A Trial of Gefitinib in Combination With BKM120 in Patients With Advanced Non-Small Cell Lung Cancer, With Enrichment for Patients Whose Tumours Harbour Molecular Alterations of PI3K Pathway and Known to Overexpress EGFR

NCT01570296 | Completed Phase 1

• 1 other identifier: NCC-11-03
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

The safety, tolerability and recommended phase 2 dose (RP2D) of the combination of gefitinib and BKM120 will be determined.

Conditions

Non-Small Cell Lung Cancer; Solid Tumors

Keywords

Advanced Non-Small Cell Lung Cancer; tumors harbor molecular; alterations of PI3K pathway; known to overexpress EGFR

Outcome Measures

Primary Outcomes (1)

• Recommended phase 2 dose for gefitnib and BKM120 combination therapy

  24 months

Secondary Outcomes (3)

• Pharmacokinetic (PK) profile of BKM120 in combination with gefitinib.

  22 time points up to 4 weeks

• Preliminary antitumor activity

  24 months

• Number of Participants with Adverse Events as a Measure of Safety and Tolerability

  24 months

Study Arms (1)

Gefitinib and BKM120

EXPERIMENTAL

Patients with NSCLC who progress on treatment with single-agent EGFR TKI (e.g., gefitinib or erlotinib), and meet the clinical definition of EGFR TKI resistance (Jackman et al., 2010): 1. A tumour that harbours an EGFR mutation known to be associated with drug sensitivity 2. Previous objective clinical benefit from treatment with an EGFR TKI Patients should have systemic progression of disease (by RECIST) while on continuous treatment with gefitinib or erlotinib. Patients that have previously progressed on EGFR TKI (not in the preceding line of treatment) may also be enrolled and will receive gefitinib and BKM120 sequentially. Patients with any solid tumour-type and "activated" PI3 kinase pathway and historically known to over express EGFR may also be recruited. Once the RP2D is reached, an expansion cohort of 40 patients will be accrued for extended safety experience and to ascertain preliminary activity.

Drug: Gefitinib and BKM120

Interventions

Gefitinib and BKM120 DRUG

Dose escalation study of gefitinib and BKM120 with expansion cohort

Gefitinib and BKM120

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Two patient groups are eligible for enrolment. Either:
• Patients with histologically or cytologically proven NSCLC who meet the clinical definition of EGFR TKI resistance, and are progressing on existing treatment or have previously progressed on EGFR TKI (Patient Group 1 "EGFR TKI Resistant")
• Enrichment Cohort (Patient Group 2 "Pathway Driven Group") Activated PI3K status (Section 7.1) in patients whose tumours are known historically to overexpress EGFR. Patients permitted in this group are those in whom no standard treatment options are available.
• Age \</= 21 years
• WHO performance status \</= 2
• Patients must have at least one site of measurable disease \[only in dose expansion phase\] (per RECIST for solid tumors or the appropriate disease classification/criteria for the target population)
• Life expectancy of \</= 12 weeks
• Adequate bone marrow function as shown by: ANC 1.0 x 109/L, Platelets 100 x 109/L, Hb \>9 g/dL
• Adequate coagulation profile with INR \< 2
• Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed)
• Magnesium \> the lower limit of normal
• Alanine aminotransferase (ALT) and aspirate aminotransferase (AST) within normal range (or 3.0 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
• Serum creatinine 1.5 x ULN or 24-hour clearance 50 mL/min
• Serum amylase \< ULN

You may not qualify if:

• Patients who have received prior treatment with a PI3K inhibitor.
• Patients with a known hypersensitivity to BKM120 or to its excipients
• Patients with symptomatic brain metastases are excluded. However, patients with metastatic CNS tumors that are controlled and asymptomatic may participate in this trial, if the patient is \> 4 weeks from therapy completion (incl. radiation and/or surgery), or is clinically stable at the time of study entry and is not receiving chronic corticosteroid therapy for CNS metastases
• Patients with acute or chronic liver, renal disease or pancreatitis
• Patients with the following mood disorders as judged by the Investigator or a psychiatrist, or as result of patient's mood assessment questionnaire:
• i. 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) ii. CTCAE grade 3 anxiety iii. meets the cut-off score of 10 in the PHQ-9 or a cut-off of 15 in the GAD-7 mood scale, respectively, will be excluded from the study unless overruled by the psychiatric assessment. iv. 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) Note: The psychiatric judgment overrules the mood assessment questionnaire result/investigators judgment.
• Patients with diarrhea \< CTCAE grade 2
• Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: i. ST depression or elevation of \< 1.5 mm in 2 or more leads ii. Congenital long QT syndrome iii. History or presence of ventricular arrhythmias or atrial fibrillation iv. Clinically significant resting bradycardia (\< 50 beats per minutes) v. QTc \> 480 msec on screening ECG vi. Complete left bundle branch block vii. Right bundle branch block + left anterior hemiblock (bifascicular block) viii. Unstable angina pectoris \< 6 months prior to starting study drug ix. Acute myocardial infarction \< 6 months prior to starting study drug x. Other clinically significant heart disease such as congestive heart failure requiring treatment (NYHA Class III or IV) or uncontrolled hypertension (please refer to WHO-ISH guidelines)
• Patients with uncontrolled diabetes mellitus or steroid-induced diabetes mellitus
• Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Patients with unresolved diarrhea will be excluded as previously indicated
• Patients who have been treated with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) 2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued
• Patients who are currently receiving treatment with medication that has the potential to prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug
• Patients who have received corticosteroids 2 weeks prior to starting study drug. Topical and systemic corticosteroids should not be administered with BKM120
• Patients receiving chronic treatment with steroids or another immunosuppressive agent.

Sponsors & Collaborators

• National Cancer Centre, Singapore: lead
• Novartis: collaborator

Study Sites (1)

National Cancer Centre Singapore

Singapore, 169610, Singapore

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Gefitinib; NVP-BKM120

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Daniel SW Tan, BSc, MRCP

  Early Clinical Research Unit, Medical Oncology, National Cancer Centre Singapore

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 27, 2012
• First Posted: April 4, 2012
• Study Start: October 3, 2011
• Primary Completion: February 22, 2016
• Study Completion: December 17, 2018
• Last Updated: March 29, 2023

Record last verified: 2023-03

Locations

SG (1)