| Eligibility |
Inclusion Criteria:
1. 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.
2. Age </= 21 years
3. WHO performance status </= 2
4. 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)
5. Life expectancy of </= 12 weeks
6. Adequate bone marrow function as shown by: ANC 1.0 x 109/L, Platelets 100 x 109/L, Hb
>9 g/dL
7. Adequate coagulation profile with INR < 2
8. Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use
for malignant hypercalcemia control is not allowed)
9. Magnesium > the lower limit of normal
10. Alanine aminotransferase (ALT) and aspirate aminotransferase (AST) within normal range
(or 3.0 ULN if liver metastases are present)
11. 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
12. Serum creatinine 1.5 x ULN or 24-hour clearance 50 mL/min
13. Serum amylase < ULN
14. Serum lipase < ULN
15. Fasting plasma glucose < 120 mg/dL (6.7 mmol/L)
16. Negative serum pregnancy test within 48 hours before starting study treatment in women
with childbearing potential
17. Signed informed consent
Exclusion Criteria:
1. Patients who have received prior treatment with a PI3K inhibitor.
2. Patients with a known hypersensitivity to BKM120 or to its excipients
3. 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
4. Patients with acute or chronic liver, renal disease or pancreatitis
5. 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.
6. Patients with diarrhea < CTCAE grade 2
7. 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)
8. Patients with uncontrolled diabetes mellitus or steroid-induced diabetes mellitus
9. 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
10. 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
11. 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
12. 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
13. Patients who have received corticosteroids 2 weeks prior to starting study drug.
Topical and systemic corticosteroids should not be administered with BKM120
14. Patients receiving chronic treatment with steroids or another immunosuppressive agent.
15. Patients who are currently 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. Please refer to Table
3-5 for a list of moderate to strong inhibitors of CYP3A4 (Please note that
co-treatment with weak inhibitors of CYP3A4 is allowed).
16. Patients who have received chemotherapy or targeted anticancer therapy 4 weeks (6
weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug or who
have not recovered from side effects of such therapy
17. Patients who have received any continuous or intermittent small molecule therapeutics
(excluding monoclonal antibodies) or 5 effective half lives prior to starting study
drug or who have not recovered from side effects of such therapy
18. Patients who have received wide field radiotherapy 4 weeks or limited field radiation
for palliation 2 weeks prior to starting study drug or who have not recovered from
side effects of such therapy
19. Patients who have undergone major surgery 4 weeks prior to starting study drug or who
have not recovered from side effects of such therapy
20. Patients who are currently taking therapeutic doses of warfarin sodium or any other
coumadin-derivative anticoagulant.
21. Women who are pregnant or breast feeding or adults of reproductive potential not
employing an effective method of birth control. Double barrier contraceptives must be
used through the trial by both sexes. Oral, implantable, or injectable contraceptives
may be affected by cytochrome P450 interactions, and are therefore not considered
effective for this study. Women of child-bearing potential, defined as sexually mature
women who have not undergone a hysterectomy or who have not been naturally
postmenopausal for at least 12 consecutive months (i.e., who has had menses any time
in the preceding 12 consecutive months), must have a negative serum pregnancy test <
48 hours prior to initiating treatment
22. Known diagnosis of human immunodeficiency virus (HIV) infection
23. History of another malignancy within 3 years, except cured basal cell carcinoma of the
skin or excised carcinoma in situ of the cervix
24. Patient is unable or unwilling to abide by the study protocol or cooperate fully with
the investigator
|
