Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Docetaxel

Tubulin Modulators

Antimitotic Agents

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.

LDE225

Study Director

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.

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

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"

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

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.

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).

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.

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.

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.

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.

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.

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.

Novartis

Spanish Breast Cancer Research Group

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

Cohort 1: Eligible patients were included and treated with docetaxel intravenously (75mg/m2) in every 3 weeks cycles and LDE225 400mg was administered orally one a day. Treatment was repeated on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity or withdraws informed consent.

LDE225 (Sonidegib) 400mg in Combination With Docetaxel

Cohort 2: Eligible patients were included and treated with docetaxel intravenously (75mg/m2) in every 3 weeks cycles and LDE225 600mg was administered orally one a day. Treatment was repeated on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity or withdraws informed consent.

LDE225 (Sonidegib) 600mg in Combination With Docetaxel

Cohort 3: Eligible patients were included and treated with docetaxel intravenously (75mg/m2) in every 3 weeks cycles and LDE225 800mg was administered orally one a day. Treatment was repeated on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity or withdraws informed consent.

LDE225 (Sonidegib) 800mg in Combination With 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.

Dose Level 1: 5 patients were included (2 of them were replaced due to progression before completing cycle 2)

Dose Level 2: 4 patients were included (1 of them were replaced due to progression before completing cycle 2)

Dose Level 3: 3 patients were included

LDE225 (Sonidegib) in Combination With Docetaxel

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Spain

Region of Enrollment

Pre-menopausal

Post-menopausal

Menopausal status

Scientific Director / Medical Lead / Project Manager

Cohort 1: Eligible patients were included and treated with docetaxel intravenously (75mg/m2) in every 3 weeks cycles and LDE225 400mg was administered orally QD. Treatment was repeated on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity or withdraws informed consent.

Cohort 2: Eligible patients were included and treated with docetaxel intravenously (75mg/m2) in every 3 weeks cycles and LDE225 600mg was administered orally QD. Treatment was repeated on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity or withdraws informed consent.

Cohort 3: Eligible patients were included and treated with docetaxel intravenously (75mg/m2) in every 3 weeks cycles and LDE225 800mg was administered orally QD. Treatment was repeated on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity or withdraws informed consent.

Incidence Rate of DLT Within the First Two Cycles of LDE225 (Sonidegib) in Combination With Docetaxel

Eligible patients were 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 was repeated on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity or withdraws informed consent.

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

Maximum Tolerated Dose (MTD) of LDE225 (Sonidegib) in Combination With Docetaxel

Recommended Phase II Dose (RP2D) of LDE225 (Sonidegib) in Combination With Docetaxel

The Number of Participants Who Experienced Adverse Events (AE)

Cycle 3, Predose

Cycle 3, 1 hour

Cycle 3, 2 hours

Cycle 3, 4 hours

Cycle 3, 6 hours

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.

Changes in QT/QTc From Baseline and Cycle 3 ECG Values.

Time To Progression (TTP)

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

LDE225 (Sonidegib) Trough Concentration (Pharmacokinetics (PK))

Cycle 1 Day 1

Cycle 2 Day 1

Docetaxel Clearance on Cycle 1 and Cycle 2 (Pharmacokinetics (PK))

Objective Response Rate (ORR)

Cohort 1: Eligible patients were included and treated with docetaxel intravenously (75mg/m2) in every 3 weeks cycles and LDE225 400mg was administered orally one a day (QD). Treatment was repeated on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity or withdraws informed consent.

Cohort 2: Eligible patients were included and treated with docetaxel intravenously (75mg/m2) in every 3 weeks cycles and LDE225 600mg was administered orally one a day (QD). Treatment was repeated on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity or withdraws informed consent.

Cohort 3: Eligible patients were included and treated with docetaxel intravenously (75mg/m2) in every 3 weeks cycles and LDE225 800mg was administered orally one a day (QD). Treatment was repeated on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity or withdraws informed consent.

Spots Global Cancer Trial Database for hormonal receptor negative