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 maximum two prior chemotherapy regimens for metastatic breast cancer.
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; serum potassium between 3.0mmol/L and 5.5 mmol/L; Corrected serum calcium between8.0mg/dL and 11.5mg/dL (OR between 1.0mmol/L and 1.5mmol/L of Ionized calcium); serum magnesium between 1.2mg/dL and 3.0 mg/dL; 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). An exception to this rule are those 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)

Patients with a history or active episodes of major depression, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, history of suicide attempts or suicidal thoughts (eg. Risk of hurting or harming others) or patients with severe personality disorders (as defined by the DSM-IV) are not eligible. Note: For patients who are treated with psychotropic drugs at baseline, the dose and schedule shall not be changed during the 6 weeks prior to initiation of treatment with the study drug.
≥ CTCAE v 4.0 grade 3 anxiety
Patients on concurrent use of other approved or investigational antineoplastic and / or chemotherapy or any continuous or intermittent treatment with therapeutic agents of low molecular weight (excluding monoclonal antibodies) in ≤ 21 days prior to enrollment in this study or who have not recovered from the effects such therapy will not be eligible.
Radiotherapy ≤ 28 days prior to enrollment in this study 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% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)Note: ECHO/MUGA is only required at baseline if patient has a history of abnormal cardiac test results
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 arrhythmias 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
History of documented congestive heart failure (New York Heart Association functional classification III-IV)
Documented cardiomyopathy
Treatment with QT prolonging medication known to have a risk to induce Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
Chronic treatment with steroids or another immunosuppressive agent. Note: Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local injections (e.g., intra-articular) are allowed. Patients with previously treated brain metastases, who are on a stable low dose corticosteroids treatment (e.g., dexamethasone 2 mg/day, prednisone 10 mg/day) 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 her participation in the clinical study (e.g., chronic pancreatitis, active chronic hepatitis etc.)
History of non-compliance to medical regimen
Current treatment with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug
Known history of HIV (testing not mandatory) infection
Pregnant or nursing (lactating) woman
Woman of child-bearing potential unwilling to observe total sexual abstinence or to use a double barrier method for birth control throughout the trial. Reliable contraception should be maintained throughout the study and for 6 months after study drug discontinuation