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.

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.

Inclusion Criteria:

1. The patient is capable to understand and comply with the protocol and has signed the informed consent document.
2. Females with histologically confirmed advanced breast cancer.
3. 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.
4. Measurable or non-measurable disease according to RECIST 1.1 criteria.
5. Patient is at least 18 years of age.
6. World Health Organization (WHO) Performance Status ≤ 1.
7. Life expectancy ≥ 12 weeks.
8. Common laboratory values within normal range (…)
9. 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.

Exclusion Criteria:

1. Have received more than 3 prior chemotherapy regimens for ABC.

2. 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.

3. Patients with acute or chronic liver or renal disease or pancreatitis.

4. Patients with a second primary malignancy that is clinically detectable at the time of consideration for study enrollment.

5. Patients unable to swallow tablets.

6. History of a positive HIV test (HIV testing is not mandatory).

7. History of a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result (Hepatitis B or C testing is not mandatory).

8. Impairment of gastrointestinal (GI) function or GI disease (e.g. ulcerative disease, uncontrolled nausea, vomiting, grade ≥ 2 diarrhea, malabsorption syndrome or small bowel resection).

9. Peripheral vascular disease requiring active therapy or having had surgery < 12 months prior to starting study drug.

10. 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)

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

    …

Through study treatment, average of 2 months

AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.