Drug development withdrawn

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.

Inclusion Criteria:

1. Female or male ≥ 18 years

2. WHO performance status ≤ 1

3. Locally advanced, recurrent or metastatic, histologically confirmed HER2 positive (IHC 3+ or FISH positive) breast cancer after failure of trastuzumab treatment.

   while on trastuzumab or within 4 weeks since the last infusion of trastuzumab for metastatic disease within 12 months of the last infusion for patients who received trastuzumab as adjuvant or neoadjuvant treatment

4. For the phase II part, progression on trastuzumab must have occurred within 16 weeks before entering this trial.

5. should not have received more than 3 lines of anti-HER2 therapy.

6. For the phase II part, activation of PI3K/AKT pathway

7. capable of understanding the protocol and has signed the informed consent

8. laboratory values within normal range

9. Measurable disease

10. Patients may have received treatment for brain metastases, but must be neurologically stable

11. Baseline LVEF>50% (MUGA or ECHO)

12. Affiliation to social security

Exclusion Criteria:

1. Previous treatment with lapatinib, neratinib or a PI3K inhibitor

2. untreated brain metastases.

3. acute or chronic liver, renal disease or pancreatitis

4. any peripheral neuropathy ≥ CTCAE grade 2

5. 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)

   • Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others)
   • ≥ CTCAE grade 3 anxiety

6. diarrhea ≥ CTCAE grade 2

7. active cardiac disease

8. history of cardiac dysfunction

9. poorly controlled diabetes mellitus (HbA1c > 8 %)

10. Other severe and/or uncontrolled concomitant medical conditions

11. Impairment of gastrointestinal function that may significantly alter the absorption of BKM120

12. been treated with any hematopoietic colony-stimulating growth factors ≤ 2 weeks prior to starting study drug.

13. currently receiving treatment with medication with a known risk prolong the QT interval or inducing Torsades de Pointes

14. currently being treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A

15. receiving chronic treatment with steroids or another immunosuppressive agent.

16. have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, antibodies [other than trastuzumab] or mitomycin-C) prior to starting study drug or who have not recovered from side effects of such therapy

17. have received small molecule therapeutics (excluding monoclonal antibodies) ≤ 5 effective half lives prior to starting study drug or who have not recovered from side effects of such therapy

18. have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy

19. have undergone major surgery ≤ 28 days prior to starting study drug or who have not recovered from side effects of such therapy

20. Known diagnosis of HIV infection

21. History of another malignancy within 3 years

22. Patient is unable or unwilling to abide by the study protocol

23. pregnant or breast feeding women