Conditions: Advanced Breast Cancer
Keywords: Advanced Breast Cancer LDE225 Triple Negative Hormonal Receptor negative Her2 negative
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

Brief summary:
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.

Detailed description:
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:

* To determine the safety and tolerability of LDE225 given in combination with docetaxel.
* To characterize the effects of LDE225 in combination with docetaxel on corrected QT (QTc) intervals and their correlation with systemic drug exposure.
* To evaluate the efficacy of the combination of docetaxel with LDE225 in TN ABC patients.
* To evaluate the Pharmacokinetics (PK) of the combination of docetaxel with LDE225.

Secondary End-points:

* Safety will be assessed by standard clinical and laboratory tests (hematology, serum chemistry). Adverse events grade will be defined by the NCI CTCAE v4.0.
* Changes in QT/QTc from baseline ECG values and correlation with systemic drug exposure.
* The efficacy endpoints are Time To Progression (TTP) and Objective Response Rate (ORR). TTP is measured from the initiation of treatment till disease progression and ORR is defined by RECIST 1.1 criteria as complete response rate + partial response rate.
* The PK will determine whether LDE225 influences the pharmacology of docetaxel. Blood samples will be taken at the times defined in the protocol.

Exploratory Objectives:

* To study potential predictive biomarkers of efficacy by evaluating activation of Hh signaling pathway and related pathways.
* To analyze the pharmacodynamic (PD) treatment effects on the expression of Smo related biomarkers and Hg target genes in correlative samples.
* To correlate biomarker, PD and PK findings with efficacy and toxicity data.

Exploratory End-points:

* Hh gene expression signature associated to pathway activation (at least Shh, Smo, Ptch1, Ptch2, Gli1, Gli2), analyzed in tumor samples.
* Changes in Smo related pathway biomarkers (at least Gli1) in skin and blood correlative samples.
* Pharmacodynamic and biomarker analysis results will be correlated with PK findings, efficacy and toxicity data.

Demographics and Baseline Characteristics:

Standard descriptive statistics, such as the mean, median, range and proportion, will be used to summarize the patient sample and to estimate parameters of interest. 95% confidence intervals will be provided for estimates of interest wherever possible.

Safety Analyses:

Adverse events data and serious adverse events will be reported in frequency tables (overall and by intensity). The safety analysis will be performed in the population that has received at least one dose of the drugs.

Efficacy Analyses:

Response will be analyzed in patients with measurable disease that have received at least one dose of the drugs.

TTP will be evaluated in all patients that have received at least one dose of the drugs.

Study population:

Patient with hormonal receptors negative and HER2 negative ABC.

Arms:
arm 1: 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.

Interventions: intervention 1: LDE225 intervention 2: Docetaxel
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document: