Phase 1b/2 Study of BKM120 Plus Trastuzumab in Patients With HER2-positive Breast Cancer

This study will assess the safety and efficacy of BKM120 in combination with trastuzumab in patients with relapsing HER2 overexpressing breast cancer who have previously failed trastuzumab.

The study will further assess the safety and preliminary efficacy of BKM120 in combination with trastuzumab and capecitabine in patients with relapsing HER2 overexpressing breast cancer and brain metastases (BM) who have previously failed trastuzumab.


Eligibility Criteria:
Inclusion Criteria:

* World Health Organization (WHO) Performance Status of ≤ 2
* Patients with HER2+ breast cancer by local laboratory testing (immunohistochemistry \[IHC\] 3+ staining or fluorescence in situ hybridization \[FISH\] confirmation for IHC 2+ and 1+)
* Documented tumor resistance to trastuzumab:

  * Recurrence while on trastuzumab or within 12 months since the last infusion for patients who received trastuzumab as adjuvant treatment
  * Progression while on or within 4 weeks since the last infusion of trastuzumab for patients who received trastuzumab for metastatic disease.
* Documented evidence of progressive disease per Response Evaluation Criteria in Solid Tumors (RECIST) on trastuzumab-based therapy defined as:

  * Phase Ib: at any time before study entry
  * Phase II: within 16 weeks before date of first dosing
* Received at least 1 but no more than 4 prior anit-HER2 based regimens including at least 1 regimen containing trastuzumab (adjuvant or neo-adjuvant trastuzumab will be considered as one prior regimen). HER2 directed therapies are defined as comprising trastuzumab, lapatinib, and trastuzumab-DM1 (T-DM1) only.

  • Phase II only: trastuzumab, T-DM1 or lapatinib must be part of the most recent line of therapy
* Previous lines of cytotoxic chemotherapy:

  * Phase Ib: no more than 4 lines of cytotoxic chemotherapy
  * Phase II: no more than 3 lines of cytotoxic chemotherapy

Measurable disease:

* Phase Ib: patient has at least one measurable lesion or non-measurable disease as defined per RECIST
* Phase II: patient has at least one measureable lesion as defined per RECIST

\|\| Specific Inclusion Criteria for patients in BM cohorts:

* Patient has evidence of progressing brain metastases and/or new metastatic brain lesion(s) without leptomeningeal disease.
* Patient has received prior WBRT and/or SRS at at \>28 and \>/= 14 days, respectively, prior to starting study drug and the patient must have recovered from the side effects of the therapy
* WHO performance status of \</=1
* PT INR \</= 1.5
* Any number of prior HER2-directed and cytotoxic regimens, and the most recent line may be any type of anti-neoplastic therapy

\|\| Exclusion Criteria:

* Patients with untreated brain metastases
* Patients with acute or chronic liver, renal disease or pancreatitis
* Patients with any peripheral neuropathy ≥ Common Terminology Criteria for Adverse Events (CTCAE) grade 2
* Patients with a history of mood disorders or ≥ CTCAE grade 3 anxiety
* Patient with clinical manifest diabetes mellitus or steroid-induced diabetes mellitus

\|\| Specific Exclusion Criteria for patients in BM cohorts

* Prior treatment with capecitabine
* Patient has known dihydropyrimidine dehydrogenase (DPD) deficiency
* Patient is currently receiving treatment with EIAED
* Other protocol-defined inclusion/exclusion criteria may apply