BKM120 in Esophageal Squamous Cell Carcinoma After Failure of First Line Chemotherapy

There is a need for more effective therapy for patients with esophageal squamous cell carcinoma who developed disease progression after first line therapy. Currently, there is no standard second-line therapy for this disease.

BKM-120 is a pan-PI3K inhibitor currently tested in clinical trials. In a cellular model of oral-esophageal carcinogenesis, it has shown that EGFR overexpression activated PI3/AKT pathway. Therfore, there is interest to see the efficacy and safety of BKM120 in this setting.


Eligibility Criteria:
Inclusion Criteria:

* Patient has provided a signed Informed Consent Form (ICF) obtained prior to any screening procedure.
* Age ≥ 18 years old
* Histologically confirmed diagnosis of esophageal squamous cell carcinoma and available archival tissue for evaluation of further studies.
* Metastatic or unresectable disease
* Received one prior chemotherapy or biological therapy regimen for unresectable or metastatic disease
* More than 30 days since prior chemotherapy, surgery, radiotherapy, or investigational agents
* Measurable disease in at least 1 diameter by CT scan or MRI as per RECIST 1.1 criteria
* No evidence of brain metastasis
* ECOG ≤ 2
* Patient has adequate bone marrow and organ function

  * Absolute Neutrophil Count (ANC) ≥ 1.5 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 or Creatinine clearance \> 60 mL
  * AST and ALT not more than 2.5 times ULN (not more than 5.0 times ULN if there is liver metastasis)
  * 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 serum glucose \< 1.5 times ULN

Exclusion Criteria:

* Patient has received previous treatment with PI3K inhibitors
* Patient has 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 and should not be receiving chronic corticosteroid therapy for the CNS metastases.
* Patient has a concurrent malignancy or has a malignancy within 5 years of study enrollment, (with the exception of nonmelanoma skin cancer or cervical carcinoma in situ.
* Patient has 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)
* 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 (immediate risk of doing harm to others) ≥ CTCAE grade 3 anxiety
* Patient is concurrently using other approved or investigational antineoplastic agent
* Patient has had major surgery within 28 days prior to starting study drug or has not recovered from major side effects of the surgery
* Patient has poorly controlled diabetes mellitus(HbA1c \> 8 %)
* Patient has active cardiac disease including any of the following:

  * LVEF \< 50%
  * 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
* Patient has a 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
* Patient is currently receiving 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
* Inability to swallow, impaired gastrointestinal (GI) function, or GI disease that would significantly alter the absorption of study drugs or preclude the use of oral medications
* Patient has 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.)
* Patient is currently being treated 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.