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

This study will assess the safety of combining two agents (Everolimus and BKM120) for the treatment of advanced cancer arising from solid organ in patients who are no longer benefiting from or unable to withstand standard treatment of these conditions.

The purpose of this study is to study the combination of two anticancer drugs, everolimus and BKM120 in patients whose cancer is no longer responding to standard treatment or patients who are unable to tolerate the standard treatment for their cancer. The investigators seek to establish the safety of taking these two medications together and to determine the appropriate doses of the two drugs when given together as well as identify potential side effects when the drugs are administered together.

Another purpose of this study is to determine the effectiveness and side effects of the combination of RAD001 and BKM120 by looking at the patient's response to the treatment. The investigators want to find out what effects, good or bad, the drugs have on the patient's cancer.

This study will also look at specific biomarkers in the patient's blood and in the tumor tissue which are involved in the growth of tumor cells and determine if the levels of these biomarkers are related to the patient's response to treatment or development of side effects.

Everolimus, also known by the brand name, Afinitor, is a biologic drug approved by the Food and Drug Administration (FDA) for the treatment of kidney cancer. It works by preventing cancer cell from multiplying and it also renders them easily susceptible to death.

BKM120 is a new study drug that is being tested for its ability to treat cancer. However, it has not yet been approved by the FDA for the treatment of any specific cancer type.

• Drug: BKM120
  BKM120 (20mg to 100mg) The study drug BKM120 will be self-administered (by the patients themselves). The investigator will instruct the patient to take the study drug exactly as specified in the protocol. BKM120 will be administered on a continuous once daily dosing schedule. Patients should be instructed to take the dose of BKM120 daily in the morning, one hour after a light breakfast (morning meal) at approximately the same time each day. BKM120 should be taken with a glass of water and consumed over as short a time as possible. Patients should swallow the capsules as a whole and not chew them. Patients should continue to fast for 2 hours after the administration of each BKM120 dose.
• Drug: Everolimus
  RAD001 will be self-administered (by the patients themselves). The investigator will instruct the patient to take the study drug exactly as specified in the protocol. RAD001 will be administered orally as once daily dose of 5mg or 10 mg (based on the dose cohort) continuously from study day 1 until progression of disease or unacceptable toxicity. Patients will be instructed to take RAD001 in the morning, at the same time each day.
  Other Name: RAD001

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.