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)

  1. 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.
  2. ≥ 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:

  1. 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
  2. QTc \> 480 msec on screening ECG (using the QTcF formula
  3. Angina pectoris that requires the use of anti-anginal medication
  4. Ventricular arrhythmias except for benign premature ventricular contractions
  5. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
  6. Conduction abnormality requiring a pacemaker
  7. Valvular disease with documented compromise in cardiac function
  8. Symptomatic pericarditis
* History of cardiac dysfunction including any of the following;

  1. Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function
  2. History of documented congestive heart failure (New York Heart Association functional classification III-IV)
  3. 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