Inclusion Criteria:

1. Male or female adult patients (> 18 years)
2. Patients with histologically/cytologically confirmed diagnosis of the following advanced tumors that have progressed despite standard therapy or that have no available established treatments: metastatic breast cancer, pancreatic adenocarcinoma, metastatic CRC or recurrent GBM will be included.
3. Provision of an archival tumor sample to a Novartis designated laboratory for molecular profiling. The tumor material submitted for these analyses may have been obtained at any time during the course of the patient's disease.
4. Measurable disease as assessed by RECIST 1.1 for non-GBM tumors and by RANO criteria for GBM.
5. ECOG (WHO) performance status 0-2
6. Adequate bone marrow and organ function
7. Patient is able to swallow and retain oral medication
8. Negative serum pregnancy test; non-lactating or post-menopausal women.

Exclusion Criteria:

1. Use of other investigational drugs within 30 days of enrollment or 5 half-lives of enrollment, whichever is longer.
2. History of hypersensitivity to LDE225, BKM120 or to drugs of similar chemical classes.
3. Patient has received previous treatment with PI3K inhibitors and/or smoothened inhibitors.
4. Patients with recurrent GBM who have received radiotherapy within 3 months of initiating study treatment.
5. Patients with primary CNS tumor (except recurrent GBM), uncontrolled or symptomatic CNS metastasis. However, patients with controlled, asymptomatic or with resected CNS metastases with no radiological evidence of disease or with stable brain metastasis with no progression may be are eligible.
6. Patients who have neuromuscular disorders or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as HMG CoA inhibitors (statins), clofibrate and gemfibrozil. If it is essential that the patient remains on a statin to control hyperlipidemia, only Pravastatin may be used with extra caution.
7. Patients who require the use of warfarin (substrate of CYP2C9) cannot be enrolled as LDE225 and BKM120 are competitive inhibitors of CYP2C9 based on in-vitro data.
8. Patient is currently being treated with drugs known to be strong inhibitors or inducers of CYP3A4/5, which cannot be discontinued or switched to a different medication 7 days prior to starting study treatment and for the duration of the study.
9. Patient has a score ≥12 on the PHQ-9 questionnaire. A normal evaluation by a psychiatrist or psychologist can overrule this exclusion.
10. Patients who select responses of "1", "2" or "3" to question number 9 on the PHQ-9 questionnaire regarding potential for suicidal thoughts or ideation (independent of the total score of the PHQ-9), (a normal evaluation by a psychiatrist or psychologist can overrule this exclusion).
11. Patient has a GAD-7 mood scale score ≥ 15, (a normal evaluation by a psychiatrist or psychologist can overrule this exclusion)
12. Patient has a documented medical history of or active major depression episode, bipolar disorder (I or II), obsessive compulsive disorder, schizophrenia, a history of suicidal attempts or ideation, or homicidal ideation (e.g. risk of doing harm to self or others)
13. Patient has ≥CTCAE grade 3 anxiety
14. Current medical history of the following:
    • Use of a pacemaker
    • History of or presence of clinically significant ventricular or atrial tachyarrhythmia
    • Clinically significant resting bradycardia (< 45 beats per minute)
    • History of clinically documented myocardial infarction
    • History of unstable angina pectoris
    • History of known structural abnormalities (i.e. cardiomyopathy)
15. Clinically significant cardio-vascular disease
16. Clinically significant abnormal ECG
17. Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated Acquisition (MUGA) scan or echocardiogram (ECHO)
18. 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 7 days prior to starting the study and for the duration of the study
19. Patients who are not willing to apply highly effective contraception as defined by the protocol during the study and through the duration of the study. Note: Hormonal contraception methods (e.g. oral, injected, implanted) are not allowed as it cannot be ruled out that the study drug decreases the effectiveness of hormonal contraception
20. Sexually active males who are unwilling to use a condom during intercourse while taking drug and for 6 months after stopping investigational medications and agree not father a child in this period.
21. Patients is currently receiving increasing or chronic treatment with corticosteroids ((≥ the anti-inflammatory potency of 4mg dexamethasone) or another immunosuppressive agent.
22. Patient has 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 before enrollment, may be continued
23. Patient who has received chemotherapy, targeted therapy or immunotherapy ≤ 3 weeks (6 weeks for nitrosourea, mitomycin-C or monoclonal antibodies; 1 week for hormonal anti-cancer therapy) prior to starting study drug or who have not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia, bone marrow and organ functions)
24. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of LDE225 and BKM120 (e.g., ulcerative colitis, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
25. Patient has a known history of HIV infection (testing not mandatory)

AMENDMENT 1 CHANGES:

Inclusion Criteria:

3. Provision of an archival tumor sample to a Novartis designated laboratory for molecular profiling. It is accepted that it may not be possible to obtain all samples prior to commencing study treatment. It is also accepted that it may not be possible to obtain a sample (e.g. if sufficient sample does not exist), and in this situation inclusion of the patient should be discussed with Novartis (as this may not make a patient ineligible).

Exclusion Criteria:

5. Patients with primary CNS tumor (except recurrent GBM), uncontrolled or symptomatic CNS metastasis. However, patients with controlled, asymptomatic or with resected CNS metastases with no radiological evidence of disease or with stable brain metastasis with no progression may be eligible. The patient must have completed any prior treatment for CNS metastases (including radiotherapy and/or surgery) ≥ 28 days (> 14 days for stereotactic radiosurgery).

9. Patient has a score ≥12 on the PHQ-9 questionnaire. A normal evaluation by a psychiatrist can overrule this exclusion.

10. Patients who select responses of "1", "2" or "3" to question number 9 on the PHQ-9 questionnaire regarding potential for suicidal thoughts or ideation (independent of the total score of the PHQ-9), (a normal evaluation by a psychiatrist can overrule this exclusion).

11. Patient has a GAD-7 mood scale score ≥ 15, (a normal evaluation by a psychiatrist can overrule this exclusion)

AMENDMENT 2 CHANGES:

Updated Inclusion Criteria:

3. Revised to specify the groups of patients that will be included in the dose escalation and dose expansion parts (NEW tumor type added here): Patients with histologically/cytologically confirmed diagnosis of the following advanced tumors that have progressed despite standard therapy or that have no available established treatments: four group of patients during the dose escalation part: metastatic breast cancer, advanced pancreatic adenocarcinoma, metastatic CRC or recurrent GBM and five groups during the dose expansion part: triple negative metastatic breast cancer, hormone receptor positive (ER+/PR+, and Her2-) metastatic breast cancer, recurrent GBM, GASTRIC/GASTROESOPHAGEAL JUNCTION CANCER, advanced pancreatic adenocarcinoma or metastatic CRC will be included.

6. ECOG (WHO) performance status 0-2. ADDED "only applies to patients enrolled under the original and Amendment 1 protocol versions."

7. Two sub-bullets updated: Potassium, and calcium, within normal limits for the institution. Out of range values should be clinically insignificant. Serum Creatinine ≤ 1.5 x ULN and 24-hour creatinine clearance ≥ 50 mL/min (determined by inputting the serum creatinine result into the Cockcroft-Gault formula).

9. NEW Inclusion criterion: Recurrent GBM patient has a Karnofsky performance status (KPS) score ≥ 70.

10. NEW Inclusion criterion:ECOG (WHO) performance status 0-1 (only applies to patients enrolled under Amendment 2 and any later protocol versions). 

Updated Exclusion Criteria:

12. Patient has a score ≥12 on the PHQ-9 questionnaire. REMOVED "A normal evaluation by a psychiatrist can overrule this exclusion."

13. Patients who select responses of "1", "2" or "3" to question number 9 on the PHQ-9 questionnaire regarding potential for suicidal thoughts or ideation (independent of the total score of the PHQ-9). REMOVED "A normal evaluation by a psychiatrist can overrule this exclusion."

14. Patient has a GAD-7 mood scale score ≥ 15. REMOVED "A normal evaluation by a psychiatrist can overrule this exclusion."

15. Patient has a documented medical history of or active major depression episode, bipolar disorder (I or II), obsessive compulsive disorder, schizophrenia, a history of suicidal attempts or ideation. ADDED "or homicidal ideation (e.g. risk of doing harm to self or others), or patients with active severe personality disorders (defined according to DSM- IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition) are not eligible. Note: for patients with psychotropic treatments ongoing at baseline, the dose and the schedule should not be modified within the previous 6 weeks prior to start of study drug."

23. REMOVED mention of "Double barrier method" term under "Male patient" section 27. Patient who has received chemotherapy, targeted therapy or immunotherapy ≤ 3 weeks (6 weeks for nitrosourea, or mitomycin-C; or 6 weeks for monoclonal antibodies if carryover effects are suspected; 1 week for hormonal anti-cancer therapy) prior to starting study drug or who have not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia, bone marrow and organ functions). ADDED clarification concerning the washout period for monoclonal antibodies.