a phase 1/2 trial of
untitled h2

Protocol Number: CC \#11952 Study Drug: BKM120 Version Number: 8.0 Version Date: June 24, 2013 IND Number: 113646 Novartis study number CBKM120ZUS21T
a phase 1/2 trial of
principal investigator

Alain Algazi, MD (PI) University of California, San Francisco 1600 Divisadero Street Mt. Zion Building A, Room A739 San Francisco, CA 94143-1770 Phone: (415) 353-7552 Pager: (415) 443-0409 Cell: (415) 418-8039 Email: *alain.algazi@ucsf.edu* Fax: (415) 353-7999  
| Co-Investigators Adil Daud, MD (Co-PI) University of California, San Francisco 1600 Divisadero Street Mt. Zion Building A, Room A741 San Francisco, CA 94143-1770 Phone: (415) 353-7392 Pager: (415) 443-2233 Email: adil.daud@ucsf.edu Fax: (415) 353-9956   |
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Revision History  
Amendment 8 June 24, 2013 Amendment 7 March 22, 2013 Amendment 6 September 28, 2012 Amendment 5 April 27, 2012 Amendment 4 March 22, 2012 Amendment 3 November 8, 2011 Amendment 2 October 11, 2011 Amendment 1 August 23, 2011 Initial Protocol July 26, 2011
a phase 1/2 trial of
protocol signature page protocol no.

1. I agree to follow this protocol version as approved by the UCSF Protocol Review Committee (PRC),
Committee on Human Research (CHR), and Data Safety Monitoring Committee (DSMC).  
2. I will conduct the study in accordance with applicable CHR requirements, Federal regulations, and state and local laws to maintain the protection of the rights and welfare of study participants.  
3. I certify that I, and the study staff, have received the requisite training to conduct this research protocol.  
4. I have read and understand the information in the Investigators" Brochure (or Manufacturer"s Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In accordance with the FDA Modernization Act, I will ensure the registration of the trial on the www.clinicaltrials.gov website.  
5. I agree to maintain adequate and accurate records in accordance with CHR policies, Federal, state and local laws and regulations.
a phase 1/2 trial of
participating site(s)

PI: StergiosMoschios, MD University of North Carolina at Chapel Hill Physician Office Building 170 Manning Drive, Chapel Hill, NC 27599 PI: Karl Lewis, MD  
  
  
  
  
 University of Colorado Anschutz Cancer Pavilion 1665 Court Room, 32 Aurora, CO 80045 Principal Investigator **Site**  
  
Signature Date  
  
| Version date: June 24, 2013                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Protocol CC#: 11952   |
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| Table of contents Table of contents 2 1 Background 7 1.1 Disease Background - Overview 7 1.2 Vemurafenib (PLX4032, RO5185426, RG7204) 7 1.2.1Vemurafenib preclinical studies 8 1.2.1.1Vemurafenib preclinical efficacy 8 1.2.1.2Vemurafenib preclinical safety 10 1.2.1.3Vemurafenib preclinical pharmacology 10 1.2.2Vemurafenib clinical experience 11 1.2.2.1Vemurafenib clinical efficacy 11 1.2.2.2Vemurafenib safety 11 1.2.3Vemurafenib clinical pharmacology 13 1.3 BKM120 13 1.4 PI3K Pathway and mechanism of action 14 1.4.1 BKM120 preclinical studies 14 1.4.2 BMK120 clinical experience 18 1.5 Study Rationale 20 2Study Objectives 21 3 Study plan 22 3.1 Overall study design 22 3.2 Study population 23 3.2.1 Patient population 23 3.2.2 Inclusion and exclusion criteria 23 3.3Treatments 28 3.3.1 Vemurafenib 28 3.3.2 BKM120 29 3.3.3 Vemurafenib and BKM120 Administration 30 3.3.4 Treatment dosing and schedule 30 3.3.4.1Phase 1 dosing and dose escalation 30 3.3.4.2Follow-up for dose-limiting toxicities 33 3.3.4.3Dose expansion and phase 2 dosing 35 3.3.5Interruption or discontinuation of treatment 35 3.3.6Monitoring vemurafenib suspected toxicities 42 3.3.6.1Known undesirable side effects of vemurafenib 42 3.3.6.2Known Undesirable Side Effects of BKM120 43 3.3.7 Concomitant therapy 48 3.4 Visit schedule and assessments 51 |                       |  
| Version date: June 24, 2013                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Protocol CC#: 11952                                                                                                                                                                                                                                                                                                                                                                                                                                       |
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| 3.4.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Visit schedule 51                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| 3.4.2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Efficacy assessments 54                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| 3.4.6                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Drug levels and pharmacokinetic assessments 56                                                                                                                                                                                                                                                                                                                                                                                                            |
| 3.4.7                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Correlative studies and pharmacodynamic assessments 57                                                                                                                                                                                                                                                                                                                                                                                                    |
| 3.5Treatment compliance 59 3.6 Safety monitoring plan 59 3.6.1 Safety assessments 59 3.6.5 Oversight and monitoring 63 3.6.5.1Monitoring and reporting guidelines 63                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Protocol amendments, or changes in study conduct 65                                                                                                                                                                                                                                                                                                                                                                                                       |
| 5                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Statistical methods 65 5.1 Study Design/Endpoints 65 5.2. Sample Size/Accrual Rate 66                                                                                                                                                                                                                                                                                                                                                                     |
| 6                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Procedures and instructions 68 6.1.1 Publication of results 68 6.1.2 Disclosure and confidentiality 68 6.1.3 Discontinuation of study 68 6.2 Ethics and Good Clinical Practice 68 6.2.1 Institutional Review Board/Independent Ethics Committee 69 6.2.2 Informed consent 69 6.2.3 Multicenter communication 69 6.2.4 Record Keeping and Record Retention 69 6.2.5 Coordinating Center Documentation of Distribution 70 6.2.6 Regulatory Documentation 70 |
| References 72 Appendices Appendix1 Questionnaires………………………………………………… 80 Table A1 Toxicity grading based on mood questionnaire scores…………………… 80 Table A2 GAD-7 anxiety scale……………………………………………………… 81 Table A3 PHQ-9 depression scale…………………………………………………… 82 Appendix 2 Prohibited medications………………………………………………………... 83 Table A4 List of prohibited CYP3A Inhibitors and Inducers……………………….. 83 Table A5 List of CYP450 Substrates to be used with caution………………………. 84 Appendix 3 QT prolonging drugs………………………………………………………….. 85 Table A6 QT prolonging drugs with risk of Torsades de Pointes to avoid…..……… 85 Table A7 List of QT prolonging drugs to be used with caution…………………….. 87 Appendix 4 BKM120 pharmacokinetic analysis……………………………………..……. 89 Appendix 5 Vemurafenib pharmacokinetics and correlative studies assessments………… 91 Appendix 6 Multicenter Institutional Studies……………………………………………... 92 |                                                                                                                                                                                                                                                                                                                                                                                                                                                           |  
| List of Abbreviations AE Adverse Event AKT See PKB (protein Kinase B) ALT Alanine aminotransferase/glutamic pyruvic transaminase/GPT ANC Absolute Neutrophil Count AST Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT BRAF B-RAF seronine / threonine kinase BUN Blood Urea Nitrogen CBC Complete Blood Count CHR UCSF Committee for Human Research (IRB) CK Creatine Kinase CK-MB Creatine Kinase - Muscle and Brain isoenzyme CR Complete Response CT Computed Tomography CTC Circulating Tumor Cells CTCAE Common Terminology Criteria for Adverse Events DLT Dose Limiting Toxicity DSMB Drug Safety Monitoring Board ECG Electrocardiogram ECHO Echocardiogram EGFR Epidermal Growth Factor Receptor ERK ERK extracellular signal-regulated kinase 18F-FDG [18F]-Fluorodeoxyglucose FPG Fasting Plasma Glucose GCP Good Clinical Practice GI Gastrointestinal HIV Human Immunodeficiency Virus ICH International Conference on Harmonization HDL High density lipoprotein IEC Independent Ethics Committee IRB Institutional Review Board LDL Low density lipoprotein   |
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| List of Abbreviations LVEF Left Ventricular Ejection fraction MRI Magnetic Resonance Imaging MEK MEK mitogen activated protein kinase MUGA Multiple Gated Acquisition Scan NTD Non-Tolerated Dose PD Pharmacodynamic PET Positron Emission Tomography PI3K Phosphatidylinositol 3"-kinase PK Pharmacokinetic PKB Protein Kinase B (or AKT) PT Prothrombin Time PTEN Phosphatase and Tensin homolog PTT Partial Thromboplastin Time (also known as APTT) QTc QT interval (corrected) RBC Red Blood Cells REB Research Ethics Board RP2D Recommended Phase 2 Dose RECIST Response Evaluation In Solid Tumors S6K Protein Kinase S6 SAE Serious adverse event SOP Standard Operating Procedure SUV Standardized Uptake Value TTP Time to Progression ULN Upper Limit of Normal WBC White Blood Count WCBP Women of Childbearing Potential   |
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a phase 1/2 trial of
background

1.1 **Disease Background - Overview** In 2010 over 60,000 patients were diagnosed with melanoma in the US and over 8,000 died from this disease1. Despite many advances in oncology, the prognosis of metastatic melanoma remains dismal2, and melanoma is highly refractory to standard chemotherapy. A better understanding of melanoma biology and rational development of targeted therapies is urgently needed. The identification of tumor driving oncogenes now promises to revolutionize the treatment of melanoma. Mutations in the BRAF seronine-threonine kinase leading to constitutive activation of the MAP kinase pathway occur in over half of melanoma tumors and over 90% of these mutations results in a substitution of either glutamic acid or lysine for valine at amino acid 600
(BRAFV600E or BRAFV600K)
3,4. Vemurafenib(also cited in the literature under the names PLX4032, RO5185426, and RG7204)is a potent BRAF inhibitor that induces objective tumor responses in half of BRAFV600E/K mutant advanced melanoma cases, but these responses are transient, with a median PFS of 5.3 months in phase 3 testing5. The limitations of vemurafenib are not surprising given that BRAFV600E/K mutations alone do not cause melanoma. BRAF
mutations are common in benign nevi6 and animal studies suggest that BRAF must cooperate with additional oncogenic mutations to yield a malignant phenotype7. Constitutive PI3 kinase pathway activation, often in the setting of PTEN mutations, is common in melanoma cell lines and melanoma metastases, particularly those harboring BRAF mutations8,9. While BRAF
mutations alone cannot induce melanoma, a BRAF mutation combined with PI3K pathway activation is sufficient to transform melanocytes in preclinical models7. In such models, inhibition of either the MAP kinase or PI3 kinase pathway leads to tumor growth inhibition in vivo, and concurrent inhibition of *both* pathways is synergistic leading to tumor regression.  
Given this and the evidence supporting the role of PI3K activation in the malignant melanoma phenotype in BRAFV600E/K mutant melanoma tumors, the limitations of BRAF-specific therapies may stem from the failure to block constitutive PI3K signaling. Indeed, PTEN loss, which increases PI3K activity, was recently identified a predictor of decreased progression free survival in BRAFV600E melanoma patients treated with vemurafenib10. BKM120 is a potent, orally bioavailable PI3K inhibitor that that induces marked reductions in PI3K pathway activity in patients with advanced solid tumors11. This is a phase 1/2 clinical trial with the goal of determining whether the addition of BKM120 to vemurafenib will lead to clinically significant improvements in 6-month progression free and in BRAFV600E/K mutant melanoma.
a phase 1/2 trial of
1.2 vemurafenib(plx4032 ro5185426 rg7204)

Vemurafenib is a highly selective oral, ATP-competitive inhibitor of the mutant BRAFV600E/Kserinine/threonine kinase. Vemurafenib inhibits the mutated BRAFV600E and BRAFV600K kinases at low nanomolar concentrations *in vitro* with minimal activation of other kinases at concentrations less than 100 nM with the exception of ACK1, KHS1, and SRMS12.  
Vemurafenib and related compounds potentiate MAP kinase signaling the cells that are wild type for BRAF13,14.
a phase 1/2 trial of
1.2.1 vemurafenib preclinical studies 1.2.1.1

Vemurafenib demonstrates *in vitro* and *in vivo* efficacy in cell lines and xenografts that are  
  
homozygous or heterozygous for sensitive BRAF mutations, but it does not demonstrate antitumor activity in BRAF wild-type tumors**12,15,16**. In BRAFV600E mutant colorectal cancer xenograft (COLO205) studies in mice, vemurafenib induced dose-dependent tumor growth inhibition with tumor regression at higher doses12. At doses of 25 mg/kg bid 7 of 10 animals achieved a complete response and 3 of 10 had partial responses. At doses of50 mg/kg bid, 10/10 animals had CRs. Significant tumor regressions were noted in mice at doses of 20 mg/kg bid (AUC0-24 approximately 300 Mh) in several BRAFV600Exenograft models including COLO205, NCI-LOX, and COLO82912. Vemurafenib demonstrated similar efficacy in murine xenograft models of BRAFV600E mutant melanoma15. Complete tumor regressions were observed in 5/9 LOX xenograft mice treated at 12.5 mg/kg and partial regressions were seen in the remaining four animals (*Figure 2A*).  
Complete regressions were observed of 10/10 LOX xenograft mice treated with doses of 25 and 75 mg/kg. Dose-dependent improvements in survival were also noted (*Figure 2B*). In an A375 murine xenograft model, initial dosing at 75 mg/kg followed by dosing at 25 mg/kg yielded improvements in survival in comparison with vehicle controls to continuous dosing at 75 mg/kg15.
a phase 1/2 trial of
1.2.1.2 vemurafenib preclinical safety

No toxicity was observed in rats and dogs receiving doses of up to 1,000 mg/kg/day of vemurafenib for 28 days. Extended dosing over 13 weeks in dogs and 26 weeks in rats was tolerable despite high overall exposure levels of 820 mMh and 2,600 mMh in dogs and rats respectively. In particular, no histological changes were seen in the animals" skin in any of these studies12. There was also no toxicity observed in a mouse xenograft study at doses of up to 100 mg/kg and drug exposures up to an AUC of 3810 Mh15.
a phase 1/2 trial of
1.2.1.3 vemurafenib preclinical pharmacology

In a melanoma mouse model, single doses of vemurafenib of 100 mg/kg yielded a peak plasma  
 concentration of 124 mmol/l at 2 hours while a peak intratumoral concentration of 37.8 mmol/L
were observed at 4 hours (*Figure 3*)
15.Pharmacodynamic analysis by Western Blot revealed stable pMEK inhibition of 64.8% until 8 hours post-dose, and maximum pERK inhibition of 52% at 2 hours. These phosphoprotein levels were thought to be underestimated due to stromal contamination. At time points (Tmax) ranging from 2-4 hours, continuous dosing of the microprecipitated bulk powder formulation of vemurafenib yielded peak concentrations (Cmax) of 68.4, 139, 164, and 196 M at doses of 25, 50, 75, and 100 mg/Kg respectively. The total drug exposures (AUC) were 1250, 2340, 3070, and 3810 Mh respectively. In a murine colorectal carcinoma xenograft model using a less bioavailable formulation of vemurafenib, the AUC0-24 was approximately 50, 200, and 300 Mh at doses of 6 mg/kg daily, 20 mg/kg daily, and 20 mg/kg bid respectively12.  
Figure 3.PD and PK relationship of vemurafenib in the LOX melanoma xenograft model. Plasma and tumor samples were obtained at 2, 4, 8, and 24 h post dose for PD and PK analysis from mice administered a single dose of 100 mg/kg vemurafenib orally when tumors were ∼300 mm3. A, tumor samples were subjected to Western blot analysis with antibodies specific for pMEK1/2 and pERK1/2. B, mean PD and PK parameters were calculated from three animals analyzed at each time point and plotted as a function of time post dose. Vemurafenib plasma and tumor concentrations are plotted on the left Y-axis. Inhibitions of MEK1/2 and ERK1/2 phosphorylation are plotted on the right Y-axis15.  
Vemurafenib undergoes minimal hepatic metabolism, primarily through CYP3A4. Vemurafenib is a mild inducer of CYP3A4, and an inhibitor of CYP2C9, CYP1A2, CYP2C19, CYP2D6, and P-gp. In addition, vemurafenib induces mild to moderate increases mRNA expression of CYP3A4 and CYP1A2.
a phase 1/2 trial of
1.2.2 vemurafenib clinical experience 1.2.2.1

A phase 3 clinical trial presented at the plenary session of the 2011 ASCO Annual Meeting and in the New England Journal of Medicine demonstrated that vemurafenib is superior to standardof-care dacarbazine in terms of clinical response rate (48 vs. 5%), median progression-free survival (5.3 vs. 1.6 months), and 6 month overall survival (84 vs. 64%)5. Additional trials of vemurafenibinclude a phase 1 dose-escalation trial with an extension cohort at the phase 2 study dose, a phase 2 trial, a study of the effect of food on the metabolism of vemurafenib, and an additional phase 1 pharmacokinetic study to test a micro-precipitated bulk powder (MBP) form of vemurafenib in tablets that has replaced an MBP product in capsules. In the original phase 1 study4, 49 melanoma patients (and 6 patients without melanoma) were enrolled in a dose escalation phase and 32 additional patients, all with BRAFV600E mutant melanoma were enrolled in a dose expansion phase. In the dose escalation phase, the maximum administered dose (MAD) was 1120 mg PO bid. At this dose level, four of six patient developed dose limiting toxicities (DLTs, 3 with grade 3 rash, 1 with grade 3 arthralgias). The recommended phase 2 dose identified was 960 mg PO bid. No responses were seen in melanoma patients whose tumors did not harbor the BRAFV600E mutation. In the dose escalation phase, 10/16 patients receiving doses of 240 mg PO bid or more of vemurafenib had partial tumor responses and 1 had a complete response. In the expansion phase, 24/32 patients had partial responses and 2 had complete responses. Notably, objective tumor responses were not confirmed in the data presented in the published report, and the confirmed response rate has been reported as 59%17.  
The median PFS was approximately 7 months. The phase 2 trial enrolled 132 patients, and as of 9/27/2010, the confirmed response rate was 52% with 3/132 CRs and 66 PRs. 39 additional patients had stable disease. The median PFS was 6.2 months, and the median response duration was 6.8 months17.
a phase 1/2 trial of
1.2.2.2 vemurafenib safety

Common grade 2 or higher drug-related adverse events of vemurafenib include rash, photosensitivity, pruritis, palmar-plantar dysesthesias, squamous cell carcinomas of the skin/keratoacanthomas, fatigue, nausea, and arthralgias4,5. In 87 patients in the phase 1 trial, only four patients had grade 4 adverse events potentially related to vemurafenib: two had GGT elevations, one had fatigue, and one had pancytopenia. No deaths were associated with treatment with vemurafenib. 32 patients on this trial were treated in an extension cohort at the recommended phase 2 dose of 960 mg PO bid. 13 (41%) of these patients required dose reductions for adverse events. In 10 of these patients, a dose of 720 mg PO bid was well tolerated, one was dose-reduced to 600 mg PO bid, and two ultimately received 480 mg PO bid.  
| Dacarbazine                                                                     |                                                     |         |
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| Adverse Event                                                                   | (N=336)?                                            | (N-282) |
| no. of patients (%)                                                             |                                                     |         |
| 60 (18)                                                                         | l (<1)                                              |         |
| Grade 2                                                                         |                                                     |         |
| Grade                                                                           | 1 (3)                                               | 2 (<1)  |
| 3 (10)                                                                          |                                                     |         |
| Grade                                                                           | 0                                                   |         |
| 28 (8)                                                                          |                                                     |         |
| Grade                                                                           | o                                                   |         |
| Fatigue                                                                         | 38 (11)                                             | 3 (12)  |
| Grade                                                                           | 6 (2)                                               | 5 (2)   |
| 40 (12)                                                                         | l (<1)                                              |         |
| 7 (2)                                                                           | o                                                   |         |
| 20 (6)                                                                          | o                                                   |         |
| 25 (7)                                                                          | 32 (11)                                             |         |
| Grade                                                                           | 4 (1)                                               | 5 (2)   |
| Aopecia                                                                         | 26 (8)¶                                             | o       |
| Grade                                                                           |                                                     |         |
| Grade 2                                                                         | 19 (6)                                              | o       |
| S (1)                                                                           | o                                                   |         |
| Grade                                                                           |                                                     |         |
| Hyperkeratos                                                                    | 17 (5)                                              | o       |
| 4 (1)                                                                           |                                                     |         |
| Grade                                                                           | 0                                                   |         |
| Diarrhea                                                                        | 16 (5)                                              |         |
| Grade                                                                           | 4 (1)                                               |         |
| Grade 3                                                                         | 2 (<1)                                              | 1 (<1)  |
| Headache                                                                        | 15 (4)                                              | 5 (2)   |
| Grade 2                                                                         | 2 (<1)                                              |         |
| Vomiting                                                                        |                                                     |         |
| Grade                                                                           | 9 (3)                                               | 14 (5)  |
| 4 (1)                                                                           | 3 (1)                                               |         |
| Grade 3                                                                         |                                                     |         |
| Neutropenia                                                                     | 1 (<1)                                              | 4 (1)   |
| Grade 2                                                                         |                                                     |         |
| Gade 3                                                                          | 0                                                   | 15 (5)  |
| Grade                                                                           | 1 (<1)                                              | 8 (3)   |
| Grade 9                                                                         | 1 (<1)                                              |         |
| * Listed are all adverse events of grade 2 or higher that were reported in more |                                                     |         |
| than 5% of patients in either study gro                                         |                                                     |         |
| One patient in the dacarbazine group who was                                    |                                                     |         |
| e vemuratenib group for the assessment                                          |                                                     |         |
| in the protocol a                                                               | were reported as grade 3, according to the National |         |
| Cancer Institute Comp                                                           |                                                     |         |  
  
The emergence of secondary keratoacanthomas and other secondary squamous cell carcinomas of the skin were of particular concern. The median time to appearance of these lesions was 8 weeks. All were treated with local excision and no treatment interruptions were required. No other secondary malignancies were observed. Additional adverse event data from the recentlycompleted phase 3 trial are given in *Table 1*.  
1.2.3 Vemurafenib clinical pharmacology  
  
In phase 1 testing, exposure to vemurafenib in the MBP formulation increased proportionally to dose for doses ranging from 240 mg PO bid to 960 mg twice daily4. 24-hour exposure (AUC0-24)
at the recommended phase 2 dose was 1741±639 mMh and the maximum concentration at steady state was 86±32 M. The estimated half-life of vemurafenib was approximately 50 hours (range 30-80 hours), and all patients were exposed to relativelyconstant daily drug levels at the steady state with twice daily dosing. Vemurafenib has very low aqueous solubility and > 99.5% of the drug is bound to plasma protein12.  
Figure 4. Panel A - mean AUC0-24 for vemurafenib with twice daily dosing. Panel B - mean concentration of vemurafenib after the administration of a single dose on day 1 or multiple doses at the steady state on day 15 at the recommended phase 2 dose of 960 mg PO bid. I bars indicate standard deviations.  
Paired biopsy specimens revealed marked reductions in tumor levels of phosphorylated ERK,
cyclin D1 and Ki-67 at day 15 at dose levels of 240 mg PO bid or higher**4,12** indication marked inhibition of the MAPkinase pathway.
a phase 1/2 trial of
1.3 bkm120

NVP-BKM120 (BKM120) is an oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor belonging to the 2,6-dimorpholino pyrimidine derivative family. The eight members of the PI3K family have been classified into three classes: Class I PI3Ks are key players in the PI3K-PDK1- AKT pathway, which regulates cell proliferation, growth, survival and apoptosis. In many tumors the PI3K signaling pathway is constitutively activated. This is thought to be a critical step in mediating the transforming potential and growth stimulating activity of various oncogenes (ErbB2, EGFR, p53, Ras, Src, etc.) contributing to the onset and growth of solid tumors as well as hematological tumors.
a phase 1/2 trial of
1.4 pi3k pathway and mechanism

PI3K signaling is a hallmark of many cancers. Subsets of cancers become also dependent on PI3K pathway signaling ("pathway addicted")18 as a result of mutations of the PIK3CA gene itself or of regulators of PI3K (e.g. PTEN, HER2). As a consequence, pathway mutated tumors are particularly sensitive towards PI3K-pathway inhibition. The superfamily of PI3 kinases is characterized by primary sequence homologies within the catalytic domain of these enzymes. Currently, 8 members of this family are known, belonging to three classes (I-III). At structural level, the enzyme PI3K is composed of a 110-kDa catalytic subunit and an 85-kDa adaptor subunit. PI3K signaling regulates diverse cellular functions, including protein synthesis and glucose metabolism, cell survival and growth, proliferation, cellular resilience and repair, cell migration, and angiogenesis19. PI3K is negatively regulated at the level of PIP3 by phospholipids phosphatases, such as the phosphatase and tensin homologue PTEN and the inositol 5′ phosphatase-2 SHIP2. In addition, signaling through the PI3K pathway is modulated by crosstalk with other signals and pathways, including hormones (estrogen, thyroid hormones), vitamins, integrins, intracellular calcium and the Ras-dependent MAPK pathway. Constitutive activation of PI3K signaling is deemed to be a critical step in mediating the transforming potential of oncogenes and tumor suppressors and, in many tumors, the PI3K pathway is constitutively activated. Moreover, preliminary data suggest that activation of the PI3K pathway may be a predictor of poor prognostic outcome in many cancers. Several lines of evidence suggest that inhibition of the PI3K signaling pathway might provide benefit for the treatment of many cancers: solid tumors (breast cancer, prostate cancer, glioblastomamultiforme, colon cancer, lung cancer etc.) and tumors of the hematopoetic system20-29.  
The molecular changes leading to constitutive activation of the PI3K pathway are diverse and fall into four categories: (1): Gain-of-function mutations of oncogenes encoding positive regulators of PI3K (HER2, EGFR, ras, c-src), including oncogenes coding for components of PI3K itself (PIK3CA that codes for the subunit p110α, gene coding for p85) (2): Loss-of function mutations affecting negative regulators of PI3K such PTEN (i.e. loss of PTEN
expression or function)30,31 (3): Mutations of genes encoding downstream effectors of the PI3K
signaling cascade (e.g. PDK-1, Akt/PKB, RPS6KB1) (4): Mutation of the tumor suppressor p53 (i.e. that regulates PI3K signaling through repression of PIK3CA).
a phase 1/2 trial of
1.4.1 bkm120 preclinical studies

BKM120 activity against class I PI3K (p110α, -β, -δ and -γ), Class III (Vps34), the class IV mTor related PI3K or PI4Kβ, was assessed using either using a luciferase luminescence (class I or III PI3Ks and PI4Kβ) or a TR-FRET assay (Class IV mTor). The IC50 in these assays is outlined below in *Table 2*. Table 2.Inhibitory activities (IC50) of BKM120 against other PI3K or related kinases BKM120 significantly inhibits p110α and the most common p110α mutations (H1047R, E454K, E542K), p110β, p110δ and p110γbut not the related proteins Vps34, mTor or PI4Kβ. Hence BKM120 is classified as a pure pan-class I PI3K inhibitor. Enzymatic characterization of the inhibitory properties of the compound revealed that BKM120 is a mixed inhibitor of PI3Kα with a strong competitive component (largest on Vmax). The cocrystal X-ray structure of BKM120 with PI3Kγ confirmed that BKM120 interacts with PI3K into the ATP catalytic cleft. The PI3K pathway regulates the activity of the mTORC1 complex, when cells are challenged through mitogenic stimuli. In order to assess in cells the potential impact of the BKM120 on the mTORC1 complex, the compound was tested in TSC1 null cells. These cells express a constitutively activated mTORC1 complex that uncouples the mTor pathway from the PI3K
upstream input32. When exposed to TSC1 null MEFS, BKM120 reduced the S235/236P-RPS6 levels with an IC50 of 1785 nM, in agreement with the data obtained in the mTor biochemical assay. In contrast, and as expected the allosteric mTORC1 inhibitor RAD001 displayed subnanomolar inhibitory activity in this assay.  
In contrast to molecules with distinct mechanism of action (BCR-Abl inhibitor STI571, mTORC1 allosteric inhibitor RAD001), BKM120 is able to decrease the phosphorylation status of various either direct (GSK3β, FKHRL1/FOXO3a) or indirect downstream Akt effectors (p70S6K, through mTor) in the PTEN null U87MG cell line, as efficiently as prototypical PI3K inhibitors such as LY294002 and Wortmannin. Forkhead transcription factors (such as FKHRL1) are re-located from the nucleus to the cytosol upon phosphorylation by Akt. Treatment of U2OS cells stably expressing GFP - FKHRL1 chimera to GFP with BKM120 produced a strong nuclear localization of the fluorescence signal, in agreement with the reduction of the phosphorylated FKHRL1 levels. Signaling pathways from membrane receptors to nuclear transcription factors involve many different players such as kinases or molecular adaptors. To test whether BKM120 does influence other signaling molecules outside of the PI3K pathway, induction of various pathways (mitogenic with EGF and PDGF, stress pathways with anisomycine and interleukine pathways with IL-4) were interrogated in the presence of the compound. In all cases, BKM120 showed specific PI3K pathway attenuation, as demonstrated by specific attenuation of S473P-Akt levels, without affecting the non PI3K driven read –outs such as activated receptors (EGFR, PDGFR), MAPK kinases (ERK, JNK and p38) or Jak cytosolic tyrosine kinases responsible for Stat transcription factor phosphorylation.
a phase 1/2 trial of
preclinical safety

Safety pharmacology studies in rats revealed no effects on neuronal (behavior) or respiratory functions. Cardiac safety studies, conducted *in vitro* and *in vivo*, did not indicate a prominent electrophysiological risk. In the isolated rabbit heart, effects pointing towards a shortened repolarization were seen only at 10 µM. BKM120 inhibited hERG channel activity significantly at concentrations ≥ 100 M (IC50: 190 M). No relevant electrophysiological effect was seen in dogs. The only effect considered relevant was a trend towards an increase in systolic and diastolic blood pressure, observed in two dog telemetry studies.  
Repeated-dose studies (up to 13 weeks of duration) were performed in rats and dogs. In rats, clinical pathology and histopathology findings showed a decrease in lymphocyte counts in the peripheral blood, decreases in germinal center development in different lymph nodes, and lymphocytolysis in the thymus. In dogs, similar findings occurred. In both species, erythropoiesis was affected, as evidenced by reduced erythrocyte counts, accompanied by bone marrow depression observed in rats. The pancreas was seen to be affected by treatment with BKM120, particularly in dogs, where acinar cell toxicity was seen in the exocrine part of this organ. In addition, in one of the four recovery animals minimal acinar cell atrophy was observed after four weeks treatment-free period. In rats, in the 4-week study, no pancreas toxicity was observed (however, in the 2-week dose range finding study, at higher doses, there were histopathological findings of the endocrine as well as the exocrine pancreas). Male sexual organs and associated tissues were found to be targets of toxicity in both rats and dogs. Changes included minimal to slight germ cell depletion, formation of spermatic giant cells and abnormal spermatids, and cellular debris in epididymal tubules. Testicular toxicity did not fully reverse after the 4-week treatment-free period in rats (highest dose) although a clear trend towards recovery was seen. In individual female rats, minimal to slight cyst formation occurred in the Graafian follicles; in addition, an increased incidence of diestrus stage of the estrous cycle was seen. In dogs, there was no effect on female sexual organs. Insulin/glucose homeostasis was impacted in various species (mice, rats, dogs), as expected from the mode of action of BKM120. However, in both rats and dogs, at the doses used in the 4-week studies, these effects were minimal. After up to 2 weeks of treatment with up to 2.5 mg/kg/day, decreased levels of glutamate, dopamine, serotonin and epinephrine as well as elevated levels of glutamine, GABA (gammaamino butyric acid) and HIAA (5-hydroxyindoleacetic acid, a serotonin breakdown product)
were seen in rats. The increased levels of HIAA and decreased levels of serotonin indicate an increased serotonin breakdown, pointing to a potential perturbation of the serotonin release and/or re-uptake. Generally, the decreased levels of glutamate, dopamine, serotonin and epinephrine points to an exhaustion of these neurotransmitters. No such effects were seen in cerebrospinal fluid (CSF) or plasma of those animals. Both in vitro and in vivo, BKM120 elicited a genotoxic potential. While no evidence for a direct DNA interaction was found in an Ames test and two chromosome aberration tests in vitro, a potential for genotoxicity was concluded based on the observation of an aneugenic potential, seen in this latter experiment. In line with this result, BKM120 treatment resulted in an elevated frequency of micronucleated polychromatic erythrocytes in the bone marrow of rats. In conclusion, the majority of the observed effects were related to the pharmacological activity of BKM120 as an inhibitor of PI3K, such as a potential influence on glucose/insulin homeostasis and the risk of increased blood pressure. Main target organs of toxic effects were bone marrow and lymphoid tissue, pancreas, and male as well as, to a lesser extent, female reproductive organs. Further, neurotransmitter fluctuations were seen in the brain of rats, not visible in plasma or cerebrospinal fluid.  
Please refer to the Investigator"s Brochure for additional information on the preclinical testing of BKM120.
a phase 1/2 trial of
1.4.1.1 pharmacodynamics

BKM120 inhibits wild-type PI3Kα (IC50: 35 nM), with at least 50 fold selectivity towardprotein kinases. The compound is equipotent against somatic PI3Kα mutations (H1047R-,E542K- and E545K-p110α) and is active against the other three PI3K paralogs (PI3Kβ, -γ, -δ;108 to 348 nM range). BKM120 does not significantly inhibit the related kinases mTor andVps34, nor does it inhibit (IC50 >10 μM) other receptors and ion channels profiled.BKM120 reduces the phosphorylation of direct downstream effector Akt in mechanistic andrelevant tumor cell lines (IC50: 93 nM for S473P-Akt in Rat1-p110α cells). This biologicalactivity correlates with inhibition of various Akt downstream signaling pathway componentsand with its antiproliferative activity against a variety of tumor cell lines. Our data suggestthat response to BKM120 in breast cancer cell lines is associated with HER amplificationand/or PIK3CAmu. The role of PTEN loss-of-function as predictor of response seems to beless clear. BKM120 demonstrated significant tumor growth inhibition in tumor xenografts of a variety ofcancer types in mice and rats, including several models of breast cancer. In particular,BKM120 showed high anti-tumor activity and synergism when combined with trastuzumab inthe HER2amplified breast cancer model BT474 (as well as in the Her2-amplified gastricmodel NCI-N87). In vivo PK/PD analyses of tumor tissues showed a good correlationbetween exposure, PI3K pathway blockade (S473P-Akt levels) and anti-tumor activity.
a phase 1/2 trial of
1.4.1.2 preclinical pharmacology pharmacokinetics and

BKM120 was rapidly absorbed with a good oral bioavailability in all animal species tested.The compound has a moderate plasma CL and Vss. BKM120 is moderately bound to plasmaprotein across all species examined and widely distributed to most tissues in the rat. Drugrelated radioactivity enters the brain and testes, and has an affinity to melanin containingtissues. No unique, major phase 1 metabolites were identified in human hepatocytes. BKM120and metabolites have a low potential for covalent binding to protein. BKM120 is not asubstrate for nor an inhibitor of P-glycoprotien (MDR-1) or Multidrug Resistance Related Protein 2 MRP2. The compound is also not an inhibitor of Breast Cancer Resistance Protein (BCRP). With respect to potential drug-drug interactions, at 100 mg qd BKM120 is predicted to be a weak reversible inhibitor of CYP3A4 (Ki 13.6 µM, 0.1 < I/Ki <1). BKM120 also weakly inhibited the CYP2C family (2C8, 2C9 and 2C19) with IC50 values ranging from 35-65 µM (34-59 µM
unbound). BKM120 shows no apparent time dependent inhibition of CYP1A2, CYP2C9, CYP2D6 or CYP3A4/5. Oxidative metabolism of BKM120 was found to be predominantly mediated by CYP3A4 (estimated fm> 0.9), with only minor contributions of CYP1A1. Hence, BKM120 is a sensitive CYP3A4 substrate and there is potential for drug-drug interactions with co-medications that are inhibitors or inducers of CYP3A4. It is possible that BKM120 may activate PXR in vivo and induce CYP3A4 at concentrations ≥ 50 μM. The potential for drugdrug interactions between BKM120 and vemurafenib based on their hepatic metabolism is summarized in *Table 3*.
a phase 1/2 trial of
table 3. the metabolism of

Vemurafenib undergoes minimal hepatic metabolism, primarily by CYP3A4, and BKM120 is a weak CYP3A4 inhibitor. BKM120 undergoes significant metabolism by CYP3A4. Vemurafenib increases CYP3A4 mRNA expression and is a mild CYP3A4 inducer.  
| PLX4032        | BKM120                                 |                                                                             |
|----------------|----------------------------------------|-----------------------------------------------------------------------------|
| Metabolized/   | CYP3A4                                 |                                                                             |
| Transported by | Minimal hepatic metabolism P-gp (weak) | CYP3A4 (major; fm>0.9) CYP1A1 (minor)                                       |
| Metabolites    | Eight                                  | None                                                                        |
| Induces        | CYP3A4 (mild)                          | Potential induction of 3A4 @  ≥50uM                                         |
| Inhibits       | CYP2C9 CYP1A2 CYP2C19 CYP2D6 P-gp      | CYP3A4 (weak, reversible,  Ki 13.6mM) CYP2C8 (weak, 35-65mM) CYP2C9 CYP2C19 |
| Increased mRNA | CYP3A4 (weak to moderate)              |                                                                             |
| expression     | CYP1A2                                 |                                                                             |
a phase 1/2 trial of
1.4.2 bmk120 clinical experience 1.4.2.1

Pharmacokinetic data observed so far showed that BKM120 is rapidly absorbed after oral administration with mean peak plasma concentrations (Cmax) ranging between 0.5 to 4 h post dose (tmax). The median tmax at the MTD dose (100 mg daily) was about 1 hour. After reaching Cmax, BKM120 plasma concentrations decreased in a bi-exponential manner. Apparent total body clearance from plasma (CL/F) was low: ~5.0 L/h, indicating that BKM120 is a low clearance drug. BKM120 accumulated ~3-fold in achieving steady-state, consistent with an effective halflife of ~40 h. Steady-state can be expected to be reached after approximately 7-10 days of daily dosing in most patients. Approximate dose-proportional increase in Cmaxand AUC was found in the dose range of 12.5-150 mg. Intersubject variability in Cmax and AUC differed at each dose level but was relatively low and generally around 40%. Doses of 50mg/day and above led to steady-state drug exposure (AUC0-24,.SS) > 10,000 ng*h/mL, a target efficacious exposure level estimated preclinically. Due to the difficulty to obtain fresh tumor tissue during treatment, pharmacodynamic measurements were limited to surrogate tissues such as skin and blood. The parameters assessed have been selected for their relevance to PI3K/mTOR signaling modulation: phosphorylated S6 ribosomal protein in the skin (S6 is a well known downstream target ofmTOR/PI3K pathway) and C-peptide and glucose levels in the blood (PI3K/mTOR signaling has a critical role in glucose metabolism). A formal analysis of these assessments is currently ongoing. Consistent suppression of S6 activation in skin was evident at the highest doses tested (100 and 150mg/day) with 30 to 80% decrease from baseline levels. Occasional increases of C-peptide have been seen at all doses, while hyperglycemia was one of the DLTs suggesting potential impairment of glucose transport and utilization by the tissues (insulin resistance). More information is provided in the BKM120 Investigators" Brochure.
a phase 1/2 trial of
1.4.2.2 clinical experience with bkm120

As of 20th August 2010, a total of 80 patients were enrolled and received at least one BKM120 treatment among whom 75 patients [in trials CBKM120X2101 (N=66) and CBKM120X1101(N=9)] received BKM120 treatment in monotherapy setting and 5 patients [in trials CBKM120B2101 (N=4) and CBKM120X1107 (N=1)] received BKM120 in combination settings. In monotherapy setting, 6 dose levels have been explored: 12.5 mg/d (N=1), 25 mg/d (N=5), 50 mg/d (N=8), 80 m/d (N=11), 100 mg/d (N=46), and 150 mg/d (N=4). For combination therapy, BKM120 has been tested so far with GSK1120212 [CBKM120B2101 (N=4)] and trastuzumab [CBKM120X2107 (N=1)] at 30 mg/d and 50 mg/d respectively. Seven dose-limiting toxicities (DLTs) were observed in CBKM120X2101: 2 patients with grade 4 hyperglycemia (150mg/d); 1 patient withgrade 3 upper abdominal pain, 1 patient with grade 3 skin rash, 1 patient with grade 2 mood alteration, 1 patient with grade 3 mood alteration (100mg/d); and 1 patient with grade 2 mood alteration (80 mg/d). The maximum tolerated dose (MTD) for BKM120 single agent study was defined as 100 mg/d in Dec 09. As of 20- Aug-10, one DLT, grade 4 liver function abnormal, has been observed in CBKM120X1101; and no DLT has yet been observed in BKM120 combination studies CBKM120B2101 and CBKM120X2107. The MTD in BKM120X1101 (for Japanese patient population) and combination therapy has not been determined yet. The largest clinical experience is based on an ongoing Phase 1 first-in-man study of single-agent oral BKM120, CBKM120X2101. The study has been designed as a Bayesian Logistic Regression dose-escalation trial with a MTD dose-expansion arm enrolling patients with advanced solid tumors. Patients, who are pre-selected for molecular alterations of PI3K and/or PTEN gene, are currently being enrolled in the MTD expansion arm to further characterize the safety, PK and PD profile of BKM120 at the MTD dose. Overall the treatment has been generally well tolerated. As of 20-Aug-10, the most common adverse events in CBKM120X2101( ≥ 15%) regardless of grade and causalitywere decreased appetite (45.5%), nausea (39.4%), constipation, diarrhea, fatigue (each 31.8%), rash (30.3%), hyperglycemia (27.3%), asthenia (25.8%), abdominal pain, vomiting (each 22.7%), anxiety (21.2%), depression (19.7%), mucosal inflammation, pruritus (each18.2%), dyspnea (16.7%), AST increase, dry skin, dyspepsia, pyrexia, and somnolence (each 15.2%).The CTCAE grade 3 or 4 adverse events suspected to be BKM120 treatment related (with a frequency > 2%) included increased transaminases (total 13.6%, with overlappedtransaminitis, AST increase and ALT increase as 7.6%, 3.0%, 3.0% respectively), rash (6.1%), hyperglycemia (4.5%), diarrhea, pruritus, depression, mood altered, and affective disorder (each 3.0%).Newly or worsened CTCAEgrade 3 and4 abnormalities (≥ 15%) in blood biochemistry included AST increase (20.6%) and ALT increase (15.9%). Newly or worsened CTCAEgrade 3 and 4 hematologic abnormalities (≥ 15%) were limited to low absolute lymphocytes (19.1%).Thirty three out of 66 patients (50.0%) experienced at least one QT alteration.No patient had new QTcF or QTcB> 500 msec and/or increased from baseline > 60 msec. New clinically meaningful ECG abnormalities (≥ 15%) included sinus tachycardia (23.1%), sinus bradycardia, and atrial premature contractions (APC) (each 16.7%).Nine deaths were reported, as of 20-Aug-10, and all were due to disease progression. The common adverse events leading to study discontinuation, regardless of study drug relationship, were hyperbilirubinemia and hyperglycemia (each 3.0%).Please refer to the BKM120 Investigators Brochure for safety profile detail of first-in-human trial CBKM120X2101. To date, the safety profiles of study [CBKM120X1101(N=9), CBKM120X2017 (N=1), and CBKM120B2101 (N=4)], look similar to the safety profile of BKM120 in study CBKM120X2101. Further data are being collected, the overall safety profile is subject to change. Based on the observed safety profile, clinicians using BKM120 should pay special attention to significant adverse events related to liver function abnormalities as recently reported. In the first-in-humans study, CBKM120X2101, forty-five (45) patients to date are evaluable for efficacy assessed both with Computed Tomography (CT) scan and 18-FluorodeoxyglucosePositron Emission Tomography (18 F-FDG PET) scan. Two RECIST partial responses have been observed. Twenty-six patients (58%) had a stable disease as best response. With regards to the PI3K pathway activation, of the two responders described above, one had a tumor with the PIK3CA mutation. Moreover, 8 out 18 patients had a stable disease lasting for 16 weeks or longer had tumors with an activated PI3K pathway.Please refer to the Investigator"s Brochure for additional information on the available clinicalexperience with BKM120.
a phase 1/2 trial of
1.5 study rationale

Mutations in the BRAF seronine-threonine kinase leading to constitutive activation of the MAP
kinase pathway occur in over half of cutaneous melanoma tumors3. Vemurafenibis a potent BRAF inhibitor that induces objective tumor responses in the majority of BRAFV600E/K mutant advanced melanoma cases, but these responses are transient, lasting approximately 6 months4,12.  
The limitations of vemurafenib are not surprising given that BRAFV600E/K mutations alone do not cause melanoma. BRAF mutations are common in benign nevi6 and animal studies suggest that BRAF must cooperate with additional oncogenic mutations to yield a malignant phenotype 7.  
Constitutive PI3 kinase pathway activation, often in the setting of PTEN mutations, is common in melanoma cell lines and melanoma metastases particularly those harboring BRAF
mutations8,9. While BRAF mutations alone cannot induce melanoma, BRAF mutation combined with PI3K pathway activation is sufficient to transform melanocytes in preclinical models 7.  
Based on the premise that PI3K activation is necessary to maintain the malignant melanoma phenotype in BRAFV600E/K mutant melanoma tumors, this trial will test the hypothesis that the limitations of BRAF-specific therapies frequently stem from the failure to block constitutive PI3K signaling. BKM120 is a potent, orally bioavailable PI3K inhibitor that that induces marked reductions in PI3K pathway activity in patients with advanced solid tumors11. This is a phase 1/2 clinical trial with the goal of determining whether the addition of BKM120 to vemurafenib will lead to improved 6-month progression-free survival in BRAFV600E/K mutant melanoma.
a phase 1/2 trial of
2 study objectives primary phase

Part A:Determine the recommended phase 2 dose (RP2D) of the PI3K pan class I alpha inhibitor BKM120 when administered in combination the BRAF inhibitor vemurafenib in BRAF inhibitor naïvepatients with BRAFV600E/K mutant melanoma.  
Part B:Determine the recommended phase 2 dose (RP2D) of the PI3K pan class I alpha inhibitor BKM120 when administered in combination the BRAF inhibitor vemurafenib in patients with BRAFV600E/K mutant melanoma who were previously treated with a BRAF inhibitor.  
Phase 2 Determine the 6-month progression-free survival rate (PFS6) in patients with BRAFV600E/K
positive advanced melanoma treated with BKM120 in combination withvemurafenib.
a phase 1/2 trial of
secondary phase 1

Determine the pharmacokinetics (PK) of BKM120 administered alone and in combinationwith vemurafenib in Part A (BRAF inhibitor naïve patients with BRAFV600E/K mutant melanoma) and in Part B (BRAFV600E/K mutant melanoma who were previously treated with a BRAF inhibitor).  
Phase 2 1. Determine the objective response rate, (ORR = CR + PR), PFS and OS for BRAFV600 mutant advanced melanoma patients treated with BKM120 in combination withvemurafenib. 2. Determine the safety and tolerability associated with BKM120 in combination withvemurafenib in patients with BRAFV600E/K positive advanced melanoma.  
3. Determine whether pre-treatment PTEN expression is associated with better progression-free survival. 4. Determine whether greater reduction in PI3K-pathway signaling is associated with better progression-free survival. 5. i. Determine whether responding tumors lack gene expression signatures of both PI3K and MAPK pathway activation.ii. Determine whether progressing tumors demonstrate gene expression signatures of either PI3K or MAPK pathway activation.
a phase 1/2 trial of
part a

The phase 1portion of this trial is a 3+3 dose escalation study. In *Part A* ofthe phase 1 portion of the study, there will be a 7 day lead-in period (cycle 0) to allow for single dose pharmacokinetic analysis of BKM120 alone. Patients will receive continuous dosing of vemurafenib and BKM120 starting on cycle 1, day 1 (See *Figure 5*, Study design). Cycle 1 (28 days) will be defined as the DLT period.
a phase 1/2 trial of
part b

In *Part B* of the phase 1 portion of the study, there will no lead in period, but patients must discontinue BRAF therapy at least 2 weeks or 5 half-lives prior to starting combination therapy on trial (whichever is shorter). Patients with prior disease progression on a BRAF inhibitor will receive continuous dosing of vemurafenib and BKM120 starting on cycle 1, day 1 (See *Figure 5*,
Study design). Cycle 1 (28 days) will be defined as the DLT period.
a phase 1/2 trial of
part a & b

During the phase 1 portion of the study, vemurafenib and BKM120 doses will be escalated using a standard 3+3 dose escalation scheme with the goal of identifying the recommended phase 2 dose (RP2D). Phase 1 dose levels are described in *Table 5* and details regarding dose escalation and identifying the RP2D are given in section 3.3.2.1.
a phase 1/2 trial of
phase 2

In the phase 2 portion of the study, patients will receive continuous dosing of vemurafenib and BKM120 starting on Cycle 1, Day 1 at RP2D.
a phase 1/2 trial of
3.2 study population 3.2.1 patient

All patients enrolled willhave metastatic or locally advanced, unresectable BRAFV600E or BRAFV600K mutant melanoma. The study will enroll an estimated total of 61 patients based on an estimate of 27patients in the phase 1 portion of the study and 37 in the phase 2 portion including 6 patients in the phase 1 MTD cohort.
a phase 1/2 trial of
3.2.2 inclusion and exclusion criteria

Patients must have baseline evaluations performed prior to the first dose of study drug and must meet all inclusion and exclusion criteria. Results of all baseline evaluations assuring that all inclusion and exclusion criteria have been satisfied must be reviewed by the Principal Investigator or his/her designee prior to enrollment of that patient. In addition, the patient must be thoroughly informed about all aspects of the study, including the study visit schedule and required evaluations and all regulatory requirements for informed consent. The written informed consent must be obtained from the patient prior to enrollment. Patients eligible for enrollment in the treatment phase of this study **must meet all** of the following criteria:
a phase 1/2 trial of
inclusion criteria

1. Histologically or cytologically confirmed diagnosis of unresectable stage III and stage IV
melanoma 2. BRAFV600E or BRAFV600K mutation-positive 3. Age ≥ 18 years 4. ECOG performance status 2 5. Patients must have at least one site of measurable disease [if applicable] (per RECIST for solid tumors or the appropriate disease classification/criteria for the target population)
6. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L,
Hb>9 g/dL
7. Total calcium (corrected for serum albumin) less than the upper limit of normal
(biphosphonate usefor malignant hypercalcemia control is not allowed)
8. Magnesium ≥ the lower limit of normal 9. Potassium within normal limits for the institution 10. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than the upper limit of normal for the institution (or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are present)
11. Serum bilirubin less than the upper limit of normal for the institution(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. INR ≤ 2 16. Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) 17. Negative serum pregnancy test within 72hours before starting study treatment in women with childbearing potential 18. Phase 1, Part B cohort -
Patients must have previously tolerated continuous dosing of Vemurafenib(at least 720 mg, bid, or higher) without grade 3 or higher toxicity related to the drug (with the exception of keratoacanthomas or squamous cell carcinoma of the skin, grade 3 nausea or vomiting that resolves to Grade ≤ 1 within 7 days of appropriate supportive therapy, grade 3 diarrhea that resolves to Grade ≤ 1 within 7 days with appropriate supportive therapy, grade ≥ 3 fatigue that resolves to Grade ≤ 2 within 7 days, or grade 3 rash that is not deemed to be clinically intolerable).
a phase 1/2 trial of
exclusion criteria

1. Patients who have received prior treatment with a PI3K inhibitor or a BRAF inhibitor are excluded. BRAF inhibitor exposure:
Phase 1, Part A: Patients who have been previously treated with a BRAF inhibitor are excluded. Prior treatment with sorafenib is permitted. Phase 1 Part B: Patients are required to have had disease progression on a potent BRAF inhibitor such as vemurafenib, dabrafenib, or LGX-818. Phase 2: Patient population will be determined once Phase 1 has been completed.  
2. Patients with a known hypersensitivity to BKM120 or to its excipients 3. Patients with untreated brain metastases are excluded. However, patients with metastatic CNS tumors may participate in this trial, if the patient is > 4 weeks from therapy completion (incl. radiation and/or surgery) and clinically stable at the time of study entry.  
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 a result of patient"s mood assessment questionnaire (See Appendix 1, *Tables A2 and A3*):
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) ≥ CTCAE grade 3 anxiety Meets the cut-off score of ≥ 10 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9)
6. Patients with ≥ CTCAE grade 2diarrhea 7. Patient has active cardiac disease including any of the following:
Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) QTc> 480 msec on screening ECG (using the QTcF formula) Personal or family history of prolonged QT syndrome Angina pectoris that requires the use of anti-anginal medication Ventricular arrhythmias except for benign premature ventricular contractions Supraventricular and nodal arrythmias requiring a pacemaker or not controlled with medication Conduction abnormality requiring a pacemaker Valvular disease with document compromise in cardiac function Symptomatic pericarditis 8. Patient has a history of cardiac dysfunction including any of the following:
Myocardial infarction within the last 6 months, documents by persistent elevated cardiac enzymes or persistentregional wall abnormalities on assessment of LVEF function History of documented congestive heart failure (New York Heart Association functional classification III-IV)
Documented cardiomyopathy 9. Patient has poorly controlled diabetes mellitus (HbA1c > 8 %) 10. 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 Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco, O2 saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates.  
11. 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.  
12. 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.  
13. Patients who are currently receiving treatment with medication with a known risk 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. Please refer to *Table A6* or a list of prohibited QT prolonging drugs with risk of Torsades de Pointes.  
14. Patients receiving chronic treatment with steroids or another immunosuppressive agent.  
Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intr-articular) are allowed. Patients with previously treated brain metastases, who are on stable low dose corticosteroids treatment (e.g. dexamethasone 2 mg/day, prednisone 10 mg/day) for at least 14 days before start of study treatment are eligible.  
15. Patients who have taken herbal medications and certain fruits within 7 days prior to starting study drug. Herbal medications include, but are not limited to St. John"s Wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Fruits include the CYP3A inhibitors Seville oranges, grapefruit, pomelos, or exotic citrus fruits.  
16. 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 A4* for a list of prohibited inhibitors and inducers of CYP3A (Please note that co-treatment with weak inhibitors of CYP3A is allowed).  
17. Chemotherapy or targeted anticancer therapy (other than potent BRAF inhibitors)within 5 half-lives of the prior drug orwithin4 weeks (whichever is shorter). Patients may not have exposure to nitrosourea, antibodies or mitomycin-C within 6 weeks prior to starting study drug. Patients must have resolution of treatment related adverse events to baseline or grade 1 before starting the trial.  
18. 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 19. Patients who have undergone major surgery ≤ 2 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 potentialmust have a negative serum pregnancy test ≤ 72 hours prior to initiating treatment.  
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [*for US only*: and estradiol
< 20 pg/mL] or have had surgical bilateral oophorectomy (with or without hysterectomy)
at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during treatment and for 4 weeks (5 T1/2) after stopping treatment. The highly effective contraception is defined as either: 1. True abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. 2. Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. 3. Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female subjects on the study, the vasectomised male partner should be the sole partner for that patient.  
4. Use of a combination of the following (a+b):
a) Placement of an intrauterine device (IUD) or intrauterine system (IUS) b) Barrier method of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository Oral contraception, injected or implanted hormonal methods are not allowed as BKM120 potentially decreases the effectiveness of hormonal contraceptives. Fertile males, defined as all males physiologically capable of conceiving offspring must use condom during treatment,and for 4 weeks (5 T1/2) after stopping treatment and for additional 12 weeks (16 weeks in total after study drug discontinuation) and should not father a child in this period. Female partner of male study subject should use highly effective contraception during dosing of any study agent and for 16 weeks after final dose of study therapy 22. Known diagnosis of human immunodeficiency virus (HIV) infection  
23. History of another malignancy within 3 years, except cured or curable basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix. Patients with lesions curable by excision must have these lesions excised prior to the initiation of treatment on study.  
24. Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator
a phase 1/2 trial of
3.3 treatments 3.3.1 vemurafenib warnings

Cutaneous squamous cell carcinomas (cuSCC) occurred in 24% of patients. Perform dermatologic evaluations prior to initiation of therapy and every two months while on therapy. Manage with excision and continue treatment without dose adjustment. Serious hypersensitivity reactions, including anaphylaxis, have been reported during and upon re-initiation of treatment. Discontinue ZELBORAF in patients who experience severe hypersensitivity reactions. Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. Discontinue treatment in patients who experience severe dermatologic reactions. QT prolongation has been reported. Monitor ECG and electrolytes before treatment and after dose modification. Monitor ECGs at day 15, monthly during the first 3 months of treatment, every 3 months thereafter, or more often as clinically indicated. If the QTc exceeds 500 ms, temporarily interrupt ZELBORAF, correct electrolyte abnormalities, and control for cardiac risk factors for QT prolongation. Liver laboratory abnormalities may occur. Monitor liver enzymes and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Photosensitivity has been reported. Advise patients to avoid sun exposure while taking ZELBORAF. Serious ophthalmologic reactions, including uveitis, iritis and retinal vein occlusion, have been reported. Monitor patients routinely for ophthalmologic reactions. New primary malignant melanomas have been reported. Manage with excision, and continue treatment without dose modification. Perform dermatologic monitoring as outlined above. Pregnancy: May cause fetal harm. Advise women of potential risk to the fetus. BRAFV600E testing - confirmation of BRAFV600E mutation using an FDA-approved test is required for selection of patients appropriate for ZELBORAF therapy. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma.
a phase 1/2 trial of
adverse reactions

Most common adverse reactions (≥ 30%) are arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin papilloma.  
Version date: June 24, 2013 Protocol CC\#: 11952 Complete and updated adverse event information is available in the Investigational Drug Brochure and/or product package insert.
a phase 1/2 trial of
3.3.2 bkm120 table 4.serious adverse

| MedDRA System Organ Class                                                     | Preferred Term                                             |
|-------------------------------------------------------------------------------|------------------------------------------------------------|
| Blood and lymphatic system disorders                                          | Anaemia,  Lymphopenia, Thrombocytopenia                    |
| Cardiac disorders                                                             | Cardio-respiratory arrest (life-threatening)               |
| Eye disorders                                                                 | Cataract                                                   |
| Gastrointestinal disorders                                                    | Abdominal pain, Colitis, Colitis ulcerative, Constipation, |
| Diarrhoea, Erosive oesophagitis, Mouth ulceration,                            |                                                            |
| Nausea, Stomatitis, Vomiting                                                  |                                                            |
| Asthenia, Fatigue, Mucosal inflammation, Pyrexia                              |                                                            |
| General disorders and administration                                          |                                                            |
| site conditions                                                               |                                                            |
| Hepatobilary disorders                                                        | Hepatic function abnormal                                  |
| Immune system disorders                                                       | Hypersensitivity                                           |
| Infections and infestations                                                   | Infection, Lower respiratory tract infection*, Pneumonia,  |
| Pneumonia bacterial (fatal), Sepsis                                           |                                                            |
| Alanine aminotransferase increased, Aspartate                                 |                                                            |
| Investigations                                                                | aminotransferase increased, Blood alkaline phosphatase     |
| increased, Blood creatine phosphokinase increased,                            |                                                            |
| Transaminases increased                                                       |                                                            |
| Metabolism and nutrition disorders                                            | Dehydration,  Decreased appetite (life-threatening),       |
| Diabetic keto-acidosis* (life-threatening), Hyperglycemia*                    |                                                            |
| (life-threatening),  Hypercreatininemia*, Hyperglycemia,                      |                                                            |
| Hyponatraemia, Hypokalaemia (life-threatening)                                |                                                            |
| Neoplasms benign, malignant and                                               | Neoplasm malignant, Neoplasm progression                   |
| unspecified (incl. cysts and polyps)                                          |                                                            |
| Nervous system disorders                                                      | Altered state of consciousness*, Cerebral ischemia* (life  |
| threatening), Cognitive disorder*, Encephalopathy,                            |                                                            |
| Epilepsy , Leukoencephalopathy                                                |                                                            |
| Psychiatric disorders                                                         | Affective disorder, Anxiety, Confusional state,            |
| Depression,  Delirium*, Mental status changes, Mood                           |                                                            |
| altered, Personality change,                                                  |                                                            |
| Renal and urinary disorders                                                   | Renal failure acute                                        |
| Respiratory, thoracic and mediastinal                                         | Bronchospasm  (life-threatening), Dyspnoea, Interstitial   |
| disorders                                                                     | lung disease (fatal)  Pneumonitis (fatal)                  |
| Skin and subcutaneous tissue                                                  | Drug rash with eosinophilia and systemic symptoms          |
| disorders                                                                     | (DRESS), Rash, Rash maculo-papular, Photosensitivity       |
| reaction                                                                      |                                                            |
| * The late breaking information received after data cut-off date 22 Sep 2011. |                                                            |  
Complete and updated adverse event information is available in the Investigational Drug Brochure.
a phase 1/2 trial of
3.3.3 vemurafenib and bkm120 administration

Vemurafenibwill be administered on a continuous twice daily dosing schedule and BKM120 will be administered on a continuous once daily dosing schedule. Patients should take the daily dose of BKM120 and vemurafenib in the morning. Patients must fast for at least 2 hours after a light meal before taking daily morning dose of BKM120 and vemurafenib. Vemurafenib and 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 or crush them. Patients should continue to fast for 2 hours after the administration of each BKM120 dose. Patients should take the second dose of vemurafenib in the evening 2 hours after dinner (evening meal). If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before the next scheduled dose. The occurrence and frequency of any vomiting during a treatment cycle must be noted as an adverse event. In addition, on the days of full pharmacokinetic sampling, the exact time of any episodes of vomiting within the first 4 hours post-dosing on that day and within the first 4 hours following the previous day"s dosing must be noted whenever possible. If the patient forgets to take her/his BKM120 dose before 6:00 PM, then the dose should be withheld that day and BKM120 should be restarted the following day. Vemurafenib should be taken twice daily. If a patient forgets to take a dose and it is <6 hours before the next schedule dose, the missed dose should be omitted and vemurafenib should be restarted at the next scheduled dose. Patients must avoid consumption of St. John"s Wort, Seville oranges, grapefruit or grapefruit juice, grapefruit hybrids, pomelos and exotic citrus fruits from 7 days prior to the first dose of study medication and during the entire study treatment period due to potential CYP3A4 interaction with the study medication. Patients must avoid concomitant intake of strong and moderate CYP3A4/5 inhibitors and inducers. Orange juice is allowed. All dosages prescribed and dispensed to the patient and all dose changes during the study must be recorded. If a patient requires a vemurafenib or BKM120 dose delay of > 21 days from the previous dose, the patient must be discontinued from treatment completely and will only require a 28 day follow up visit for study completion. Medication labels will comply with US legal requirements and be printed in English. They will supply no information about the patient. The storage conditions for study drug will be described on the medication label.
a phase 1/2 trial of
3.3.4 treatment dosing and schedule

During the phase 1 portion, cohorts of patients will be enrolled according to a standard 3 + 3 dose escalation scheme.
a phase 1/2 trial of
part a

To establish a baseline pharmacokinetic profile for BKM120, phase 1 patients will receive a single dose of BKM120 7 days prior to the initiation of continuous therapy (cycle 0, day -7). PK sampling is described in section 3.4.6. Starting on cycle 1, day 1, patients will receive continuous therapy with vemurafenib and BKM120 during the DLT period (cycle 1 day 1 through cycle 1 day 28) unless dose limiting toxicities occur.Doses will be escalated (see Table 5) once the patients receiving the highest current dose have been observed for at least 4 weeks of combination therapy and if DLTs (see *Table 6*) have not been reported in any of 3 patients in a dose level cohort. If 1 of 3 patients experiences a DLT, the cohort will be expanded to six patients and doses will be escalated if no more than 1 of 6 patients in the expanded cohort experiences a DLT. If 2 or more patients in a dose level cohort experience a DLT, then the dose level will be defined as the non-tolerated dose (NTD). Any dose reduction required during the DLT period will be considered a DLT. The maximum tolerated dose (MTD) for *Part A*will be defined as one dose level below the NTD or BKM120 100 mg PO daily with vemurafenib 960 mg PO bid if this level is achieved without meeting the NTD definition.RP2D will be determined based on the MTD, post-DLT period toxicity, and pharmacokinetic data. There will be no intra-patient dose escalation allowed during the study. For any dose cohort, if a patient is removed from study for reasons that are clearly not treatment-related, then an additional patient will be accrued to that dose level.
a phase 1/2 trial of
part b

Patients must not take BRAF therapy for 2 weeks or 5 half-lives of the BRAF inhibitor prior to initiating combination therapy on trial (whichever is shorter). Starting on cycle 1, day 1, patients will receive continuous therapy with vemurafenib and BKM120 during the DLT period (cycle 1 day 1 through cycle 1 day 28) unless dose limiting toxicities occur.PK sampling is described in section 3.4.6. Doses will be escalated (see *Table 5*) once the patients receiving the highest current dose have been observed for at least 4 weeks of combination therapy and if DLTs (see Table 6) have not been reported in any of 3 patients in a dose level cohort. If 1 of 3 patients experiences a DLT, the cohort will be expanded to six patients and doses will be escalated if no more than 1 of 6 patients in the expanded cohort experiences a DLT. If 2 or more patients in a dose level cohort experience a DLT, then the dose level will be defined as the non-tolerated dose (NTD). The maximum tolerated dose (MTD) for *Part B* will be defined as one dose level below the NTD or BKM120 100 mg PO daily with vemurafenib 960 mg PO bid if this level is achieved without meeting the NTD definition. RP2D will be determined based on the MTD, post-DLT period toxicity, and pharmacokinetic data. There will be no intra-patient dose escalation allowed during the study. For any dose cohort, if a patient is removed from study for reasons that are clearly not treatment-related, then an additional patient will be accrued to that dose level. If the maximum tolerated dose has been identified and fewer than 15 patients have been enrolled in Phase 1, Part B, additional patients may be enrolled at the MTD or RP2D at the discretion of the principal investigator to a maximum of 15 patients.  
| Dose Level   | BKM120 Dose   | Vemurafenib Dose   |
|--------------|---------------|--------------------|
| -1           | 60 mg daily   | 480 mg bid         |
| 1            | 60 mg daily   | 720 mg bid         |
| 2            | 80 mg daily   | 720 mg bid         |
| 3            | 100 mg daily  | 720 mg bid         |
| 4            | 100 mg daily  | 960 mg bid         |  
| Table 6 - Criteria for defining dose-limiting toxicities TOXICITY ANY OF THE FOLLOWING CRITERIA Hematologic a ≥ CTCAE grade 3 neutropenia for > 7 consecutive days CTCAE grade 3 thrombocytopenia for > 7 consecutive days CTCAE grade 4 thrombocytopenia Febrile neutropenia (ANC < 1.0 x 109 /L, fever ≥ 38.5°C) Renal Serum creatinine ≥ 2.0 x ULN to ≤ 3.0 x ULN for > 7 consecutive days > CTCAE grade 3 serum creatinine Hepatic b Total bilirubin ≥ 2xULN to ≤ 3.0 x ULN for > 7 consecutive days > CTCAE grade 3 total bilirubin CTCAE grade 3 AST or ALT for > 7 consecutive days CTCAE grade 4 AST or ALT ALT or AST rise to ≥3x ULN in combination with a rise in bilirubin to ≥ 2x ULN Endocrine Grade 2 hyperglycemia (confirmed with a repeat FPG within 24 hours) that does not resolve to  grade 0 within 14 consecutive days (after initiation of glimepiride, metformin or glibenclamide) ≥ Grade 3 hyperglycemia (confirmed with a repeat FPG within 24 hours) Metabolic/ CTCAE grade 3 asymptomatic amylase and/or lipase, not reversible to ≤ CTCAE grade 2 for > 7  Laboratory consecutive days CTCAE grade 4 asymptomatic amylase and/or lipase Pancreatitis ≥ CTCAE grade 2 Cardiac Cardiac toxicity ≥ CTCAE grade 3 or cardiac event that is symptomatic or requires medical  intervention Clinical signs of cardiac disease, such as unstable angina or myocardial infarction, or Troponin ≥  CTCAE grade 3 Neurotoxicity ≥ 1 CTCAE grade level increase Mood  CTCAE grade 2 mood alteration that does not resolve to ≤ grade 1 within 14 days despite  alteration medical treatment (for Anxiety only, if worsened from baseline) ≥ CTCAE grade 3 mood alteration Dermatologic Any intolerable phototoxicity or skin toxicity (except SCC of the skin amenable to local  excision) ≥ CTCAE grade 3 that does not resolve within 7 days with medical management.  Any grade 3 or higher skin toxicity associated with superinfection or limiting self-care ADLs. Secondary squamous cell carcinoma of the skin including but not limited to keratoacanthomas  amenable to curative excision or other localized curative therapies are NOT classified as DLTs. Other adverse  Grade ≥3 non-hematologic, non-hepatic organ toxicity related to drug regimen, EXCLUDING the  events following: a. Grade 3 nausea or vomiting that resolves to Grade ≤ 1 within 7 days of appropriate supportive  therapy b. Grade 3 diarrhea that resolves to Grade ≤ 1 within 7 days with appropriate supportive therapy c. Grade ≥ 3 fatigue that resolves to Grade ≤2 within 7 days d. Grade ≥ 3 hyperuricemia that resolves to Grade ≤ 2 within 7 days e. Grade 3 fever a ≥ CTCAE grade 3 anemia will not be considered DLT unless judged to be a hemolytic process secondary tostudy drug. ≥ CTCAE grade 3  lymphopenia will not be considered DLT unless clinically significant. b For any grade 3 or 4 hepatic toxicity that does not resolve within 7 days to ≤ grade 1 (or ≤ grade 2 if liverinfiltration with tumor present),  an abdominal CT scan has to be performed to assess if it is related to diseaseprogression. A single patient is assumed not to tolerate the dose if he/she experiences at least one DLT. If a lower grade AE leads to a dose interruption of more than 7 doses of BKM120, this AE will be considered asDLT.  If the 2nd occurrence of an initially non-dose limiting toxicity (e.g., grade 3 AST that resolved to ≤ grade 1 within 7 days at 1st occurrence)  leads to a dose reduction within 28 days of the first dose of BKM120, thiswill be considered a DLT.   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
a phase 1/2 trial of
parts a & b

Toxicity will be assessed using the NCI Common Toxicity Criteria for Adverse Events, version 4.0 unless otherwise specified (e.g., hyperglycemia). A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs< 28 days following Cycle 1 Day 1 of BKM120 and vemurafenib, and meets any of the criteria listed in *Table 6*.  
Whenever a patient experiences atoxicity that fulfills the criteria for a DLT (or a potential DLT), treatment will be interrupted (if not otherwise specified) and the toxicity will be followed up as described in *Table 7*. Exceptions are CTCAE grade 2 hyperglycemia, CTCAE grade 2 mood alteration, and squamous cell carcinoma of the skin that is amenable to cure by local excision. Grade 3 skin toxicity (except SCC of the skin amenable to local excision) and grade 3 photosensitivity will only be considered DLTs if they are intolerable and if they do not resolve within 7 days with appropriate medical management. In the case of hyperglycemia and mood alteration, treatment will be continued under appropriate co-medication, and in the case of SCC of the skin, local excision will be performed. The rules for re-initiation and dose modification of BKM120 and vemurafenibtreatment are outlined in *Table 8*.Prior to enrolling patients into a higher dose level, ≥ CTCAE grade 2 adverse events will be reviewed for all patients at the current dose level.  
After the 28-day DLT period, dose modifications will be made as outlined in *Table 8*. Treating physicians must notify the PIimmediately of any unexpected ≥ CTCAE grade 3 adverse events or laboratory abnormalities.
a phase 1/2 trial of
3.3.4.2 follow-up for dose-limiting toxicities

Patients whose treatment is interrupted or permanently discontinued due to an adverse event or clinically significant laboratory value, must be followed as outlined in *Table 7*, at least once a week for 4 weeks, and subsequently at 4-week intervals, until resolution or stabilization of the event, whichever comes first. If a patient requires a dose delay of > 21 days from the intended day of the next scheduled dose, then the patient should be discontinued from the study. All patients must be followed for adverse events and serious adverse events for 28 days following the last dose of BKM120.
a phase 1/2 trial of
table 7.follow-up for dose-limiting toxicities

| TOXICITY                                                                              | FOLLOW-UP EVALUATION                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
|---------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Hematology                                                                            | If ≥ CTCAE grade 3 neutropenia or ≥ CTCAE grade 3 thrombocytopenia havebeen  demonstrated, these labsmust be repeated at least twice a weekuntil resolution to ≤ CTCAE  grade 1 neutropenia or ≤ CTCAE grade 1thrombocytopenia to allow for initiation of retreatment, and then at least weeklyuntil either resolution or until stabilization.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Renal                                                                                 | If serum creatinine ≥ 2 x ULN has been demonstrated, this parameter must berepeated at  least twice a week until resolution to ≤ CTCAE grade 1 to allow forinitiation of retreatment, and then at least weekly until either resolution or untilstabilization. If [+3]  proteinuria, hematuria ≥ CTCAE grade 2 or serum creatinine ≥ 2.0 x ULN has been  demonstrated, a 24-hour urine collection for total protein and total creatinine must be  repeated at least weekly until either resolution to baseline value or until stabilization.  Whenever a measured CrCl is obtained, a serum creatinine should be obtained within ≤ 72  hours of the urine collection.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Hepatic                                                                               | If total bilirubin ≥ 2 x ULN in combination with≥ CTCAE grade 3 AST/ALT has  beendemonstrated, these parameters must be repeated at least twice a week untilresolution  to ≤ CTCAE grade 1 (or ≤ grade 2 for AST or ALT, if liver metastasisare present) to allow  for initiation of re-treatment, and then at least weekly untileither resolution or until  stabilization. Patients with total bilirubin > ULN (any duration) should have fractionation ofbilirubin into  total/direct or indirect/direct components and any additional work-up as clinically indicated  by these results. Follow-up of hyperbilirubinemia should proceed as per the guidelines  above, irrespective of the results of fractionation. |
| Metabolic/                                                                            | If amylase and/or lipase ≥ CTCAE grade 3 (> 2 x ULN) has been demonstrated,these                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| Laboratory                                                                            | parameters must be assessed once at 2 to 4 days and once again at 7days (± 1 day) and be  repeated twice a week until resolution to ≤ CTCAE grade2 to allow for initiation of retreatment, and then at least weekly until either resolution to ≤ CTCAE grade 1 or until  stabilization. A CT scan or other imaging study to assess the pancreas, liver, and gallbladdermust be  performed within 1 week of the first occurrence of any ≥ CTCAEgrade 3 of amylase or  lipase. In patients with serum triglycerides ≥ 500 mg/dL, urine amylase needs to be tested in  addition.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Endocrine                                                                             | For details of the follow-up and treatment of ≥ grade 2 hyperglycemia refer to  the"Guidelines for the treatment of study drug-induced hyperglycemia" provided insection  3.3.6.2.2.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| Cardiac                                                                               | Patient who experience QTc prolongation should be followed as per Table 6.In addition,  patients who experience ECG abnormalities indicative of an ischemic cardiac event, ECGs  should be repeated at least twice a week until normalization or stabilization of ECG  findings. If troponin ≥ CTCAEgrade 3 has been demonstrated, this parameter must be  repeated twice a week until resolution to ≤ CTCAE grade 1 to allow for initiation of retreatment, and then at least weekly until either resolution or until stabilization                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Neurotoxicity                                                                         | Patients who experience neurotoxicity should be followed as per Table 6.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Mood alteration ≥ grade 2 Note: For grade 2  Anxietyonly, if  worsened from  baseline | For patient who experience ≥ grade 2 mood alteration a psychiatrist must be consulted for  diagnosis and determination of most appropriate medical treatment. Patients must be  followed twice weekly by patient self-rating mood scale and be seen weekly by the  psychiatrist until resolved ≤ grade 1 or baseline (for anxiety). Continue to test weekly by  mood scale until resolution to baseline or stabilization. Refer to Section 3.3.5.2.1 for more  details.                                                                                                                                                                                                                                                |
| Non-Laboratory                                                                        | Patients who experience non-laboratory DLTs must be evaluated at least once a week  following demonstration of the toxicity until resolution of the toxicity to allow for retreatment, stabilization of the toxicity, or study treatment completion.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
a phase 1/2 trial of
3.3.4.3 dose expansion and phase

After the RP2D is identified in Phase I, Part A, the RP2D cohort for BRAF inhibitor naïve patientswill be expanded to a total of 37 patients for the phase 2 portion of the trial. Dose modifications in the phase 2 portion of the trial will be made as outlined in *Table 9*.
a phase 1/2 trial of
3.3.5 interruption or discontinuation of

For patients who develop dose-limiting adverse events despite maximum supportive care after the DLT period in the phase 1 portion or at any time in the phase 2 portions of the study, dose adjustments are permitted. The criteria for dose adjustments for vemurafenib and BKM120 are described in *Table 8*. Since the study drugs have overlapping toxicities, the doses of both drugs will be reduced sequentially for all toxicities other than hyperglycemia, pneumonitis and anxiety, which are unique to BKM120. The dose levels for drug associated adverse events other than hyperglycemia, pneumonitis, and anxiety are outlined in *Table 9*. Reduction of the dose of BKM120 alone by increments of 20 mg per dose will be made for hyperglycemia, pneumonitis and anxiety with a maximum of 2 dose reductions permitted.
a phase 1/2 trial of
table 8. criteria for interruption

| Recommended Dose Modifications for vemurafenib and BKM120             |                                                                                                                                                                                               |      |       |       |          |    |    |       |    |      |
|-----------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------|-------|-------|----------|----|----|-------|----|------|
| Worst toxicity (CTCAE Grade)**                                        | Recommended Dose Modifications                                                                                                                                                                |      |       |       |          |    |    |       |    |      |
| No toxicity                                                           | Maintain dose level                                                                                                                                                                           |      |       |       |          |    |    |       |    |      |
| HEMATOLOGICAL Neutropenia (ANC) Grade 1 (ANC < LLN - 1.5 x109 /L)     | Maintain dose levels                                                                                                                                                                          |      |       |       |          |    |    |       |    |      |
| Grade 2 (ANC < 1.5 - 1.0 x 109 /L) Grade 3 (ANC < 1.0 - 0.5 x 109 /L) | Omit both drugs until resolved to ≤ Grade 1, and/or:                                                                                                                                          |      |       |       |          |    |    |       |    |      |
| Grade 4 (ANC < 0.5 x 109 /L)                                          | If resolved in ≤ 7 days, then maintain dose level If resolved in > 7 days, then vemurafenib/BKM120 1  dose level as outlined in Table 9                                                      |      |       |       |          |    |    |       |    |      |
| Febrile neutropenia                                                   | Omit both drugs until resolved, then vemurafenib/BKM120 1                                                                                                                                    |      |       |       |          |    |    |       |    |      |
| (ANC < 1.0 x 109 /L,fever ≥ 38.5°C)                                   | dose level as outlined in Table 9                                                                                                                                                             |      |       |       |          |    |    |       |    |      |
| Thrombocytopenia Grade 1 (PLT < LLN - 75 x 109 /L)                    | Maintain dose level                                                                                                                                                                           |      |       |       |          |    |    |       |    |      |
| Grade 2 (PLT < 75 - 50 x 109 /L) Grade 3 (PLT < 50-25 x 109 /L)       | Omit both drugs until resolved to ≤ Grade 1, and/or: If resolved in ≤ 7 days, then maintain dose level If resolved in > 7 days, then vemurafenib/BKM120 1  dose level as outlined in Table 9 |      |       |       |          |    |    |       |    |      |
| Grade 4 (PLT < 25 x 109 /L)                                           | Omit                                                                                                                                                                                          | both | drugs | until | resolved | to | ≤  | Grade | 1, | then |
| vemurafenib/BKM120 1 dose level as outlined in Table 9               |                                                                                                                                                                                               |      |       |       |          |    |    |       |    |      |
| HEPATIC Bilirubin (*for patients with Gilbert                         | Will be fractionated if elevated                                                                                                                                                              |      |       |       |          |    |    |       |    |      |  
| Recommended Dose Modifications for vemurafenib and BKM120                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                             |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Worst toxicity (CTCAE Grade)**                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Recommended Dose Modifications                                                                                                                                                              |
| Syndrome these dose modifications  apply to changes in direct bilirubin  only) Grade 1 (> ULN - 1.5 x ULN)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Maintain dose level with LFTs* monitored as per protocol                                                                                                                                    |
| Grade 2 (> 1.5 - 3.0 x ULN) with                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Omit both drugs until resolved to ≤ Grade 1, then:                                                                                                                                          |
| ALT or AST ≤ 3.0 x ULN                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | If resolved in ≤ 7 days, then maintain dose level If resolved in > 7 days, then vemurafenib/BKM120 1  dose level as outlined in Table 9                                                    |
| Grade 3 (> 3.0 - 10.0 x ULN) with                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Omit both drugs until resolved to ≤ Grade 1, then:                                                                                                                                          |
| ALT or AST ≤ 3.0 x ULN                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | If resolved in ≤ 7 days, vemurafenib/BKM120 1 dose level as outlined in Table 9 If resolved in 7 days discontinue patient from study  treatment                                            |
| Grade 4 (> 10.0 x ULN)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Omit both drugs and discontinue patient from study                                                                                                                                          |
| AST or ALT Grade 1 (> ULN - 3.0 x ULN)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Maintain dose level with LFTs monitored as per protocol                                                                                                                                     |
| Grade 2 (> 3.0 - 5.0 x ULN)  without bilirubin elevation to > 2.0  x ULN                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Omit dose until resolved to ≤ grade 1, then If resolved in ≤ 7 days, then maintain dose level If resolved in > 7 days, then ↓ vemurafenib/BKM120 1 dose level as outlined in Table 9        |
| Grade 3 (> 5.0 - 20.0 x ULN)  without bilirubin elevation to > 2.0  x ULN                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Omit both drugs until resolved to ≤ Grade 1 , then If resolved in ≤ 7 days, then maintain dose level If resolved in > 7 days, then vemurafenib/BKM120 1  dose level as outlined in Table 9 |
| Grade 4 (> 20.0 x ULN) without                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Omit both drugs until resolved to ≤ Grade 1, (then                                                                                                                                          |
| bilirubin elevation to > 2.0 x ULN                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | vemurafenib/BKM120 1 dose level as outlined in Table 9                                                                                                                                     |
| AST or ALT and concurrent Bilirubin AST or ALT > 3.0 x ULN and total  Discontinue study treatment permanently. bilirubin > 2.0 x ULN * LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN),  alkaline phosphatase (fractionated if alkaline phosphatase is grade 2 or higher) and GGT. Monitoring (*for patients with Gilbert Syndrome: total and direct bilirubin must be monitored,  intensified monitoring applies to changes in direct bilirubin only; the monitoring includes the  following LFTs: albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN),  alkaline phosphatase (fractionated if alkaline phosphatase is grade 2 or higher) and GGT. |                                                                                                                                                                                             |  
| Recommended Dose Modifications for vemurafenib and BKM120                    |                                           |
|------------------------------------------------------------------------------|-------------------------------------------|
| Worst toxicity (CTCAE Grade)**                                               | Recommended Dose Modifications            |
| ENDOCRINE/METABOLIC Fasting Plasma Glucose (FPG) Grade 1 (> ULN - 160 mg/dL) | Maintain dose level, check FPG every week |
| [> ULN - 8.9 mmol/L]                                                         | initiate or intensify medication with appropriate antidiabetic treatment. as per investigator"s discretion instruct patient to follow dietary guidelines provided by the  American Diabetes Association during the study  check FPG weekly for 8 weeks, then continue checking  every 2 weeks                                           |
| Grade 2 (>160 - 250 mg/dL)                                                   | First Occurrence:                         |
| [> 8.9 - 13.9 mmol/L]                                                        | Maintain dose, re-check FPG within 24 hours, if no worse than  Grade 2*: maintain dose level initiate or intensify medication with appropriate antidiabetic treatment.  instruct patient to follow dietary guidelines provided by the  American Diabetes Association during the study  If FPG does not resolve to ≤ Grade 1 within 14 days after  initiation/intensifying anti-diabetic treatment: omit BKM120 monitor FPG at least weekly until FPG resolves to ≤ Grade  1 then re-start BKM120 and  1 BKM120 dose level (-20  mg) continue with anti-diabetic treatment check FPG weekly for 8 weeks, then continue checking  every 2 weeks * if grade "worsens" then follow specific grade  recommendations                                           |
| Grade 2 (>160 - 250 mg/dL)                                                   | Second Occurrence:                        |
| [> 8.9 - 13.9 mmol/L]                                                        | maintain dose, re-check FPG within 24 hours, if no worse than  Grade 2*: omit BKM120 initiate or intensify medication with appropriate antidiabetic treatment  monitor FPG at least twice weekly until FPG resolves to  ≤ Grade 1  then re-start BKM120 and  1 dose level (-20 mg) continue with anti-diabetic treatment                                           |  
| Recommended Dose Modifications for vemurafenib and BKM120                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                  |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Worst toxicity (CTCAE Grade)**                                                                                                                                                                                                                                                                                    | Recommended Dose Modifications check FPG weekly for 8 weeks, then continue checking  every 2 weeks * if grade "worsens" then follow specific grade  recommendations                                                                                                                                                                              |
| Grade 3 (> 250 - 500 mg/dL)                                                                                                                                                                                                                                                                                       | First Occurrence:                                                                                                                                                                                                                                                                                                                                |
| [> 13.9 - 27.8 mmol/L]                                                                                                                                                                                                                                                                                            | Omit BKM120, initiate or intensify medication with appropriate  anti-diabetic treatment, re-check FPG within 24 hours, if no  worse than Grade 3*: monitor FPG at least twice weekly until FPG resolves to  ≤ Grade 1  stop or reduce insulin medication  then re-start BKM120 and  1 BKM120 dose level(-20  mg) continue with anti-diabetic treatment as appropriate instruct patient to follow dietary guidelines provided by the  American Diabetes Association during the study  check FPG weekly for 8 weeks, then continue checking  every 2 weeks Second Occurrence: Same process as for first occurance, however at the second reinitiation BKM120 may be dose-reduced a second time.  * if grade "worsens" then follow specific grade  recommendations                                                                                                                                                                                                                                                                                                                                                  |
| Grade 4 (> 500 mg/dL)                                                                                                                                                                                                                                                                                             | Immediately omit BKM120, initiate or intensify medication                                                                                                                                                                                                                                                                                        |
| [≥ 27.8 mmol/L]                                                                                                                                                                                                                                                                                                   | with appropriate anti-diabetic treatment, re-check within 24  hours, if confirmed Grade 4: Discontinue patient from BKM120 Patient may continue  vemurafenib. instruct patient to follow dietary guidelines provided by the  American Diabetes Association during the study  check FPG weekly for 8 weeks, then continue checking  every 2 weeks |
| CARDIAC Cardiac - Left Ventricular systolic dysfunction Asymptomatic,  resting ejection fraction 50 - 40%; or 10-20% drop from baseline Maintain dose level Omit both drugs until resolved to ≤ Grade 1, then  Symptomatic,  responsive to intervention,  vemurafenib/BKM120 1 dose level as outlined in Table 9 |                                                                                                                                                                                                                                                                                                                                                  |  
| Recommended Dose Modifications for vemurafenib and BKM120                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Worst toxicity (CTCAE Grade)**                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Recommended Dose Modifications                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| ejection fraction 39 - 20%                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | LVEF measurement to be repeated, if not resolved to ≤ Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| or > 20% drop from baseline                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | within 3 weeks, permanently discontinue patient from study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Refractory or poorly controlled,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Omit both drugs and discontinue patient from study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| ejection fraction < 20% Cardiac - QTc prolongation QTcF> 500 ms (≥ Grade 3)  or > 60 ms change from baseline on at least two separate ECGs                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | First Occurrence: Omit both drugs  Perform an analysis of serum potassium and  magnesium, and if below lower limit of normal,  correct with supplements to within normal limits.  Concomitant medication usage must be reviewed. Perform a repeat ECG within one hour of the first  QTcF of > 500 ms If QTcF remains > 500 ms, repeat ECG as clinically  indicated, but at least once a day until the QTcF  returns to < 480 ms. Once QTcF prolongation has resolved, BKM120 may  be restarted at a one lower dose level  Second Occurrence: discontinue patient from vemurafenib/BKM120 |
| Other Cardiac Events Grade 1 or 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Maintain dose level                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Omit both drugs until resolved to ≤ Grade 1, then  vemurafenib/BKM120 1 dose level as outlined in Table 9                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Discontinue patient from study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| OTHER Mood alteration * See Table A1-3 for toxicity grading of mood questionnaires. Questionnaire scores should be  considered when assigning the AE Grade but psychiatric consult, if required, may determine the  grade Grade 1 (or Grade 2 anxiety if present at  baseline) Maintain dose level Note: If question 9 on the PHQ-9 has a positive response, or  worsens in severity, the patient should be referred for  psychiatric consult regardless of the total questionnaire score Grade 2 (for Anxiety only, if worsened from  baseline) Institute appropriate co-medication under the guidance of the  psychiatrist. Maintain dose level. If the condition does not resolve to ≤ Grade 1 within  14 days despite medical treatment; then  1 BKM120  dose level (-20 mg, continue to co-medicate) |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
a phase 1/2 trial of
table 8. criteria for interruption

| Recommended Dose Modifications for vemurafenib and BKM120                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                      |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Worst toxicity (CTCAE Grade)**                                                                                                                                                           | Recommended Dose Modifications Note: If question 9 on the PHQ-9 has a positive response, or  worsens in severity, the patient should be referred for  psychiatric consult regardless of the total questionnaire score                                                                                                                                |
| Grade 3                                                                                                                                                                                  | Omit dose until resolved to ≤ Grade 1, then  1 BKM120  dose level (-20 mg, co-medicate) Note: If question 9 on the PHQ-9 has a positive response, or  worsens in severity, the patient should be referred for  psychiatric consult regardless of the total questionnaire score                                                                      |
| Grade 4                                                                                                                                                                                  | Omit BKM120 dose and discontinue BKM120. Patient may  continue to receive vemurafenib. Note: If question 9 on the PHQ-9 has a positive response, or  worsens in severity, the patient should be referred for  psychiatric consult regardless of the total questionnaire score                                                                        |
| Rash Grade 1                                                                                                                                                                             | Maintain dose level. Consider to initiate appropriate skin  toxicity therapy (such as antihistamines, topical  corticosteroids)                                                                                                                                                                                                                      |
| Grade 2                                                                                                                                                                                  | Maintain dose level. Initiate/intensify appropriate skin toxicity  therapy (such as antihistamines, topical corticosteroids)                                                                                                                                                                                                                         |
| Grade 3                                                                                                                                                                                  | Hold both drugs for any grade 3 rash that is intolerable,  associated with superinfection, or limiting self-care ADLs until  resolved to CTCAE Grade ≤ 2, then: If resolved in ≤ 7 days, vemurafenib/BKM120 1 dose level as outlined in Table 9 If resolved in 7 days (despite appropriate skin toxicity  therapy), discontinue patient from BKM120 |
| Grade 4                                                                                                                                                                                  | Omit both drugs and discontinue patient from study                                                                                                                                                                                                                                                                                                   |
| Fatigue (asthenia) Grade 1 or 2                                                                                                                                                          | Maintain dose level                                                                                                                                                                                                                                                                                                                                  |
| Grade 3                                                                                                                                                                                  | Omit dose until resolved to ≤ Grade 1, then: If resolved in ≤ 7 days, maintain dose level If resolved in 7 days, vemurafenib/BKM120 1 dose level as outlined in Table 9                                                                                                                                                                             |
| Grade 4                                                                                                                                                                                  | Omit dose and discontinue patient from BKM120. Patient  may continue to receive vemurafenib                                                                                                                                                                                                                                                          |
| Other non-hematological adverse events Grade 1 or 2 Maintain dose level Grade 2 (pancreatitis) Omit dose until resolved to ≤ Grade 1, then: If resolved in ≤ 7 days, maintain dose level |                                                                                                                                                                                                                                                                                                                                                      |  
| Recommended Dose Modifications for vemurafenib and BKM120              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
|------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Worst toxicity (CTCAE Grade)**                                         | Recommended Dose Modifications If resolved in 7 days, vemurafenib/BKM120 1 dose level as outlined in Table 9                                                                                                                                                                                                                                                                                                                                                                 |
| Grade 3                                                                | Omit both drugs until resolved to ≤ Grade 1, then  vemurafenib/BKM120 1 dose level as outlined in Table 9.  No treatment changes are required for keratoacanthomas or  other squamous cell carcinoma skin lesions that are curable  by local excision. For grade 3 asymptomatic lipase and/or lipase, omit both  drugs until resolved to ≤ Grade 1, then  vemurafenib/BKM120 1 dose level as outlined in Table 9 if not  reversible to ≤ grade 2 within 7 consecutive days. |
| Grade 4                                                                | Omit both drugs and discontinue patient from study Note: Omit dose for ≥ Grade 3 nausea, vomiting or diarrhea only if the nausea, vomiting or diarrhea cannot be controlled  with optimal antiemetic or antidiarrheal regimen.  No treatment changes are required for keratoacanthomas or  other squamous cell carcinoma skin lesions that are curable  by local excision.                                                                                                    |
| Pneumonitis                                                            | See Table 11                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
| ** Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |  
Table 9. *Vemurafenib-BKM120 dose reductions for all toxicities other than hyperglycemia* and anxiety  
| Dose Level at which toxicity        | Reduce to:                                     |
|-------------------------------------|------------------------------------------------|
| requiring dose reduction occured -1 | Vemurafenib 240 mg bid with BKM120 60 mg daily |
| 1                                   | Table 5, dose level -1                         |
| 2                                   | Table 5, dose level 1                          |
| 3                                   | Table 5, dose level 2                          |
| 4                                   | Table 5, dose level 3                          |  
Dose levels are outlined in Tables 5
a phase 1/2 trial of
table 8. criteria for interruption

Common grade 2 or higher drug-related adverse events of vemurafenib in phase 1 testing included rash, photosensitivity, pruritis, palmar-plantar dysesthesias, squamous cell carcinomas of the skin/keratoacanthomas, fatigue, nausea, and arthralgias4. Only four patients had grade 4 adverse events potentially related to vemurafenib: two had GGT elevations, one had fatigue, and one had pancytopenia. In general, pain complaints should be managed with acetaminophen and mild narcotic pain medications, and nausea should be managed with oral prochlorperazine or ondansetron as needed. Dose adjustments may be required for persistent symptoms or laboratory abnormalities despite optimal symptomatic support (see *Table 8*).
a phase 1/2 trial of
3.3.6.1.1 dermatologic events

15% of patients in the phase 1 dose-escalation cohort and 31% in the dose expansion cohort developed treatment-associated squamous-cell carcinomas and nearly all of these were histologically consistent with keratoacanthomas4. The median time to appearance of these lesions was 8 weeks. All were treated with local excision and no treatment modifications were required. No other squamous cell malignancies have been reported with vemurafenib. Patients on the current study will be assessed by the study dermatologist prior to the initiation of treatment on vemurafenib and all lesions that are suspicious for malignancy should be excised. During pre-treatment and follow-up visits, pre-malignant lesions may be treated with excision, cyroablation, or other standard-of-care techniques at the discretion of the dermatologist. Followup dermatologic evaluation will be scheduled prior to the initiation of BKM120 and then every eightweeks (+/- 3 days) and earlier evaluations should be scheduled if any suspicious lesions emerge between these scheduled visits. Rash is a common adverse event associated with vemurafenib and symptomatic treatments including antihistamines, antibiotics such as tetracyclines, and topical corticosteroids may be used at the discretion of the treating clinician. Short-term oral corticosteroids (< 10 days) may be used with the consent of the Principal Investigator, and patient receiving both oral corticosteroids and BKM120 should be instructed regarding home blood glucose monitoring.
a phase 1/2 trial of
monitoring of bkm120 suspected toxicities

Patients whose treatment is interrupted or permanently discontinued due to an adverse event or clinically significant laboratory value, must be followed as outlined in *Table 7*, at least once a week for 4 weeks, and subsequently at 4-week intervals, until resolution or stabilization of the event, whichever comes first. After the DLT evaluation period, if a patient requires a dose delay of > 21 days from the intended day of the next scheduled dose, then the patient should be discontinued from the study. If the patient requires more than 2 dose reductions, the patient should be discontinued from the study.
a phase 1/2 trial of
3.3.6.2 known undesirable side effects

This adverse event emerged as a side effect related to BKM120. Studies conducted *in vitro* and in vivo hypothesize that PI3K/Akt and Akt/GSK3 signaling pathways are associated and modulated by changes of monoamine transmitters (dopamine and serotonin 5-HT)33-35. BKM120 showed penetration in brain tissue in animal models. In preclinical safety studies with BKM120 neither an evidence of impaired neuronal function nor any morphologic changes of the central nervous system were detected. Clinically, as of 10/25/10, 29 out of 69 patients (42%), treated with BKM120 as a single agent (in trial BKM120X2101), experienced mood alterations such as anxiety, agitation, crying episodes, depression and behavioral changes with aggressive components. Grade 3 events (severe mood alteration interfering with active daily life activities) were reported in 5 patients (7%). No grade 4 events have been observed thus far. All the events have been observed at a BKM120 dose of 80 mg/day or higher with onset occurring within 28 days after treatment initiation. Symptoms improved when treatment was interrupted. Patients with a medical history of depression or anxiety experienced the most severe episodes, however if concomitantly treated with antidepressants, did not develop psychiatric symptoms during study drug administration. In some patients the causal relationship with BKM120 was not clearly established because the patients may have been influenced by negative events related to their close family or friends. Benzodiazepine introduction and BKM120 dose reduction well controlled the mood in patients who continued on treatment. Due to the frequency and peculiarity of this side effect, a scientific advice was sought through an advisory board held in November 2009. Some corrective measures identified by the advisory board included additional exclusion criteria and new procedures for mood alteration monitoring and follow-up. Patient self-rating mood questionnaires for anxiety (GAD-7) and depression
(PHQ-9) were implemented in the study BKM120X2101 in January 2010. As shown in *Table 10* these measures have led to a reduction in the number and the severity of the observed events of mood disorder as well as the number of discontinuations due to this adverse event.
a phase 1/2 trial of
table 10.mood disorders adverse events

| Mood disorders   | Before Jan 2010 (N=42)   | After Jan 2010 (N=27)   |
|------------------|--------------------------|-------------------------|
| All grades       | 26 (62%)                 | 10 (37%)                |
| Grade 3          | 3 (7%)                   | 2 (7%)                  |
| Discontinuations | 2 (5%)                   | None                    |  
In order to lower the risk of experiencing significant mood alterations within the proposed study, cancer patients with an active or history of major depressive episode, bipolar disorder, obsessivecompulsive disorder, schizophrenia, a history of suicide attempt or ideation, or homicide/homicidal ideation as judged by the investigator and/or based on recent psychiatric assessment will not qualify for study participation. For patients with corresponding symptoms CTCAE Grade ≥ 2, thestudy psychiatrist will be consulted for diagnosis and determination of most appropriate medical treatment Medical treatment with mood stabilizers (2nd generation antipsychotics) such as olanzapine and quetiapine may be applied as per investigator"s discretion and following consultation of the study psychiatrist. The study psychiatrist at UCSF is: Laura Dunn, MD
Associate Professor in Residence UCSF Department of Psychiatry Box 0984 - F, 401 Parnassus Ave, LangPorter LP254 University of California, San Francisco San Francisco, CA. 94143 - 0984 Phone: (415) 476-7518
a phase 1/2 trial of
management of mood alteration

Patient self-rating mood questionnaires GAD-7 (anxiety, Appendix, *Table A2*), and PHQ-9 (depression, Appendix, *Table A3*) will be used:  
to support assessment of eligibility at Screening to monitor for newly occurring or worsening mood alterations during the study
The mood alteration grading system is outlined in the appendix and in *Table A1*. At Screening, a patient as judged by the investigator or who 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.  
During the study, for patients who meet the cut-off score of ≥ 10 (≥ CTCAE grade 2 moodalteration) in either questionnaire, a psychiatrist will be consulted for diagnosis and determination ofmost appropriate medical treatment. For anxiety, this applies only if status has worsened frombaseline. Patients who experience ≥ grade 2 mood alteration will be followed weekly by patient self-rating mood scale and will be seen weekly by the psychiatrist until resolved ≤grade 1 or baseline (for anxiety). Questionnaire responses will be checked by the psychiatristat the weekly visits (until resolution to Grade 1) or baseline (for anxiety).
a phase 1/2 trial of
3.3.6.2.2 hyperglycemia

In preclinical studies, insulin/glucose homeostasis was impacted in various species (mice, rats, dogs), as expected from the mode of action of BKM120. In both rats and dogs, at the doses used in the 4-week studies, these effects were minimal. However, in mice treated at high doses (30 or 60 mg/kg/day) a clear induction of insulin resistance/insensitivity was observed. There wasno clear influence of the dose or the time point of testing. Histopathologically, pancreas and liver showed changes were noted which are in concordance with this activity. Grade 4 Hyperglycemia was also observed in a Phase 1a study of BKM120 in patients with solid tumors (CBKM120X2101). Therefore, no patients with uncontrolled diabetes mellitus will be enrolled in this study. In all patients, fasting plasma glucose will obtained at screening and will be monitored throughout the trial. For the treatment of glucose disturbances occurring under BKM120 treatment investigators are advised to adhere to the protocol guidelines outlined in Table 8 and in the following section.
a phase 1/2 trial of
management of hyperglycemia

In addition to the dose modification and hyperglycemia treatment guidelines in *Table 8*:
Insulin regimen should be initiated according to institutional standard of care or the TreatTo-Target Algorithm for Lantus®36.  
For any hyperglycemia ≥ grade 1, the patient should continue to follow dietary guidelinesprovided by the American Diabetes Association (American Diabetes Association 2004). Patients with ≥ grade 3 hyperglycemia who do not have indications for hospitalization should be advised to initiate home glucose monitoring with twice daily finger sticks until hyperglycemia resolves to ≤ grade 1.  
For each patient, once a dose level reduction has occurred, the dose level may not be reescalated in that patient during future treatment cycles with BKM120.  
For each patient, a maximum of 2 dose reductions will be allowed after which the patient should be discontinued from the study. In addition, a patient must discontinue treatment with BKM120, if after treatment is resumed at a lower dose, hyperglycemia recurs at a worse severity. Based upon the results of preliminary clinical data and actual laboratory values (e.g., glucose, insulin) generated, the treatment recommendations for study drug induced hyperglycemia may be modified as needed.
a phase 1/2 trial of
3.3.6.2.3 cardiac events

Cardiac safety studies, conducted in vitro and in vivo, did not indicate a prominentelectrophysiological risk. The only effect considered relevant was a trend towards an increasein systolic and diastolic blood pressure, observed in two dog telemetry studies.As a precaution in the first-in man study with BKM120 no patients with a severe orunstablecardiac disease or cardiac disease requiring continuous treatment, and no patients withuncontrolled hypertension will be enrolled in early clinical studies. In addition, all patientswill be assessed for cardiac diseases before start of treatment, while all patients enrolled in thetrial will undergo regular cardiac monitoring throughout the conduct of the trial. EKGs will be reviewed by the Principal Investigator and recorded in the OnCore clinical trial records system. For thetreatment of acute cardiac events occurring under BKM120 treatment investigators areadvised to adhere to the protocol guidelines. Vital signs, including pulse rate and bloodpressure, will closely be followed during the early clinical studies.
a phase 1/2 trial of
management of cardiac events

A 12-lead electrocardiogram (ECG), and an echocardiogram will be performed at the Screening Visit to assess eligibility. Repeat ECGs will be performed (+/- 2 days) on cycle 1 day 15, on cycle 2, 3, and 4 day 1, and every 3 months thereafter in accordance with the manufacturer"s standard-of-care recommendations for vemurafenib. An ECHO/MUGA will be repeated at Cycle 4 and then every 4th cycle thereafter.
a phase 1/2 trial of
management of pneumonitis

Pneumonitis is a known side effect of rapamycin analogues. Based on the literature, the class of PI3K inhibitors has not previously been associated with the development of Pneumonitis. Clinically significant Pneumonitis is typically accompanied by non-specific symptoms including dyspnea, nonproductive cough, fatigue, and fever. Diagnosis is generally suspected in individuals who develop these symptoms or in asymptomatic individuals in whom a routine chest CT scan reveals a new ground glass or alveolar infiltrate.  
In ongoing clinical trials with BKM120 in the single agent setting two cases of pneumonitis occurred. In the study BKM120X2101 one patient experienced grade 2 pneumonitis eight weeks after the first dose of BKM120 at 100mg which resolved in 7 days after antibiotic therapy and discontinuation of the study treatment due to fatigue. In the Japanese study BKM120X1101 one case of pneumonitis occurred in a patientone month after the start of study medication with BKM120 at a dose of 100 mg daily. The patient experienced pneumonitis with concomitant progression of underlying malignancy including the progression of existing and the appearance of new lesions in combination with increasing pleural effusion (please see current IB for more details). The patient ultimately died from this episode. All patients participating in clinical trials administering BKM120 will be routinely asked about the occurrence of adverse events which could include new or changed pulmonary symptoms (consistent with lung abnormalities). CT scans and pulmonary function test should be done, as clinically indicated, or if there are symptoms that indicate that the patient has developed pneumonitis. In case of a documented pneumonitis, guidelines (including dose modifications) for management are described in*Table 11*. Consultation with a pulmonologist is highly recommended for any pneumonitis case identified during the study.
a phase 1/2 trial of
table 11management of pneumonitis

| Worst       | BKM120                                                                                                                                                                                                                                                                                         |                                                                                              |                                                                                                                                                                                                                                                          |      |    |        |
|-------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------|----|--------|
| Grade       | Management of                                                                                                                                                                                                                                                                                  |                                                                                              |                                                                                                                                                                                                                                                          |      |    |        |
| Pneumonitis | Required Investigations                                                                                                                                                                                                                                                                        | Pneumonitis                                                                                  | Dose Adjustment                                                                                                                                                                                                                                          |      |    |        |
| Grade 1     | CT scans with lung windows.  Repeat at least every 8 weeks  until return to within normal  limits.                                                                                                                                                                                             | No specific therapy is                                                                       | Administer                                                                                                                                                                                                                                               | 100% | of | BKM120 |
| required    | dose.                                                                                                                                                                                                                                                                                          |                                                                                              |                                                                                                                                                                                                                                                          |      |    |        |
| Grade 2     | CT scan with lung windows.  Consider pulmonary function  testing includes: spirometry,  DLCO, and room air O2  saturation at rest. Repeat at  least every 8 weeks until  return to within normal limits.  Consider a bronchoscopy with  biopsy and / or BAL.                                   | Symptomatic only.  Consider  corticosteroids if  symptoms are  troublesome.                  | Reduce BKM120 dose by 1 dose  level (see Table 9) until recovery  to < Grade 1. Study treatment may  also be interrupted if symptoms are  troublesome. Patients will  discontinue study treatment if they  fail to recover to < Grade 1 within  3 weeks. |      |    |        |
| Grade 3     | CT scan with lung windows  and pulmonary function  testing includes: spirometry,  DLCO, and room air O2  saturation at rest. Repeat at  least every 6 weeks until  return to within normal limits.  Bronchoscopy with biopsy and  / or BAL is recommended.                                     | Consider  corticosteroids if  infective origin is  ruled out. Taper as  medically indicated. | Hold treatment with BKM120 until  recovery to < Grade 1. May restart  study treatment within 3 weeks at a  reduced dose (by one level) if  evidence of clinical benefit.                                                                                 |      |    |        |
| Grade 4     | CT scan with lung windows  and required pulmonary  function testing, if possible,  includes: spirometry, DLCO,  and room air O2 saturation at  rest. Repeat at least every 6  weeks until return to within  normal limits. Bronchoscopy  with biopsy and / or BAL is  recommended if possible. | Consider  corticosteroids if  infective origin is  ruled out. Taper as  medically indicated. | Discontinue treatment with  BKM120.                                                                                                                                                                                                                      |      |    |        |
a phase 1/2 trial of
management of liver toxicities

Monitoring Cycle 1 and 2: **every other week** (if visit schedule allows a more frequent monitoring this should be considered) or more frequently if clinically indicated especially for patients with borderline acceptable AST/ ALT/ bilirubin* values. Monitoring Cycle 3 and more:**monthly** or more frequently if clinically indicated. In case of any occurrence of ALT/ AST/ bilirubin* increase **≥ grade 2** the liver function tests must be monitored **weekly** or more frequently if clinically indicated until resolved to ≤ grade 1.  
In case of any occurrence of ALT/ AST/ bilirubin* increase **≥grade 3** the liver function tests must be monitored **weekly** or more frequently if clinically indicated **until resolved to ≤ grade 1**;
thereafter the monitoring should be continued **every other week** or more frequently if clinically indicated **until the end of treatment with study medication.** Patients who discontinued study treatment should be monitored weekly, including LFTs* or more frequently if clinically indicated **until resolved to ≤ grade 1 or stabilization** (no CTCAE grade change over 4 weeks).
a phase 1/2 trial of
study discontinuation

All interruptions or changes to study drug administration must be recorded.  
The investigator or his staff will document whether each patient completes, and the reason for the cessation of treatment on study or the cessation of data collection will be recorded. Reasons that a patient may discontinue participation in a clinical study are considered to constitute one of the following: 1. adverse event(s) 2. abnormal laboratory value(s) 3. abnormal test procedure result(s) 4. disease progression 5. protocol violation 6. subject withdrew consent 7. lost to follow-up 8. administrative problems 9. death
a phase 1/2 trial of
3.3.7 concomitant therapy

All medications (excluding prior chemotherapy and biologic, immunologic or radiation therapy) taken within 4 weeks prior to the administration of vemurafenib and BKM120 and all concomitant therapy administration during the study with reasons for therapy should be recorded. All prior chemotherapy; biologic, immunologic or radiation therapy; and surgery within 4 weeks prior to the administration of study drug, will be recorded. Patients on chronic medications that can be given concomitantly with vemurafenib and BKM120 should be maintained on the same dose and dose schedule throughout the study period, as medically feasible. The investigator should instruct the patient to notify the study site about any new medications he/she takes after the start of the study drug. All medications (other than study drug) and significant non-drug therapies (including herbal medicines, physical therapy and blood transfusions) administered after the patient starts treatment with study drug, and any changes in dosing should be recorded. In general, the use of any concomitant medication/therapies deemed necessary for the care of the patient is permitted with the following exceptions described in section 3.3.6.1.