Safety and Efficacy of BKM120 and Lapatinib in HER2+/PI3K-activated, Trastuzumab-resistant Advanced Breast Cancer (PIKHER2)
This study is based upon the following points:
- Resistance to trastuzumab, either primary or secondary, is a clinically relevant issue.
PI3K/AKT activation, due to loss of expression/function of PTEN and/or activating mutations of PIK3CA, is a mechanism of resistance with clinical relevance in breast cancer. Such activation can be detected by:
- IHC evaluation of PTEN protein expression
- genotyping of PIK3CA exon 9 and 20
- IHC evaluation of phospho-AKT expression
- BKM120 is an effective PI3K inhibitor. BKM120 and anti-HER2 therapy may have a synergistic antitumor activity in preclinical model of HER2+ breast cancer.
- Lapatinib is an effective anti-HER2 therapy in trastuzumab-resistant disease.
- For the evaluation of novel targeted therapies, selecting a patient population enriched for activation of the target to be modulated should allow to maximize the differences in clinical outcome that are expected in the experimental arm, and thus to minimize the patient number to include.
- We propose to test in a phase I/II study the combination of lapatinib and BKM120 in trastuzumab-resistant HER2+ MBC patients, enriched for activation of PI3K/AKT as detected by loss of expression of PTEN (IHC), and/or mutation of PIK3CA and/or overexpression of phospho-AKT (IHC). Only for phase II patients, mutational status will be an inclusion criteria. For phase I patients molecular status will be a retrospective exploratory analysis.
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||A Phase Ib/II Open-label Study Evaluating Safety and Efficacy of Oral BKM120 in Combination With Lapatinib in HER2+/PI3K-activated, Trastuzumab-resistant Locally Advanced, Recurrent and Metastatic Breast Cancer. PIKHER2/IPC 2011-001|
- Phase Ib: maximum-tolerated dose (MTD) [ Time Frame: Day 28 ]To determine the maximum-tolerated dose (MTD) of BKM120 when administered orally in combination with daily lapatinib to adult patients trastuzumab-resistant HER2+ locally advanced, recurrent and metastatic breast cancer.
- Phase II: objective response rate (ORR) [ Time Frame: until progression assessed up to 1 year ]To determine the efficacy of daily BKM120 in combination with daily lapatinib as measured by objective response rate (ORR), defined by complete response (CR) or partial response (PR) of target and non target lesions according to RECIST V1.1., in patients with activation of PI3K/AKT pathway detected according to one at least of the following criteria, measured on primary or metastatic tissue: PTEN negative by IHC and/or somatic mutations (exons 9 and 20) of PIK3CA and/or Overexpression of phospho-AKT by IHC.
- safety [ Time Frame: until progression or end of treatment assessed up to 1 year ]Number of patients with adverse events (according to CTCAE V4)
- clinical benefit (CB) [ Time Frame: until progression assessed up to 1 year ]- To evaluate clinical benefit (CB defined as complete response (CR) + partial response (PR) + Stable disease (SD) > 6 months)
- progression-free survival (PFS) [ Time Frame: until progression assessed up to 1 year ]- To assess progression-free survival (PFS)
- pharmacokinetics [ Time Frame: D1, D8, D15, D22, D28 post dose ]- To determine pharmacokinetics profile (CMax, AUC) of oral BKM120 in combination with orally lapatinib and to monitor exposure to lapatinib
|Study Start Date:||December 2011|
|Estimated Study Completion Date:||January 2018|
|Estimated Primary Completion Date:||January 2018 (Final data collection date for primary outcome measure)|
BKM120 40, 60 or 80 mg/day per os for 28 days cycle
+ Lapatinib 750, 1000 or 1250 mg/day per os for 28 days cycle
Drug: BKM120 + lapatinib
BKM120 40, 60 or 80 mg/day per os for 28 days cycle associated to lapatinib 750, 1000 or 1250 mg/day per os for 28 days cycle until progression or toxicity
Other Name: BKM120 and lapatinib
Please refer to this study by its ClinicalTrials.gov identifier: NCT01589861
|Marseille, France, 13008|
|Principal Investigator:||Anthony GONCALVES, MD PhD||Institut Paoli-Calmettes|