A Phase I Study of BKM120 and Everolimus in Advanced Solid Malignancies

Inclusion Criteria:

1. Histologic or cytologic confirmation of a solid malignancy with established
intolerance or refractoriness to standard therapies

2. Age ≥ 18 years

3. ECOG performance status £ 2 (see appendix A for details)

4. Patients must have at least one site of measurable disease (per RECIST 1.1 criteria)

5. Life expectancy in the estimation of the investigator of ≥ 12 weeks

6. Adequate organ function including:

1. Bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb
>9 g/dL

2. Electrolytes: Total calcium (corrected for serum albumin) within normal limits
(ongoing requirement for bisphosphonate to control malignant hypercalcemia is
not allowed but prophylactic use of bisphosphonate to prevent skeletal
complication of bone metastasis is allowed); Magnesium ≥ the lower limit of
normal

3. Liver function: AST/SGOT and ALT/SGPT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤
5.0 x ULN if liver metastases are present; Serum bilirubin ≤ 1.5 x ULN

4. Renal function: serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min or
calculated GFR of 60cc/ml using the formula of Cockroft and Gault.

7. Serum amylase ≤ ULN

8. Serum lipase ≤ ULN

9. Fasting plasma glucose ≤ 140 mg/dL (7.8 mmol/L)

10. Negative serum pregnancy test within 48 hours before starting study treatment in
women with childbearing potential

11. Ability and willingness to participate in the informed consent process and signing a
copy of the informed consent form

Exclusion Criteria:

1. Patients who have received prior treatment with a P13K inhibitor or RAD001 (if
discontinued for toxicity).

2. Patients with a known hypersensitivity to BKM120, RAD001 (including other rapalogs)
or their excipient

3. Patients with untreated symptomatic brain metastases are excluded. However, patients
with metastatic CNS tumors may participate in this trial, if the patient is > 4 weeks
from therapy completion (including radiation and/or surgery), is clinically stable at
the time of study entry and is not receiving corticosteroid therapy for the brain
mets

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:

1. 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)

2. ≥ CTCAE grade 3 anxiety Note: The psychiatric judgment overrules the mood
assessment questionnaire result or the investigators judgment.

6. Any of the following concurrent severe and/or uncontrolled medical conditions which
could compromise participation in the study:

- ST depression or elevation of ≥ 1.5 mm in 2 or more leads

- Congenital long QT syndrome

- History or presence of ventricular arrhythmias or atrial fibrillation

- Clinically significant resting bradycardia (< 50 beats per minutes)

- QTc > 480 msec on screening ECG

- Complete left bundle branch block

- Right bundle branch block + left anterior hemiblock (bifascicular block)

- Unstable angina pectoris ≤ 6 months prior to starting study drug

- Acute myocardial infarction ≤ 6 months prior to starting study drug

- 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)

7. Active diarrhea ≥ CTCAE grade 2

8. Patients with clinical manifestation of uncontrolled diabetes mellitus (i.e. treated
and/or with clinical signs) 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 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

15. Patients who have received any continuous or intermittent small molecule therapeutics
(excluding monoclonal antibodies) ≤ 5 effective half lives prior to starting study
drug or who have not recovered from side effects of such therapy

16. 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

17. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or
who have not recovered from side effects of such therapy

18. Patients who are currently taking therapeutic doses of warfarin sodium or any other
coumadin-derivative anticoagulant.

19. 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

20. Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).
Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be
done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at
screening for all patients with a positive medical history based on risk factors
and/or confirmation of prior HBV/HCV infection.

21. Known diagnosis of human immunodeficiency virus (HIV) infection

22. History of another malignancy within 3 years, except cured basal cell carcinoma of
the skin, treated DCIS, cured early stage prostate cancer without detectable PSA or
excised carcinoma in situ of the cervix

23. Patients should not receive immunization with attenuated live vaccines during study
period or within 1 week of study entry. Close contact with those who have received
attenuated live vaccines should be avoided during treatment with everolimus. Examples
of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio,
BCG, yellow fever, varicella and TY21a typhoid vaccines.

24. Patients taking medications known to be strong CYP3A inhibitors (Table 4.18).

25. Patient is unable or unwilling to abide by the study protocol or cooperate fully with
the investigator.