Safety and Efficacy of BKM120 and Lapatinib in HER2+/PI3K-activated, Trastuzumab-resistant Advanc… (NCT01589861) | Clinical Trial Compass
TerminatedPhase 1/2
Safety and Efficacy of BKM120 and Lapatinib in HER2+/PI3K-activated, Trastuzumab-resistant Advanced Breast Cancer
Stopped: Drug development withdrawn
France24 participantsStarted 2011-12
Plain-language summary
This study is based upon the following points:
1. Resistance to trastuzumab, either primary or secondary, is a clinically relevant issue.
2. 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
3. BKM120 is an effective PI3K inhibitor. BKM120 and anti-HER2 therapy may have a synergistic antitumor activity in preclinical model of HER2+ breast cancer.
4. Lapatinib is an effective anti-HER2 therapy in trastuzumab-resistant disease.
5. 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.
6. 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.
Who can participate
Age range18 Years
SexALL
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Inclusion criteria
✓. Female or male ≥ 18 years
✓. WHO performance status ≤ 1
✓. Locally advanced, recurrent or metastatic, histologically confirmed HER2 positive (IHC 3+ or FISH positive) breast cancer after failure of trastuzumab treatment.
✓. For the phase II part, progression on trastuzumab must have occurred within 16 weeks before entering this trial.
✓. should not have received more than 3 lines of anti-HER2 therapy.
✓. For the phase II part, activation of PI3K/AKT pathway
✓. capable of understanding the protocol and has signed the informed consent
✓. laboratory values within normal range
Exclusion criteria
✕. Previous treatment with lapatinib, neratinib or a PI3K inhibitor
✕. untreated brain metastases.
What they're measuring
1
Phase Ib: maximum-tolerated dose (MTD)
Timeframe: Day 28
2
Phase II: objective response rate (ORR)
Timeframe: until progression assessed up to 1 year
. acute or chronic liver, renal disease or pancreatitis
✕. any peripheral neuropathy ≥ CTCAE grade 2
✕. any of the following mood disorders, or meets the cut-off score of ≥ 10 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, respectively, or selects a positive response of '1, 2, or 3' to question number 9 regarding potential for suicidal thoughts ideation in the PHQ-9 (independent of the total score of the PHQ-9)