Study of LDE225 (Sonidegib) in Combination With Docetaxel in Triple Negative (TN) Advanced Breast Cancer (ABC) Patients (EDALINE)
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|ClinicalTrials.gov Identifier: NCT02027376|
Recruitment Status : Completed
First Posted : January 6, 2014
Results First Posted : December 4, 2018
Last Update Posted : December 4, 2018
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.
|Condition or disease||Intervention/treatment||Phase|
|Advanced Breast Cancer||Drug: LDE225 Drug: Docetaxel||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||12 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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"|
|Study Start Date :||May 2014|
|Actual Primary Completion Date :||April 2016|
|Actual Study Completion Date :||April 2016|
Experimental: 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.
Other Name: Sonidegib
Other Name: Taxotere
- Incidence Rate of DLT Within the First Two Cycles of LDE225 (Sonidegib) in Combination With Docetaxel [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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).
- The Number of Participants Who Experienced Adverse Events (AE) [ 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.
- Changes in QT/QTc From Baseline and Cycle 3 ECG Values. [ Time Frame: From baseline to cycle 3 ]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 To Progression (TTP) [ 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.
- LDE225 (Sonidegib) Trough Concentration (Pharmacokinetics (PK)) [ Time Frame: Up to cycle 2 ]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.
- Docetaxel Clearance on Cycle 1 and Cycle 2 (Pharmacokinetics (PK)) [ Time Frame: Cycles 1 and 2 ]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.
- Objective Response Rate (ORR) [ Time Frame: Through study treatment, an average of 2 months ]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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02027376
|Complejo Hospitalario Universitario A Coruña|
|A Coruña, Spain, 15006|
|Hospital General Universitario Gregorio Marañón|
|Madrid, Spain, 28007|
|Hospital Clínico Universitario San Carlos|
|Madrid, Spain, 28040|
|Hospital Clínico Universitario Virgen de la Victoria|
|Málaga, Spain, 29010|
|Hospital Universitario Virgen del Rocío|
|Sevilla, Spain, 41071|
|Study Director:||Study Director||Hospital General Universitario Gregorio Marañón|