Study of LDE225 (Sonidegib) in Combination With Docetaxel in Triple Negative (TN) Advanced Breast Cancer (ABC) Patients

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

Time frame: Up to cycle 2

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.

Time frame: Through study treatment, an average of 2 months

Population: Of the twelve patients included on the study, no Dose Limiting Toxicities (DLTs) were observed at any dose level.

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).

Time frame: Through study treatment, an average of 2 months

The QTc intervals have been characterized by comparing QTc at baseline (QTc interval measured in milliseconds (msec) by Fridericia's formula) and at cycle 3 pre-dose, 1 hour post-dose, 2 hours post-dose, 4 hours post-dose and 6 hours post-dose.

Time frame: From baseline to cycle 3

Population: Only 6 patients received cycle 3. Results are shown from the predose, at 1 hour and 2 hours post-dose for 6 patients and at 4 hours and 6 hours post-dose for 5 patients.

PK sampling of docetaxel was performed on Day 1 of Cycle 1 and 2 of treatment and docetaxel concentrations. Blood samples were collected into ethylenediaminetetraacetic acid (EDTA) K3 tubes and after plasma separation by centrifugation were stored at -70 degrees Celsius until analysis.

Time frame: Cycles 1 and 2

Population: At LDE225 600 mg, one patient was discontinued after first cycle.

To evaluate the effect of LDE225 on the docetaxel PK, the main pharmacokinetic parameters of docetaxel were estimated on Day 1 of Cycles 1 and 2 of treatment, and compared between them. PK parameters were estimated by non-compartmental approach using Phoenix® WinNonlin® software (version 7.0). In the case of the effect of docetaxel on the LDE225 PK, since patients were always under both drugs at all the assessed PK profiles, the trough LDE225 concentrations obtained in our study were compared with those simulated from a previous developed PK model from LDE225 given as monotherapy. Therefore, a population PK model of LDE225 reported in the literature and developed in healthy subjects and patients with advanced solid tumors was implemented in NONMEN version 7.3 program and Monte-Carlo simulations of LDE225 concentrations after the same doses than those of our study, were performed.

Time frame: Up to cycle 2

Population: At LDE225 600 mg, one patient was discontinued after first cycle.

Tumor response was assessed using RECIST 1.1 criteria. The best response across all treatment was recorded. ORR is defined as the percentage of patients with a complete or partial response out of the patients who had measurable disease at baseline.

Time frame: Through study treatment, an average of 2 months

Safety was assessed by standard clinical and laboratory tests \[vital signs including blood pressure, pulse and body temperature, triplicate 12-lead ECGs at screening and on day 1 of cycle 3, blood tests including hematology (hemoglobin, platelets count, red blood cells (RBC), white blood cells (WBC) with differential count and serum chemistry (serum creatinine, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), creatine phosphokinase (CPK))\]. Adverse events grade were defined by the NCI CTCAE v4.0.

Time frame: Through study treatment, an average of 2 months

Tumor assessments were performed until disease progression in order to evaluate the TTP. TTP is defined as the time from the date of the first dose to the first date of objectively determined progressive disease. For patients not known to have objectively-determined progressive disease, TTP will be censored at the date of the last objective progression-free assessment. For patients who receive subsequent systemic anticancer therapy (after discontinuation from the study treatment) prior to objective disease progression, TTP will be censored at the date of last objective progression-free assessment prior to the initiation of postdiscontinuation systemic anticancer therapy.

Time frame: Through study treatment, an average of 2 months