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.

Study Overview

• Status: Terminated
• Conditions: Esophageal Cancer
• Intervention / Treatment: Drug: BKM120

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• Thailand
  • Songkhla
    • Hat yai, Songkhla, Thailand, 90110
      • Songklanagarind Hospital, Prince of Songkla University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BKM120; BKM120, starting at 100 mg oral once daily	Drug: BKM120

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
disease control rate	16-week disease control rate using RECIST 1.1 criteria	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
safety	Safety data will be assessed at each study visit using CTCAE version 4.0	each follow up visit, assessed up to 12 months
progression-free survival		Time from day 1 to date of documented disease progression or death, assessed up to 12 months
overall survival		Time from day 1 to date of death, assessed up to 18 months

Collaborators and Investigators

• Sponsor: Prince of Songkla University

Publications and helpful links

General Publications

• Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, Demanse D, De Buck SS, Ru QC, Peters M, Goldbrunner M, Baselga J. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012 Jan 20;30(3):282-90. doi: 10.1200/JCO.2011.36.1360. Epub 2011 Dec 12.
• Heeg S, Hirt N, Queisser A, Schmieg H, Thaler M, Kunert H, Quante M, Goessel G, von Werder A, Harder J, Beijersbergen R, Blum HE, Nakagawa H, Opitz OG. EGFR overexpression induces activation of telomerase via PI3K/AKT-mediated phosphorylation and transcriptional regulation through Hif1-alpha in a cellular model of oral-esophageal carcinogenesis. Cancer Sci. 2011 Feb;102(2):351-60. doi: 10.1111/j.1349-7006.2010.01796.x. Epub 2010 Dec 12.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2013
• Primary Completion (Actual): April 30, 2016
• Study Completion (Actual): April 30, 2016

Study Registration Dates

• First Submitted: March 1, 2013
• First Submitted That Met QC Criteria: March 5, 2013
• First Posted (Estimate): March 7, 2013

Study Record Updates

• Last Update Posted (Actual): October 11, 2021
• Last Update Submitted That Met QC Criteria: October 3, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: esophageal cancer; second line therapy; BKM120
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma
• Other Study ID Numbers: 551691411