A Trial of BKM120 (a PI3K Inhibitor) in Patients With Triple Negative Metastatic Breast Cancer

Inclusion Criteria:

• Pathologically and radiologically confirmed metastatic TNBC (Stage IV disease), previously documented by histological analysis, which is ER-negative and PR-negative by IHC and HER2 negative by IHC or FISH/CISH.
• Subjects must have received at least two prior neoadjuvant chemotherapy regimens, adjuvant or metastatic
• Availability of a representative tumor specimen (primary or metastasis, archival tissue or fresh biopsy for patients with biopsiable tumor) at baseline.
• At least one measurable lesion by RECIST 1.1
• Age ≥ 18 years at the day of consenting to the study
• ECOG performance status ≤ 2
• Adequate bone marrow and organ function as defined by the following laboratory values:

ANC ≥ 1.0 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥ 9.0 g/dL, INR ≤ 2; potassium, calcium, magnesium within normal limits for the institution; serum creatinine ≤ 1.5 x ULN, ALT and AST within normal range (or ≤ 3.0 x ULN if liver metastases are present); serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome); fasting plasma glucose (FPG) ≤ 140 mg/dL or ≤ 7.8 mmol/L.

Exclusion Criteria:

• Previous treatment with PI3K inhibitors
• Symptomatic CNS metastases
• Patients with controlled and asymptomatic CNS metastases may participate in this trial. As such, the patient must have completed any prior treatment for CNS metastases > 28 days (including radiotherapy and/or surgery) prior to enrollment in this study. Patients with previously treated brain metastases, who are on a stable low dose corticosteroids treatment are eligible.
• Concurrent malignancy or malignancy within 3 years of study enrollment (with the exception of adequately treated basal or squamous cell carcinoma or non-melanomatous skin cancer)
• Patients with documented germline mutations in BRCA1 or 2, who may have previous history of cancer

• Any of the following mood disorders as judged by the Investigator or a Psychiatrist, 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)

  o 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. CTCAE v 4.0 ≥ grade 3 anxiety

• Concurrent use of other approved or investigational antineoplastic agent and/or chemotherapy ≤ 21 days before study accrual
• Radiotherapy ≤ 28 days prior to enrollment or failure to recover from side effects of such therapy at the time of initiation of screening procedures.
• Major surgery within 28 days prior to starting study drug or has not recovered from major side effects of the surgery
• Poorly controlled diabetes mellitus (HbA1c > 8%)

• Active cardiac disease including any of the following:

  • Left Ventricular Ejection Fraction (LVEF) < 50% by MUGA scan or ECHO QTc > 480 msec on screening ECG (using the QTcF formula
  • Angina pectoris that requires the use of anti-anginal medication
  • Ventricular arrhythmias except for benign premature ventricular contractions
  • Supraventricular and nodal arrythmias requiring a pacemaker or not controlled with medication
  • Conduction abnormality requiring a pacemaker
  • Valvular disease with documented compromise in cardiac function
  • Symptomatic pericarditis

• History of cardiac dysfunction including any of the following;

  • Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function
  • Congestive heart failure (New York Heart Association functional classification III-IV)
  • Cardiomyopathy
• Treatment with QT prolonging medication known to have a risk to induce Torsades de Pointes
• Impairment of GI function or GI disease that may significantly alter the absorption of BKM120
• Chronic treatment with immunosuppressive agent. Note: Topical applications, inhaled sprays, eye drops or local injections are allowed. Patients with who are on a stable low dose corticosteroids treatment for their brain metastases for at least 14 days before start of study treatment, are eligible
• Other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, contraindicate participation
• Current treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzyme CYP3A
• HIV infection
• Pregnant or nursing
• Woman of child-bearing potential unwilling to use acceptable methods of contraception