bkm120 in esophageal squamous cell carcinoma after failure of first line chemotherapy

Conditions: Esophageal Cancer

Summary: 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.

Keywords: esophageal cancer second line therapy bkm120