a period of time that is < the cycle length used for that treatment (e.g. < 3 weeks for fluorouracil, doxorubicine, epirubicin) prior to starting study drug or who have not recovered from the side effects of such therapy.
- •Patients who have received biologic therapy (e.g. antibodies) ≤ 4 weeks prior to starting study drug or who have not recovered from the side effects of such therapy.
- •Patients who have been treated with a small molecule therapeutic ≤ 5 t1/2 or ≤ 4 weeks (whichever is shorter) prior to starting study drug or who have not recovered from the side effects of such therapy.
- •Patients who have received any other investigational agents ≤ 5 t1/2 or ≤ 4 weeks (whichever is shorter) prior to starting study drug or who have not recovered from the side effects of such therapy.
- •Patients who have received wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
- •Patients who are currently receiving treatment with therapeutic doses of warfarin sodium (Coumadin) who cannot discontinue this treatment at least 5 days prior to starting study drug.
- •Patients who are currently receiving immunosuppressive treatment and in whom the treatment cannot be discontinued prior to starting study drug, except in the case of patients with basal cell carcinoma (BCC). Immunosuppressive treatment should be discontinued for at least 1 week prior to initiating LDE225 dosing.
研究组 & 干预措施
LDE225 (sonidegib) plus docetaxel
Eligible patients will be included and treated with docetaxel intravenously (75mg/m2)in every three weeks cycles and LDE225 will be administered orally at three dose levels 400, 600 and 800mg QD. Treatment will be repeated on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity or withdraws informed consent.
干预措施: LDE225 (Drug)
LDE225 (sonidegib) plus docetaxel
Eligible patients will be included and treated with docetaxel intravenously (75mg/m2)in every three weeks cycles and LDE225 will be administered orally at three dose levels 400, 600 and 800mg QD. Treatment will be repeated on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity or withdraws informed consent.
干预措施: Docetaxel (Drug)
结局指标
主要结局
Incidence Rate of DLT Within the First Two Cycles of LDE225 (Sonidegib) in Combination With Docetaxel
时间窗: Up to cycle 2
DLT was defined as the occurrence of any of the following adverse events or abnormal laboratory values (graded according to the NCI-CTCAE version 4.0) assessed as possibly, probably or definitively related to study drugs, occurring within the first two cycles of treatment: Neutropenia grade 4 lasting more than one week, febrile neutropenia, thrombocytopenia grade 3 with bleeding more than grade 2, thrombocytopenia grade 4, Increased plasma creatinine phosphokinase (CK) grade 3-4, any non-hematologic grade 4 toxicity, or grade 3 toxicity except nausea and vomiting, Grade 2 GI toxicity (except nausea and vomiting) lasting more than 2 weeks, Inability to resume dosing for cycles 2 or 3 at the current dose level within 14 days, due to treatment-related toxicity. Dose reductions in cycles 1 and 2 will be considered a DLT
Maximum Tolerated Dose (MTD) of LDE225 (Sonidegib) in Combination With Docetaxel
时间窗: Through study treatment, an average of 2 months
MTD was determined by testing increasing doses of LDE225 on dose escalation cohorts 1 to 6 patients. MTD reflects the highest dose tested in which a DLT is experienced by 0 out of 3 or 1 out of 6 patients among the dose levels.
Recommended Phase II Dose (RP2D) of LDE225 (Sonidegib) in Combination With Docetaxel
时间窗: Through study treatment, an average of 2 months
The RP2D was decided by the investigators taken into consideration the information obtained in the study and based on the MTD. To define the RP2D, information about toxicity observed during the full treatment were taken into consideration (relative dose intensity and toxicity observed).
次要结局
- Time To Progression (TTP)(Through study treatment, an average of 2 months)
- Changes in QT/QTc From Baseline and Cycle 3 ECG Values.(From baseline to cycle 3)
- Docetaxel Clearance on Cycle 1 and Cycle 2 (Pharmacokinetics (PK))(Cycles 1 and 2)
- Objective Response Rate (ORR)(Through study treatment, an average of 2 months)
- The Number of Participants Who Experienced Adverse Events (AE)(Through study treatment, an average of 2 months)
- LDE225 (Sonidegib) Trough Concentration (Pharmacokinetics (PK))(Up to cycle 2)