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

A Phase II Study of BKM120; a Pan-PI3K Inhibitor in Patients With 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.

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.