Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors
The purpose of this study is to determine the maximum dose of LDE225 and BKM120 that can be safely given together to patients and/or the dose that will be used in future studies. This study will also learn more about how the combination of these two investigational drugs may work for patients with certain cancers (specifically metastatic breast cancer, advanced pancreatic adenocarcinoma, metastatic colorectal cancer and recurrent glioblastoma multiforme).
Advanced Solid Tumors
Metastatic Breast Cancer
Advanced Pancreatic Adenocarcinoma
Metastatic Colorectal Cancer
Recurrent Glioblastoma Multiforme
Gastroesophageal Junction Cancer
Triple Negative Metastatic Breast Cancer
Hormone Receptor Positive (ER+/PR+, and Her2-) Metastatic Breast Cancer
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
|Official Title:||A Phase Ib, Multi-center, Open Label, Dose Escalation Study of Oral LDE225 in Combination With BKM 120 in Patients With Advanced Solid Tumors|
- Dose Limiting Toxicities [ Time Frame: 6 weeks (42 days) ] [ Designated as safety issue: Yes ]Dose Limiting Toxicities (DLTs) during the first 6 weeks (42 days) of the combination treatment of LDE225 and BKM120.
- Number of Patients with Adverse Events and Serious Adverse Events [ Time Frame: Following signing of the informed consent form, up to and including 30 days following the last dose ] [ Designated as safety issue: Yes ]Adverse and serious adverse events, changes in hematology and chemistry values, and assessment of physical and/or neurological examinations, vital signs, and electrocardiograms
- Objective response rate (ORR) [ Time Frame: 4 months ] [ Designated as safety issue: No ]ORR is the proportion of patients with best overall response of complete or partial response. ORR will be used to evaluate preliminary efficacy of the combination therapy. Tumors will be assessed using Investigator read CT/MRI assessments evaluated as per RECIST 1.1, except for patients with glioblastoma multiforme (GBM) who will be assessed per the RANO Criteria.
- Early progression rate (EPR) [ Time Frame: 6 months ] [ Designated as safety issue: No ]EPR is the proportion of patients with progressive disease within 6 months of the start of treatment. EPR will be used to evaluate preliminary efficacy of the combination therapy. Tumors will be assessed using Investigator read CT/MRI assessments evaluated as per RECIST 1.1, except for patients with GBM who will be assessed per the RANO Criteria. AMENDMENT #2 change: EPR duration modified to 6 months for recurrent GBM patients per the convention for that tumor type
- Plasma pharmacokinetics (PK) parameters [ Time Frame: In 28-day cycles: Cycle 1/Day 1 and Day 15; Cycle 2/Day 1 and Day 15; then on Day 1 of each additional cycle up to and including cycle 11 (if applicable) ] [ Designated as safety issue: Yes ]Plasma PK parameters of LDE225 and plasma PK parameters of BKM120.
|Study Start Date:||July 2012|
|Estimated Study Completion Date:||May 2015|
|Estimated Primary Completion Date:||May 2015 (Final data collection date for primary outcome measure)|
Experimental: LDE225 and BKM120 in combination
LDE225 and BKM120 in combination
|Drug: LDE225 Drug: BKM120|
The primary purpose of this study is to determine a combination maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of LDE225 and BKM120 when co-administered orally in patients with advanced solid tumors. Adult patients, aged > 18 years with advanced solid tumors that have progressed despite standard therapy or for which no standard therapies exist will be eligible for this study.
In the dose escalation part of the study, four groups of patients with the following tumor types will be enrolled: recurrent GBM, metastatic breast cancer, metastatic CRC and advanced pancreatic adenocarcinoma. It is anticipated that approximately 45 patients will be enrolled in the dose escalation part. Approximately 15 GBM patients (maximum of 2 patients per dose level) will be enrolled to previously well-tolerated doses during dose escalation if no slot is available in a cohort under active testing. In the dose expansion part of the study, five groups of patients (approximately 15 patients per group) with the following tumor types will be enrolled: recurrent GBM, triple negative metastatic breast cancer, hormone receptor positive (ER+/PR+, and Her2-) metastatic breast cancer, gastric/gastroesophageal junction cancer, and a combined maximum of 15 patients with metastatic CRC or advanced pancreatic adenocarcinoma. The dose expansion will enroll approximately 75 patients. Accounting for patients who may withdraw or who may not meet the eligibility criteria, it is expected that this study will enroll approximately 120 patients.
This is a multi-center, open-label, dose finding, phase Ib study to determine the MTD and/or RDE for the combination of LDE225 plus BKM120, followed by an expansion part to further assess safety and preliminary efficacy of the combination in patients with advanced solid tumors that are frequently associated with dysregulated Hh and/or PI3K pathways, specifically triple negative metastatic breast cancer, hormone receptor positive (ER+/PR+, and Her2-) metastatic breast cancer, advanced pancreatic adenocarcinoma, metastatic CRC, recurrent GBM and gastric/gastroesophageal junction cancer patients. Patients will be treated daily on 28-day cycles. Dose escalation will be dependent on the available toxicity information (including adverse events that are not DLTs), PK, PD, and efficacy information, as well as the recommendations from the Bayesian Logistic Regression Model (BLRM).
Please refer to this study by its ClinicalTrials.gov identifier: NCT01576666
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|Study Director:||Novartis Pharmceuticals||Novartis Pharmceuticals|