Safety and Efficacy of BKM120 in Combination With Trastuzumab in Patients With Relapsing HER2 Overexpressing Breast Cancer Who Have Previously Failed Trastuzumab

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