Conditions: BRAF Mutant Metastatic Melanoma
Keywords: BKM120 BRAF Melanoma PI3K
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
This is a phase 1/2 clinical trial with the goal of determining whether the addition of the investigational agent BKM120 to vemurafenib will lead to improved 6-month progression-free survival in patients with BRAFV600E/K mutant melanoma.

Detailed description:
The phase 1 portion of this trial is a dose escalation study; the phase 2 portion is a single-stage, single arm prospective clinical trial. All patients will receive continuous doses of vemurafenib twice a day and BKM120 once a day.

In the phase 1 portion of the study, there will be a 7 day lead-in period to allow for single dose pharmacokinetic analysis of BKM120 alone. Cycle 1 (28 days) is the dose-limiting toxicity (DLT) period. During phase 1, 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.

In the phase 2 portion of the study, patients will receive continuous doses of vemurafenib and BKM120 starting on day 1 of the first cycle. In the phase 2 portion of the study, patients will receive vemurafenib and BKM120 at the recommended phase 2 dose.

Arms:
arm 1: 150 mg oral dabrafenib twice a day until disease progression, death, or unacceptable adverse events.

Interventions: intervention 1: BKM120 Combined with Vemurafenib (PLX4032)
Intervention descriptions: intervention 1: Phase I is 3+3 dose escalation study to identify the recommended phase 2 dose (RP2D)

Dose Level -1: BKM120 60 mg daily, Vemurafenib 480 mg bid

Dose Level 1: BKM120 60 mg daily, Vemurafenib 720 mg bid

Dose Level 2: BKM120 80 mg daiy, Vemurafenib 720 mg bid

Dose Level 3: BKM120 100 mg daiy, Vemurafenib 720 mg bid

Dose Level 4: BKM120 100 mg daiy, Vemurafenib 960 mg bid

Phase II is a single-stage, single arm prospective trial: patients will receive BKM120 and vemurafenib at the RP2D

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
Version date: June 24, 2013 
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Phase 1/2 – BKM120 
Page 1 of 92 
A Phase 1/2 Trial of BKM120 Combined with Vemurafenib 
(PLX4032) in BRAFV600E/K Mutant Advanced Melanoma 
 
Protocol Number:  CC #11952 
Study Drug:  BKM120 
Version Number:  8.0 
Version Date:  June 24, 2013 
IND Number:  113646 
Novartis study number CBKM120ZUS21T 
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 
 
 
 
 
 
 
 
 
 
 
 
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 


 
 
 
 
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Protocol Signature Page 
Protocol No.:       
Version Date:June 24, 2013 
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. 
UCSF Principal Investigator / Study Chair 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
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 
Printed Name 
 
 
Signature 
 
Date 
 


 
 
 
 
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Phase 1/2 – BKM120 
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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 


 
 
 
 
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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…………………………………………………........................... 
Table A1 
Toxicity grading based on mood questionnaire scores……………………
Table A2 
GAD-7 anxiety scale………………………………………………………
Table A3 
PHQ-9 depression scale……………………………………………………
Appendix 2 
Prohibited medications………………………………………………………...
Table A4 
List of prohibited CYP3A Inhibitors and Inducers………………………..
Table A5 
List of CYP450 Substrates to be used with caution……………………….
Appendix 3 
QT prolonging drugs…………………………………………………………..
Table A6 
QT prolonging drugs with risk of Torsades de Pointes to avoid…..………
Table A7 
List of QT prolonging drugs to be used with caution……………………..
Appendix 4 
BKM120 pharmacokinetic analysis……………………………………..…….
Appendix 5 
Vemurafenib pharmacokinetics and correlative studies assessments…………
Appendix 6 
Multicenter Institutional Studies……………………………………………... 
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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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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. 
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.   


 
 
 
 
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1.2.1 
Vemurafenib preclinical studies 
1.2.1.1 
Vemurafenib preclinical efficacy 
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 anti-
tumor activity in BRAF wild-type tumors12,15,16.  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. 
 
Figure 1. Tumor response as a function of time in mice treated with vemurafenib dosed twice 
daily at two dose levels compared with animals treated with vehicle control (n = 10 in each 
group) 12.  
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. 


 
 
 
 
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Figure 2.Vemurafenib inhibits tumor growth and prolongs survival in a BRAFV600E-bearing 
LOX melanoma xenograft model. Groups of mice were treated with vemurafenib administered 
bid at doses of 12.5, 25, and 75 mg/kg for 11 to 13 d starting on day 5 to 6 after implantation. 
A, efficacy data are plotted as mean tumor volume (in mm3) ± SEM. B, survival data are 
plotted as percent of animals surviving in each group using a predefined cutoff volume of 
2,000 mm3 as a surrogate for survival15. 
 


 
 
 
 
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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.  
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 


 
 
 
 
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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.  
1.2.2 
Vemurafenib clinical experience 
1.2.2.1 
Vemurafenib clinical efficacy 
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 standard-
of-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. 
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. 


 
 
 
 
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Table 1.  Drug-related adverse events of grade 2 or higher reported in more than 5% of 618 
phase 3 study patients receiving vemurafenib or dacarbazine5 
 
 
 


 
 
 
 
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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 recently-
completed 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 higher4,12 indication marked 
inhibition of the MAPkinase pathway. 
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. 


 
 
 
 
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1.4 
PI3K Pathway and mechanism of action 
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).  
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. 
 
 


 
 
 
 
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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 sub-
nanomolar 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. 


 
 
 
 
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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 (gamma-
amino 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 


 
 
 
 
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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. 
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 anti-
proliferative 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 HER2-
amplified 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. 
1.4.1.2 
Preclinical Pharmacology, Pharmacokinetics and Metabolism 
 
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, 


 
 
 
 
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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 drug-
drug interactions between BKM120 and vemurafenib based on their hepatic metabolism is 
summarized in Table 3. 
 
Table 3. The metabolism of vemurafenib and BKM120 by hepatic microsomes 
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/ 
Transported by 
CYP3A4 
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 
expression 
CYP3A4 (weak to moderate) 
CYP1A2 
 
 
 
1.4.2 
BMK120 clinical experience 
1.4.2.1 
BKM120 Pharmacokinetics and pharmacodynamics 
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 half-
life 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. 
 


 
 
 
 
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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. 
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, 


 
 
 
 
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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-Fluorodeoxyglucose-
Positron 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. 
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.   


 
 
 
 
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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. 
2 
Study Objectives 
Primary 
 
Phase 1  
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. 
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. 


 
 
 
 
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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.    
3 
Study plan 
3.1 
Overall study design 
Phase 1 
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.   
 
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.   
 
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.   
 
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. 
 
 
 


 
 
 
 
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Figure 5. Study design 
 
Phase 1-Part A 
 
 
 
 
 
 
 
 
 
 
 
Phase 1 – Part B 
 
 
 
 
 
 
 
 
Phase 2 
 
 
 
 
 
 
3.2 
Study population 
3.2.1 
Patient population 
 
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. 
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 
Phase 1 DLT Period 
Vemurafenib and 
BKM120 (3+3 escalation) 
Phase 2 
Vemurafenib and 
BKM120 at RP2D 
Phase 1 Post DLT 
Vemurafenib and 
BKM120 (Cycle 1 Doses) 
Cycle 0 (7 days) 
Cycle 1 (4 weeks) 
 
Cycle 2+ 
Phase 1 Lead-In 
Single dose 
BKM120 (d-7) 
Phase 1 DLT Period 
Vemurafenib and 
BKM120 (3+3 escalation) 
Phase 1 Post DLT 
Vemurafenib and 
BKM120 (Cycle 1 Doses) 
Cycle 1 (4 weeks) 
 
Cycle 2+ 
Phase 2 
Vemurafenib and 
BKM120 at RP2D 
Cycle 1+  
 


 
 
 
 
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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: 
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). 
Exclusion criteria 
1. Patients who have received prior treatment with a PI3K inhibitor or a BRAF inhibitor are 
excluded.   
BRAF inhibitor exposure: 


 
 
 
 
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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 %) 


 
 
 
 
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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 
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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  


 
 
 
 
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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 
3.3 
Treatments 
3.3.1 
Vemurafenib 
Warnings and Precautions 
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.  
Adverse Reactions 
Most common adverse reactions (≥ 30%) are arthralgia, rash, alopecia, fatigue, photosensitivity 
reaction, nausea, pruritus and skin papilloma.  


 
 
 
 
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Complete and updated adverse event information is available in the Investigational Drug 
Brochure and/or product package insert. 
 
3.3.2 BKM120 
Table 4.Serious Adverse Events with a suspected causality 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 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. 


 
 
 
 
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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. 
3.3.4 
Treatment dosing and schedule 
3.3.4.1 
Phase 1 dosing and dose escalation 
During the phase 1 portion, cohorts of patients will be enrolled according to a standard 3 + 3 
dose escalation scheme. 
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 


 
 
 
 
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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 Awill 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. 
 
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. 
 
Table 5. Phase 1 dose levels 
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 


 
 
 
 
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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/ 
Laboratory 
CTCAE grade 3 asymptomatic amylase and/or lipase, not reversible to ≤ CTCAE grade 2 for > 7 
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 
alteration 
CTCAE grade 2 mood alteration that does not resolve to ≤ grade 1 within 14 days despite 
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 
events 
Grade ≥3 non-hematologic, non-hepatic organ toxicity related to drug regimen, EXCLUDING the 
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. 
 


 
 
 
 
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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.  
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. 
 
 
 


 
 
 
 
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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 re-
treatment, 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 re-
treatment, 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/ 
Laboratory 
If amylase and/or lipase ≥ CTCAE grade 3 (> 2 x ULN) has been demonstrated,these 
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 re-
treatment, 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 re-
treatment, 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 re-
treatment, stabilization of the toxicity, or study treatment completion. 


 
 
 
 
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3.3.4.3 
Dose expansion and phase 2 dosing 
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. 
3.3.5 
Interruption or discontinuation of treatment 
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. 
 
Table 8. Criteria for interruption and re-initiation of vemurafenib and BKM120 treatment 
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) 
Grade 2 (ANC < 1.5 - 1.0 x 109/L) 
Maintain dose levels 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Grade 4 (ANC < 0.5 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 
Febrile neutropenia  
(ANC < 1.0 x 109/L,fever ≥ 38.5°C) 
Omit both drugs until resolved, then vemurafenib/BKM120 1 
dose level as outlined in Table 9 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75 x 109/L) 
Grade 2 (PLT < 75 - 50 x 109/L) 
Maintain dose level 
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 


 
 
 
 
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Table 8. Criteria for interruption and re-initiation of vemurafenib and BKM120 treatment 
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 
ALT or AST ≤ 3.0 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 3 (> 3.0 - 10.0 x ULN) with 
ALT or AST ≤ 3.0 x ULN 
Omit both drugs until resolved to ≤ Grade 1, then: 
 
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 
bilirubin elevation to > 2.0 x ULN 
Omit both drugs until resolved to ≤ Grade 1,  (then 
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 
bilirubin > 2.0 x ULN 
Discontinue study treatment permanently. 
* 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. 


 
 
 
 
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Table 8. Criteria for interruption and re-initiation of vemurafenib and BKM120 treatment 
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) 
[> ULN - 8.9 mmol/L] 
Maintain dose level, check FPG every week 
 
initiate or intensify medication with appropriate anti-
diabetic 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) 
[> 8.9 - 13.9 mmol/L] 
First Occurrence: 
Maintain dose, re-check FPG within 24 hours, if no worse than 
Grade 2*: 
 
maintain dose level 
 
initiate or intensify medication with appropriate anti-
diabetic 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) 
[> 8.9 - 13.9 mmol/L] 
Second Occurrence: 
maintain dose, re-check FPG within 24 hours, if no worse than 
Grade 2*: 
 
omit BKM120 
 
initiate or intensify medication with appropriate anti-
diabetic 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 


 
 
 
 
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Table 8. Criteria for interruption and re-initiation of vemurafenib and BKM120 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)  
[> 13.9 - 27.8 mmol/L] 
First Occurrence: 
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 re-
initiation BKM120 may be dose-reduced a second time.  
* if grade “worsens” then follow specific grade 
recommendations 
Grade 4 (> 500 mg/dL)  
[≥ 27.8 mmol/L] 
Immediately omit BKM120, initiate or intensify medication 
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 
Symptomatic,  
responsive to intervention,  
Omit both drugs until resolved to ≤ Grade 1, then 
vemurafenib/BKM120 1 dose level as outlined in Table 9 


 
 
 
 
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Table 8. Criteria for interruption and re-initiation of vemurafenib and BKM120 treatment 
Recommended Dose Modifications for vemurafenib and BKM120 
Worst toxicity (CTCAE Grade)** 
Recommended Dose Modifications 
ejection fraction 39 – 20% 
or > 20% drop from baseline 
LVEF measurement to be repeated, if not resolved to ≤ Grade 1 
within 3 weeks, permanently discontinue patient from  study 
Refractory or poorly controlled,  
ejection fraction < 20% 
Omit both drugs and discontinue patient from study 
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) 


 
 
 
 
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Table 8. Criteria for interruption and re-initiation of vemurafenib and BKM120 treatment 
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 


 
 
 
 
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Table 8. Criteria for interruption and re-initiation of vemurafenib and BKM120 treatment 
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 
requiring dose reduction occured 
Reduce to: 
-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 


 
 
 
 
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3.3.6 
Monitoring vemurafenib suspected toxicities 
3.3.6.1 
Known undesirable side effects of vemurafenib 
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). 
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. Follow-
up 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.  


 
 
 
 
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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. 
3.3.6.2 
Known Undesirable Side Effects of BKM120 
3.3.6.2.1 Neuropsychiatric events  
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. 
 
Table 10.Mood disorders adverse events reported in trial CBKM120X2101 (As of 10/25/10) 
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 


 
 
 
 
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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, obsessive-
compulsive 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 
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).  


 
 
 
 
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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. 
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 Treat-
To-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 re-
escalated 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. 


 
 
 
 
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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. 
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.   
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 


 
 
 
 
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management are described inTable 11. Consultation with a pulmonologist is highly 
recommended for any pneumonitis case identified during the study. 
Table 11Management of pneumonitis 
Worst 
Grade 
Pneumonitis Required Investigations 
Management of 
Pneumonitis 
BKM120 
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 
required 
Administer 100% of BKM120 
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. 
 
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. 


 
 
 
 
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Page 48 of 92 
 
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). 
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 
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. 


 
 
 
 
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Phase 1/2 – BKM120 
Page 49 of 92 
3.3.7.1 
Drugs that are prohibited 
 Other investigational therapies must not be used while the patient is on the study. 
 Systemic anticancer therapy (chemotherapy or biologic therapy) other than the study 
treatments must not be given to patients while the patient is on the study. If such agents are 
required for a patient then the patient must be discontinued from the study. 
 In vitro metabolism studies suggest that oxidative metabolism of BKM120 is predominantly 
mediated by CYP3A4 (fm>0.9), with only minor contributions of CYP1A1. As BKM120 is a 
sensitive CYP3A4 substrate, co-administration of BKM120 with strong and moderate 
CYP3A4 inhibitors and CYP3A4 inducers is prohibited.  Refer to Table A4 for a list of 
prohibited drugs.  Please note this list may not be comprehensive. 
 Based on in vitro studies, co-administration of BKM120 with CYP3A4 inducers is predicted 
to decrease the systemic exposure to BKM120, thereby increasing the risk of exposing the 
patient to subtherapeutic drug levels.  Refer to Table A4 for a list of prohibited CYP3A 
inducers.  Please note that this list may not be comprehensive. 
 Therapeutic doses of warfarin sodium (Coumadin®) or any other coumadin-derivative 
anticoagulants are not permitted. 
 If a patient requires the concomitant use of any medication included in Table A4 entitled 
“List of Prohibited QT prolonging drugs” (i.e., drugs that are generally accepted by the 
Qtdrugs.org Advisory Board of the Arizona CERT to have a risk of causing Torsades des de 
Pointes), study treatment administration must be interrupted as long as the patient requires 
therapy with the QT prolonging agent. 
 Herbal preparations/medications are not allowed throughout the study.  These herbal 
medications include, but are not limited to St. John‟s Wort, Kava, ephedra (ma huang), 
ginkobiloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng.  Patients 
should stop using these herbal medications 7 days prior to first dose of study drug. 
 Hormonal contraceptives may be affected by cytochrome P450 interactions, and are therefore 
not considered effective in this study. 
3.3.7.2 
Drugs to be used with caution 
Preliminary in vitro metabolism studies suggest that BKM120 is a weak, reversible inhibitor 
CYP3A4/5 (Ki=13.6 μM, [I]/Ki= 0.4 where [I] is the average Cmax at steady-state following 100 
mg daily dose) and a weak reversible inhibitor of CYP2C8/2C9/2C19 (IC50=34 μM, 
[I]/IC50=0.15). Note: that with the data available, we are not able to confirm whether such 
interactions will occur in patients. Therefore, investigators, at their discretion, may administer 
concomitant medications known to be metabolized by CYP3A4/5, CYP2C8, CYP2C9 and 
CYP2C19. Patients receiving such medications must be carefully monitored for potentiation of 
toxicity due to any individual concomitant medications, and may require dose titration or 
reduction of the drug substrate. Please refer to Table A5 for a list of CYP450 substrates and 
carefully consider their co-administration with BKM120. Particularly, caution is advised when 
BKM120 is co-administered with: 
 Drugs which are substrates for CYP3A4, CYP2C8, CYP2C9 or CYP2C19 and which have a 
narrow therapeutic index. 


 
 
 
 
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Phase 1/2 – BKM120 
Page 50 of 92 
 Oral anti-diabetics which are metabolized by CYP2C8 or CYP2C9 can possibly result in 
hypoglycemia. Patients who develop diabetes mellitus during the study should be treated 
according to the American Diabetes Association guidance. It is recommended that treatment 
start with metformin. Note that the use of troglitazone and pioglitazone is prohibited due to 
possible induction of CPY3A4 which can be expected to decrease BKM120 exposure to 
subtherapeutic levels. 
 Concomitant treatment with corticosteroids and BKM120 should be avoided, whenever 
possible, during this study. 
 If a patient, after study enrollment, requires the concomitant use of any medication which 
may cause QT prolongation and/or torsade de pointes then the investigators, at their 
discretion, may co-administer such medications. Patients receiving such medications must be 
monitored.  Refer to Tables A6 and A7 for a list of medications which may prolong QT. 
 Please refer to Table A5 for a list of CYP450 substrates and carefully consider their co-
administration with BKM120.  
 A short duration (< 2 weeks) of systemic corticosteroids is allowed (e.g. for chronic 
obstructive pulmonary disease, or as an anti-emetic).  Chronic dosing of corticosteroids is 
known to induce CYP3A enzymes, thereby increasing the risk or reducing BKM120 overall 
exposure to sub-therapeutic levels. 


 
 
 
 
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Phase 1/2 – BKM120 
 
Page 51 of 92 
3.4 
Visit schedule and assessments 
3.4.1 
Visit schedule 
Table 11a.  Evaluation and visit schedule for phase 1, part Aof the study 
+ / - 1 day window is allowed for cycle 1 procedures.  + / - 3 days window is allowed for all subsequent cycles unless otherwise noted. 
Assessment 
Screening13 
Cycle 0 
Cycle 1 
Cycle 2 
Cycle 3 
Future Cycles 
(even)           (odd) 
Progression 
Study Day/Visit Day 
 
-7 
-4 
1 
8 
15 
2214 
1 
15 
1 
1 
1 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Background information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
(WOCBP) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dermatology Exam 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Vitals 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neuropsychiatric 
Assessment1 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Adverse Event 
Assessment 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology2 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c  and C-peptide3 
X 
 
 
 
 
 
 
X 
 
 
(X) 
(X) 
 
Chemistry4 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation5 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Fasting Blood Glucose6 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Urinalysis7 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Radiographic Tumor 
Assessment8 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
RECIST reading 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Tumor Biopsy9 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
BRAF Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MUGA/Echo10 
X 
 
 
 
 
 
 
 
 
 
(X) 
 
 
ECG11 
X 
 
 
 
 
X 
 
X 
 
X 
(X) 
(X) 
X 
PK12 
 
X 
X 
X 
 
X 
 
X 
 
X 
(X) 
 
 
1 Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis while active on the treatment portion of the study. 
2 Hematology - WBC plus differential (neutrophil including bands, lymphocyte, monocyte, eosinophil, basophil and other counts, hemoglobin and platelets.   
3 HbA1c and C-peptide will be measured at screening and on Day 1 of every third treatment cycle starting with Cycle 2 Day 1 and at EOT.  
4 Biochemistry - K+, Na+, Ca++, Mg++, LDH, ALT, AST, total bilirubin (direct and indirect), creatinine, amylase, GGT, lipase, alkaline phosphatase (fractionated if alkaline 
phosphatase is grade 2 or higher), bicarbonate, phosphorus, uric acid, total cholesterol, HDL, LDL, triglycerides, glucose, urea or BUN, albumin, and total protein are 
required at baseline and at end of treatment.  Subsequent assessments always include K+, Na+, Ca++, ALT, AST, total bilirubin (direct and indirect), creatinine, alkaline 
phosphatase, bicarbonate, phosphorus, glucose, urea or BUN, albumin, and total protein BUT, lipase, total cholesterol, HDL, LDL, triglycerides should be obtained on the 
first day of odd numbered cycles only. C1D-7 assessments may be performed up to 72 hours prior to the scheduled visit. 
5 Coagulation - PT or INR, PTT. Patient entering the study while receiving anti-coagulation therapy or those who have the initiation of an anti-coagulation therapy should 
have their coagulation test performed on a weekly basis. 
6 Patients must be fasting overnight for at least 8 hours. Additional measurements may be performed as clinically indicated. 
7 Urinalysis includes macroscopic (protein, glucose, ketones, blood, and specific gravity). A microscopic (WBC/HPF, RBC/HPF, and any additional findings) exam need 
only be performed if the urinalysis result is abnormal. 
8 Screening radiological assessments should be performed within 4 weeks of the first dose.  Radiological tumor assessment should be performed at baseline within 28 days 
before start of treatment and subsequently every 8 weeks of combination therapy (first restaging at the end of week 8), until progression of disease or end of treatment. All 
assessments should be performed within ±7 days of the scheduled day of assessment. The assessment at the end of treatment visit is only to be performed if the prior 
assessment occurred ≥ 21 days before. 
9 Biopsies will be done at Screening, Cycle 1 Day 15, and within 14 days of any radiographic examination documenting disease progression by RECIST from all patients 
with visible or palpable disease unless the PI determines thata biopsy would pose an unacceptable risk to the patient. 
10 Echo/MUGA will be performed at baseline and every 4 cycles, or more often as clinically indicated. 
11 ECG will be performed at baseline and (+/- 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 
12 PK analysis will only be performed during the phase 1 portion of the study.  See section 3.4.6 for schedule. 
13 Laboratory assessments including hematology, blood chemistries, and fasting blood glucose do not need to be repeated prior to the first dose of BKM120 if screening 
laboratories were performed within 14 days of this date. 
14 If toxicity is present at C1D15, C1D22 visit may be done at the discretion of the physician.   
 
Note: A Brain MRI may be performed at screening and/or at any time during the study as clinically indicated 
 
 
 
 


 
 
 
 
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Protocol CC#: 11952 
Phase 1/2 – BKM120 
 
Page 52 of 92 
 
Table 11b.  Evaluation and visit schedule for phase 1, part Bof the study 
+ / - 1 day window is allowed for cycle 1 procedures.  + / - 3 days window is allowed for all subsequent cycles unless otherwise noted. 
Assessment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Future Cycles 
(even)(odd) 
Progression 
Study Day/Visit Day 
 
113 
8 
15 
2214 
1 
15 
1 
1 
1 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Background information 
X 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
(WOCBP) 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dermatology Exam 
X 
 
 
 
 
 
 
X 
 
X 
X 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neuropsychiatric Assessment1 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c and C-peptide3 
X 
 
 
 
 
X 
 
 
(X) 
(X) 
 
Chemistry4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation5 
X 
 
 
 
 
X 
 
 
X 
 
X 
Fasting Blood Glucose6 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Urinalysis7 
X 
 
 
 
 
 
 
 
 
 
X 
Radiographic Tumor 
Assessment8 
X 
 
 
 
 
 
 
X 
 
X 
X 
RECIST reading 
X 
 
 
 
 
 
 
X 
 
X 
 
Tumor Biopsy9 
X 
 
 
X 
 
 
 
 
 
 
X 
BRAF Testing 
X 
 
 
 
 
 
 
 
 
 
 
MUGA/Echo10 
X 
 
 
 
 
 
 
 
 
ECG11 
X 
 
 
X 
 
X 
 
X 
(X) 
(X) 
X 
PK12 
 
X 
 
X 
 
X 
 
X 
(X) 
 
 
1 Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis while active on the treatment portion of the study. 
2 Hematology - WBC plus differential (neutrophil including bands, lymphocyte, monocyte, eosinophil, basophil and other counts, hemoglobin and platelets.   
3 HbA1c and C-peptide will be measured at screening and on Day 1 of every third treatment cycle starting with Cycle 2 Day 1 and at EOT.  
4 Biochemistry - K+, Na+, Ca++, Mg++, LDH, ALT, AST, total bilirubin (direct and indirect), creatinine, amylase, GGT, lipase, alkaline phosphatase (fractionated if alkaline 
phosphatase is grade 2 or higher), bicarbonate, phosphorus, uric acid, total cholesterol, HDL, LDL, triglycerides, glucose, urea or BUN, albumin, and total protein are 
required at baseline and at end of treatment.  Subsequent assessments always include K+, Na+, Ca++, ALT, AST, total bilirubin (direct and indirect), creatinine, alkaline 
phosphatase, bicarbonate, phosphorus, glucose, urea or BUN, albumin, and total protein BUT, lipase, total cholesterol, HDL, LDL, triglycerides should be obtained on the 
first day of odd numbered cycles only.  
5 Coagulation - PT or INR, PTT. Patient entering the study while receiving anti-coagulation therapy or those who have the initiation of an anti-coagulation therapy should 
have their coagulation test performed on a weekly basis. 
6 Patients must be fasting overnight for at least 8 hours. Additional measurements may be performed as clinically indicated. 
7 Urinalysis includes macroscopic (protein, glucose, ketones, blood, and specific gravity). A microscopic (WBC/HPF, RBC/HPF, and any additional findings) exam need 
only be performed if the urinalysis result is abnormal. 
8 Screening radiological assessments should be performed within 4 weeks of the first dose.  Radiological tumor assessment should be performed at baseline within 28 days 
before start of treatment and subsequently every 8 weeks of combination therapy (first restaging at the end of week 8), until progression of disease or end of treatment. All 
assessments should be performed within ±7 days of the scheduled day of assessment. The assessment at the end of treatment visit is only to be performed if the prior 
assessment occurred ≥ 21 days before. 
9 Biopsies will be done at Screening, Cycle 1 Day 15, and within 14 days of any radiographic examination documenting disease progression by RECIST from all patients 
with visible or palpable disease unless the PI determines that a biopsy would pose an unacceptable risk to the patient.  
10 Echo/MUGA will be performed at baseline and every 4 cycles, or more often as clinically indicated. 
11 ECG will be performed at baseline and (+/- 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 
12 PK analysis will only be performed during the phase 1 portion of the study.  See section 3.4.6 for schedule. 
13 Laboratory assessments including hematology, blood chemistries, and fasting blood glucose do not need to be repeated prior to the first dose of BKM120 if screening 
laboratories were performed within 72 hours of C1D1. 
14 If toxicity is present at C1D15, C1D22 visit may be done at the discretion of the physician.   
Note: A Brain MRI may be performed at screening and/or at any time during the study as clinically indicated 
 
 


 
 
 
 
Version date: June 24, 2013 
Protocol CC#: 11952 
Phase 1/2 – BKM120 
 
Page 53 of 92 
 
Table 11c.  Evaluation and visit schedule for phase 2 of the study 
+ / - 1 day window is allowed for cycle 1 procedures.  + / - 3 days window is allowed for all subsequent cycles. 
Assessment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
FutureCycles  
(even)(odd) 
Progression 
Study Day/Visit Day 
 
112 
8 
15 
2213 
1 
15 
1 
1 
1 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Background information 
X 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
(WOCBP) 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dermatology Exam 
X 
 
 
 
 
 
 
X 
 
X 
X 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neuropsychiatric 
Assessment1 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Adverse Event 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c and C-peptide3 
X 
 
 
 
 
X 
 
 
(X) 
(X) 
 
Chemistry4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation5 
X 
 
 
 
 
X 
 
 
X 
 
X 
Fasting Blood Glucose6 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Urinalysis7 
X 
 
 
 
 
 
 
 
 
 
X 
Radiographic Tumor 
Assessment8 
X 
 
 
 
 
 
 
X 
 
X 
X 
RECIST reading 
X 
 
 
 
 
 
 
X 
 
X 
 
Tumor Biopsy9 
X 
 
 
X 
 
 
 
 
 
 
X 
BRAF Testing 
X 
 
 
 
 
 
 
 
 
 
 
MUGA/Echo10 
X 
 
 
 
 
 
 
 
(X) 
 
 
ECG11 
X 
 
 
X 
 
X 
 
X 
(X) 
(X) 
X 
1 Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis while active on the treatment portion of the study. 
2 Hematology - WBC plus differential (neutrophil including bands, lymphocyte, monocyte, eosinophil, basophil and other counts, hemoglobin and platelets.   
3 HbA1c and C-peptide will be measured at screening and on Day 1 of every third treatment cycle starting with Cycle 2 Day 1 and at EOT.  
4 Biochemistry - K+, Na+, Ca++, Mg++, LDH, ALT, AST, total bilirubin (direct and indirect), creatinine, amylase, GGT, lipase, alkaline phosphatase (fractionated if 
alkaline phosphatase is grade 2 or higher), bicarbonate, phosphorus, uric acid, total cholesterol, HDL, LDL, triglycerides, glucose, urea or BUN, albumin, and total 
protein are required at baseline and at end of treatment.  Subsequent assessments always include K+, Na+, Ca++, ALT, AST, total bilirubin (direct and indirect), 
creatinine, alkaline phosphatase, bicarbonate, phosphorus, glucose, urea or BUN, albumin, and total protein BUT, lipase, total cholesterol, HDL, LDL, triglycerides 
should be obtained on the first day of odd numbered cycles only.  
5 Coagulation - PT or INR, PTT. Patient entering the study while receiving anti-coagulation therapy or those who have the initiation of an anti-coagulation therapy should 
have their coagulation test performed on a weekly basis. 
6 Patients must be fasting overnight for at least 8 hours. Additional measurements may be performed as clinically indicated. 
7 Urinalysis includes macroscopic (protein, glucose, ketones, blood, and specific gravity). A microscopic (WBC/HPF, RBC/HPF, and any additional findings) exam need 
only be performed if the urinalysis result is abnormal. 
8 Screening radiological assessments should be performed within 4 weeks of the first dose.  Radiological tumor assessment should be performed at baseline within 28 days 
before start of treatment and subsequently every 8 weeks of combination therapy (first restaging at the end of week 8), until progression of disease or end of treatment. 
All assessments should be performed within ±7 days of the scheduled day of assessment. The assessment at the end of treatment visit is only to be performed if the prior 
assessment occurred ≥ 21 days before. 
9 Biopsies will be done at Screening, Cycle 1 Day 15, and within 14 days of any radiographic examination documenting disease progression by RECIST from all patients 
with visible or palpable disease unless the PI determines that a biopsy would pose an unacceptable risk to the patient.  
10 Echo/MUGA will be performed at baseline and every 4 cycles, or more often as clinically indicated. 
11 ECG will be performed at baseline and (+/- 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 
12 Laboratory assessments including hematology, blood chemistries, and fasting blood glucose do not need to be repeated prior to the first dose of BKM120 if screening 
laboratories were performed within 72 hours of C1D1. 
13 If toxicity is present at C1D15, C1D22 visit may be done at the discretion of the physician. 
 
Note: A Brain MRI may be performed at screening and/or at any time during the study as clinically indicated 
 


 
 
 
 
Version date: June 24, 2013 
 
Protocol CC#: 11952 
Phase 1/2 – BKM120 
Page 54 of 92 
3.4.2 
Efficacy assessments 
Patients will undergo systemic imaging with a contrast-enhanced CT scan of the chest, abdomen, 
and pelvis (or a whole body PET/CT scan if this scan includes a CT resolution that is comparable 
to standard institutional protocols for CT alone) with 28 days prior to the initiation of therapy 
(baseline imaging) and on the last day of every even-numbered treatment cycle(+/- 3 days).  
Imaging assessments will be made by a radiologist, and final assessment using Response 
Evaluation Criteria in Solid Tumors (RECIST, version 1.1) will be made by the PI 37,38. Any 
documentation of a PR or CR in a target or non-target lesion must be confirmed by a repeat scan 
at least4 weeksafter the initial scan indicating the PR or CR. The PI bears the final responsibility 
for determining tumor response and progression. 
3.4.3 
Laboratory evaluations 
Pregnancy Test 
A serum pregnancy test (β-HCG) is required for all women of child-bearing potential at 
screening, within 72 hours prior to the first dose of BKM120. Note: 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. 
 
Hematology 
Hematology includes the following parameters: complete blood count (CBC) consisting of red 
blood cell (RBCs), a total white blood cell count (WBC) with differential (total neutrophil count 
including bands, lymphocyte, monocyte, eosinophil, and basophil counts); hemoglobin (Hgb); 
and platelet count. 
Coagulation Profile 
The coagulation profile includes prothrombin time or INR, and activated partial thromboplastin 
time.  
Blood chemistry 
Biochemistry includes the following parameters: urea or blood urea nitrogen (BUN), creatinine, 
sodium, potassium, calcium, magnesium, phosphorus, glucose, albumin, total protein, total 
bilirubin (direct and indirect), amylase and lipase, GGT, alkaline phosphatase (fractionated if 
alkaline phosphatase is grade 2 or higher), bicarbonate, AST (SGOT), ALT (SGPT), and uric 
acid, lactic dehydrogenase (LDH), total cholesterol, high density lipoprotein (HDL), low density 
lipoprotein (LDL) and triglycerides are required at baseline and at end of treatment. Subsequent 
assessments always include K+, Na+, Ca++, ALT, AST, total bilirubin (direct and indirect), 
creatinine, alkaline phosphatase, bicarbonate, phosphorus, glucose, urea or BUN, albumin, and 
total protein BUT, lipase, total cholesterol, HDL, LDL, triglycerides should be obtained on the 


 
 
 
 
Version date: June 24, 2013 
 
Protocol CC#: 11952 
Phase 1/2 – BKM120 
Page 55 of 92 
first day of odd numbered cycles only. C1D-7assessments may be performed up to 72 hours prior 
to the scheduled visit. Cycle 1 draws may occur within 24 hours prior to the scheduled visit.  All 
other draws should occur within 3 days of the intended visit. Because accurate serum glucose 
and lipid measurements are required; patients should be fasting at the time of the blood sampling. 
Glucose monitoring (FPG, C-peptide, and HbA1C) 
Fasting plasma glucose (FPG), C-peptide, and HbA1C will be assessed.  Patients must be fasting 
overnight for at least 8 hours prior to the blood draw. The study personnel will ask the patient 
whether he or she has been fasting, which will be captured in the eCRF as well.  
HbA1cand C-peptide will be measured at screening and on Day 1 of every third treatment cycle 
starting with Cycle 2 Day 1 and at EOT.  
Urinalysis 
Urinalysis includes macroscopic (protein, glucose, ketones, blood, and specific gravity) and will 
be performed at screening visit and EOT visit. A microscopic (WBC/HPF, RBC/HPF, and any 
additional findings) exam need only be performed if the urinalysis result is abnormal. 
This must be supplemented with laboratory quantification of any potentially relevant 
abnormalities. 
3.4.4 
Clinical evaluations 
3.4.4.1 
Vital signs 
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight. Blood pressure, pulse and respiration rate should be measured on 
patients after at least 3 minutes in the sitting position 
3.4.4.2 
Physical examination 
Physical examination will be performed which must comprise a total body examination (general 
appearance, skin, neck, including thyroid, eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities and basic nervous system). 
Significant findings made after the start of study drug which meet the definition of an Adverse 
Event must be recorded. 
3.4.4.3 
Neuropsychiatric assessments 
Patient self-rating mood questionnaires for anxiety and depression (PHQ-9, GAD-7) will be 
applied at: 
 Screening 
 Days 1 and 15 of Cycle 1 
 Day 1 and 15 of Cycle 2 
 Day 1 of Cycle 3 and subsequent cycles (only for patients who have not shown mood 
alterations during the first 2 cycles, patients who did should continue to fill out the 
questionnaire on a weekly base). 


 
 
 
 
Version date: June 24, 2013 
 
Protocol CC#: 11952 
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 End of Study treatment 
Additional assessments may be done according to the clinical judgment of the Investigator. 
Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis 
while active on the treatment portion of the study. Instructions on how to instruct the patient to 
complete the questionnaires as well as how to determine the scores will be provided together 
with each instrument. 
3.4.4.4 
Performance status 
Performance status will be assessed at screening and per the visit schedule using the Eastern 
Cooperative Oncology Group (ECOG) performance scale. 
3.4.5 
Additional evaluations 
3.4.5.1 
ECG/ECHO 
A standard 12 lead ECG is to be performed at screening and significant findings must be 
recorded. An echocardiogram (ECHO) or MUGA will be performed to assess eligibility. 
ECHO/MUGA will be repeated at Cycle 4 and then every 4th cycle thereafter.   
3.4.5.2 
Brain imaging 
An MRI of the brain with gadolinium maybe performed during screening and patient with 
untreated or symptomatic brain metastases will be excluded from participation in this trial.  
Patients with asymptomatic, treated brain metastases with documented radiographic stability 
over at least 4 weeks may participate in this trial.  For all patients enrolled on the trial, additional 
MRI imaging of the brain may be obtained as clinically indicated. 
3.4.6 
Drug levels and pharmacokinetic assessments 
Data regarding the preclinical and clinical pharmacology of vemurafenib are presented in section 
1.2.1.3 and 1.2.3 respectively.  Data regarding the preclinical and clinical pharmacology of 
BKM120 are presented in section 1.4.1.3 and 1.4.2.1 respectively.  All BKM120 
pharmacokinetic analysis will be performed by Novartis (refer to Appendix 4 for details) and 
vemurafenib analysis will be performed at UCSF (refer to Appendix 5 for details). 
Phase 1, Part A 
Historical controls for PK of vemurafenib alone are well established and vemurafenib has 
minimal hepatic metabolism4. Pharmacokinetic measurements of serum levels of BKM120 after 
single dose will be made during a 7-day lead-in (day -7, t = 0, 1, 2, 6 hrs +/- 15 minutes; day -4 
at 72 hrs post-dose +/- 1 hour).  Serum levels of BKM120 and vemurafenib will be assessed on 
cycle 1 treatment day 1 (t = 0, 1, 2, 6 hrs +/- 15 minutes) and day 15 (t = 0, +/- 1 hour) as well as 
trough levels (t = 0 +/- 1 hour) on day 1 of cycles 2, 3, and 4.  Vemurafenib is a weak CYP3A4 
inducer and BKM120 is primarily metabolized by CYP3A4.  Therefore, the effect of 
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Phase 1, Part B 
Serum levels of BKM120 and vemurafenib will be assessed on cycle 1 treatment days 1 (t = 0, 1, 
2, 6 hrs +/- 15 minutes) and day 15 (t = 0, +/- 1 hour) as well as trough levels (t = 0 +/- 1 hour) 
on day 1 of cycles 2, 3, and 4.  
Phase 1, Parts A & B 
At each sample time point, two aliquots (2 mL each) of whole blood will be collected in EDTA 
blood collection tubes and the exact time of the dose and the blood draw will be noted.  Detailed 
sample collection and shipping instructions are given in Appendices 4 and 5.  Patients should 
take the daily doses of BKM120 and the first dose of vemurafenib in the morning.  Patients must 
fast forat least 2 hours after a light breakfast (morning meal) before taking 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 the morning 
doses.  PK measurements will be compared to historical controls for BKM120 and vemurafenib 
individually with the goal of comparing peak and trough exposure levels. 
3.4.7 Correlative studies and pharmacodynamic assessments 
Biopsies of palpable melanoma lesions and nodal metastases will be taken at baseline, on Cycle 
1 Day 15 (+/- 3 days), and within 14days of radiographic progression of disease.  In addition, 
existing paraffin-embedded biopsy specimens will also be obtained for analysis and archival.  
Biopsies for patients with cutaneous, subcutaneous, and palpable nodal metastatic disease may 
be waived if the PI believes that such biopsies would pose an excessive risk to the patient.  
Imaging guided biopsies of other metastatic sites are optional and permitted in patients without 
visible or palpable disease unless the PI believes that such a biopsy would pose an excessive risk 
to the patient.  For skin lesions, punch or core biopsies are preferred.  For other lesions, core 
biopsies are preferred and an attempt should be made to obtain 3 cores if core biopsies are 
selected.  Fine needle aspiration is permitted with punch or core biopsies are not feasible.  At the 
time of tumor progression, biopsies should be taken from both progressing and non-progressing 
lesions if feasible.   
 
Portions of all new tumor biopsy specimens will be immediately immersed in formalin and 
subsequently embedded in paraffin and additional tissue will be flash-frozen and stored at 
-70 oCuntil the time of analysis.  Paraffin embedded biopsies will be stored at room temperature.  
Pre-treatment melanoma tumor specimens will be analyzed by PCR to confirm the presence of a 
BRAFV600Eor BRAFV600K mutation and to assess for concurrent mutations of NRAS.  Specific 
correlative analyses are outlined below.  Any remaining tissue specimens may be archived for 
future studies that may include but that are not limited to nucleic acid sequencing, microarray 
analysis, and immunohistochemistry. 
 
6-month PFS as a function of PTEN expression 
Our hypothesis is that patients with PTEN loss at baseline will be more likely to survive for 6 
months without disease progression.  PTEN expression will be assessed as present or absent 
using immunohistochemical staining for PTEN.  Pre-treatment tissue for PTEN IHC will be 
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genotyping is required.  PTEN staining in tumor specimens will be graded as “present” or 
“absent” for each patient by a collaborating pathologist.  Attainment of 6 month PFS as a 
function of PTEN status will be assessed using Fisher‟s exact test.  
 
For PTEN and pS6 IHC, paraffin-embedded sections will be deparaffinized, rehydrated, and 
subjected to heat-induced antigen retrieval.  Sections will be incubated with appropriate primary 
antibody (PTEN: Cell Signaling D4.3, 1:50 dilution; phospho-S6 Cell Signaling Polyclonal, 
1:200 dilution) and incubated for 45 minutes. After overnight incubation with a secondary 
polyclonal rabbit antibody, slides will be developed using 3-3′-diaminobenzidine chromogen and 
counterstained with hematoxylin39.  
 
Change in phospho-S6 as a function of 6-month PFS 
Our hypothesis is that patients surviving for 6 months without disease progression will 
demonstrate a larger decrease in PI3K pathway activity as assessed by IHC for phopsho-S6 than 
those patients with disease progression or death prior to 6 months.  The change in pS6 will be 
determined by comparing H-scores to quantify pS6 protein levels by IHC prior to treatment at 
after 8 weeks of treatment40,39.  The H-Score will be calculated for staining of tumor cells using 
the following formula; H-Score  = (% at 0) * 0 + (% at 1+) * 1 + (% at 2+) * 2 + (% at 3+) * 3. 
Thus, this score produces a continuous variable that ranges from 0 to 300.  The change in 
phospho-S6 staining will be determined as follows: 
pS6 = (H4w-H0)/H0.  Patients will be 
categorized based on whether or not they survived for 6 months without disease progression. 
pS6 over the first 8 weeks of treatment will be compared between the two groups using the 
Wilcoxon rank-sum test. 
 
Gene expression profiles of PI3K and MAPK signaling in response and progression   
Our hypotheses are: 1. Treatment response by RECIST v1.1 criteria after 8 weeks of treatment 
will be associated with an absence of PI3K and MAPK signaling as assessed by gene expression 
profiling and 2. Disease progression is associated with activation of either pathway.  Gene 
expression profiling has emerged as in important tool for elucidating mechanisms of resistance to 
BRAF inhibitors in melanoma by identifying gene signatures of oncogenic pathway activation in 
an unbiased manner41. cDNA will be derived from RNA extracted from flash-frozen tissue 
specimens.  Gene expression will be determined using GeneChip Human Gene 1.0 ST Arrays 
(Affymetrix) on cycle 3 day 1 (+/- 3 days) and within 7 days of determination of tumor 
progression.  These profiles will be referenced to the profile of tumor tissue obtained prior to the 
initiation of treatment.  Expression data will be normalized and background-corrected.  
Clustering will be performed with MeV 4.4.  Differentially expressed genes will be identified 
using significance analysis of microarrays (SAM) with the R package. To identify and rank 
pathways enriched among differentially expressed genes, P-values (Fisher‟s exact test) will be 
calculated for gene sets with at least 20% differentially expressed genes. Curated gene sets of 
canonical pathways including PI3K and MAPK in the Molecular Signatures Database (MSigDB) 
will be used as the comparator.  Gene expression signatures consistent with MAPK, PI3K, or 
alternate pathways activation will be confirmed by RT-PCR and immunohistochemistry for 
phospho-protein levels such as pS6 and pERK.  Our initial goal is to perform microarray analysis 
on matched biopsy specimens from a total of 10 patients: 5 who meet the 6 month PFS endpoint, 
and 5 with early disease progression within 4 months of the initiation of treatment.  Until these 
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treatment biopsies.  Additional biopsies and additional analyses may be performed at the 
discretion of the PI. 
3.5 
Treatment compliance 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted and patients will be asked to return 
all unused study medication. 
3.6 
Safety monitoring plan 
3.6.1 
Safety assessments 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology, blood chemistry and urine values, regular 
measurement of vital signs and the performance of physical examinations.  Dermatologic 
assessments will be performed at screening, on week 3 day 1, and at every 8 week intervals 
thereafter. 
These assessments should be performed within ±1 day (during DLT period) or ±3days (all 
subsequent cycles) of the scheduled day of assessment except for adverse events that will be 
evaluated continuously through the study. Safety and tolerability will be assessed according to 
the NIH/NCI CTC: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
3.6.2 
Adverse events 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. Medical conditions/diseases present before starting study drug are only considered 
adverse events if they worsen after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. the severity grade (mild, moderate, severe) or (grade 1-4) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study drug 
permanently discontinued due to this adverse event; concomitant medication taken; non-drug 
therapy given; hospitalization/prolonged hospitalization) 
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All adverse events should be treated appropriately. Such treatment may include changes in study 
drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome.   
Information about common side effects already known about BKM120 can be found in the 
Investigators‟ Brochure and additional data regarding vemurafenib can be found in the published 
literature. This information should be included in the patient informed consent and should be 
discussed with the patient during the study as needed. 
 
Adverse Event Monitoring: Adverse events (AEs) will be recorded on the OnCoreeResearch 
database, all grade 3-5 expected and unexpected AEs will be recorded and updated at each visit. 
3.6.3 
Serious adverse events 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
 is fatal or life-threatening 
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 social reasons and respite care in the absence of any deterioration in the patient‟s 
general condition 
 is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
 after the patient has provided informed consent and until 4 weeks after the patient has 
stopped study treatment/participation 
 after the patient is randomized and until 4 weeks after the patient has stopped study treatment 
 after the patient begins taking study drug and until 4 weeks after the patient has stopped 
study treatment 
 after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-blind 
treatment, etc.) and until 4 weeks after the patient has stopped study treatment 
 after the start of any period in which the study protocol interferes with the standard medical 
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treatment to a fixed dose of concomitant medication) and until 4 weeks after the patient has 
stopped study treatment must be reported to Novartis within 24 hours of learning of its 
occurrence. Any SAEs experienced after this 4-week period should only be reported if the 
investigator suspects a causal relationship to the study drug. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
3.6.4 
Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee (DSMC) 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) or 
to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 24 business hours of knowledge of the event.  The contact may be by 
phone or e-mail. 
Reporting to UCSF’s Committee on Human Research (CHR) 
The Investigator must report events meeting the CHR definition of “Unanticipated Problem” 
(UP) within 10 working days of his/her awareness of the event. 
Guidance on Adverse Event Reporting to the CHR is available online at the UCSF Human 
Research Protection Program website.  
Expedited Reporting to the Food and Drug Administration (FDA) 
The Sponsor-Investigator is responsible for determining whether or not the suspected adverse 
reaction meets the criteria for expedited reporting in accordance with Federal Regulations 
(21 CFR §312.32).   
 
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all three 
definitions:  
 Suspected adverse reaction 
 Serious 
 Unexpected 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
 
The timeframe for submitting an IND safety report to FDA is no later than 15 calendar days 
after the Investigator determines that the suspected adverse reaction qualifies for reporting (21 
CFR 312.32(c)(1)).  
 
Any unexpected fatal or life-threatening suspected adverse reaction must be reported to FDA no  
later than 7 calendar days after the Investigator‟s initial receipt of the information (21 CFR 
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Any relevant additional information that pertains to a previously submitted IND safety report  
must be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)).  
 
The investigator (or designee) should prepare Form FDA 3500A (MedWatch)detailing the event, 
and contact the Institutional Trials Unit for assistance in the preparation of the IND Safety 
Report.    
 
For additional information and guidance on IND Safety Reports, please refer to FDA‟s Guidance 
documentSafety Reporting Requirements for INDs. 
 
Reporting to Genentech and Novartis 
Genentech 
Serious AE and AEs of Special Interest (regardless of causality) will be transmitted to Genentech 
within 24 hours of the Awareness Date.The completed MedWatch/case report should be faxed 
immediately upon completion toGenentech Drug Safety at: 
 
(650) 225-4682OR 
(650) 225-5288 
 
Additional Reporting Requirements to Genentech include the following: 
 Any reports of pregnancy following the start of administration with the vemurafenib will 
be transmitted to Genentech within thirty (30) calendar days of the Awareness Date. 
 All Non-serious Adverse Events originating from the Study will be forwarded in a 
quarterly report Genentech. 
 Relevant follow-up information should be submitted to Genentech Drug Safety as soon as 
it becomes available. 
 
Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the Sponsor will 
agree to the reconciliation periodicity and format, but agree at minimum to exchange monthly 
line listings of cases received by the other party. If discrepancies are identified, the Sponsor and 
Genentech will cooperate in resolving the discrepancies. The responsible individuals for each 
party shall handle the matter on a case-by-case basis until satisfactory resolution. 
Novartis 
All events must be reported by FAX (888-299-4565) to Novartis Pharmaceuticals DS&E 
Department within 24 hours of learning of its occurrence using an SAE Report form provided 
by Novartis.  This includes serious, related, labeled (expected) and serious, related, unlabeled 
(unexpected) adverse experiences. All deaths during treatment or within 30 days following 
completion of active protocol therapy must be reported within 5 working days. The original copy 
of the SAE Report and the fax confirmation sheet must be kept within the Study File.  
Relevant follow-up information should be submitted to Novartis Drug Safety as soon as it 
becomes available.  Follow-up information is sent to the same person(s) to whom the original 


 
 
 
 
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SAE Report Form was sent, using a new SAE Report Form stating that this is a follow-up to the 
previously reported SAE and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, and whether the patient continued or withdrew 
from study participation. 
If the SAE is not previously documented in the BKM120 or vemurafenib Investigators‟ Brochure 
or Package Insert (new occurrence) and is thought to be related to the study drugs, a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug that this 
SAE has been reported.Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in accordance 
with Directive 2001/20/EC or as per national regulatory requirements in participating countries. 
3.6.5 Oversight and monitoring 
 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and patient safety for 
all UCSF-CCC institutional clinical studies.  A summary of DSMC activities for this study 
includes:  
 Review of subject data in each cohort 
 Review of all serious adverse events 
 Minimum of a yearly audit 
3.6.5.1 
Monitoring and reporting guidelines 
Investigators will conduct continuous review of data and patient safety at monthly study group or 
site committee meetings where the results of each patient‟s treatment are discussed and the 
discussion is documented in the minutes. The discussion will include the number of patients, 
significant toxicities as described in the protocol, doses adjustments, and observed responses.  
All grade 3-5 AEs and SAEs will be entered in the HDFCCC OnCoreClinical Trial Management 
System (CTMS).   
 
Review of Adverse Event Rates: If the study has an increase of unexpected or expected 
Adverse Event grade 3 or 4 above the rate reported in the Investigational Brochure or package 
insert, the increase rate of AEs will be reported to the DSMC at the time of Identification. The 
Chair and PI will discuss the finding and proceed with a written course of action.  If at any time 
the Investigator stops enrollment or stops the study due to safety issues the DSMC Chair and 
Administrator must be notified within 24 business hours via e-mail.  The DSMC must receive a 
formal letter within 10 business days and the CHR must be notified. 
 
 


 
 
 
 
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Data Safety Monitoring Committee Contacts: 
DSMC Chair:  Thierry Jahan, MD 
DSMC Monitors - address 
Phone:  
Email: 
Address:  
415-353-2745 
venook@cc.ucsf.edu 
Box 1705 
UCSF Helen Diller Family 
Comprehensive Cancer Center 
San Francisco, CA 94143 
Box 1297 
UCSF Helen Diller Family 
Comprehensive Cancer Center 
San Francisco, CA 94115 
3.6.6 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
Novartis. The pregnancy should be followed up for 3 months after the termination of the 
pregnancy to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment of 
the possible relationship to the Novartis study treatment of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
The team needs to prepare information for the female partner of the male patient on required 
contraception. This information needs to be given to the male patient at the ICF signing for him 
to share it with his female partner.  
Information for female partners of male study participants 
Your male partner is offered to participate in a clinical research study. As a prerequisite to 
participate in this study your partner must agree to use a condom during intercourse. This is 
important because test results of the study treatment in pregnant animals indicated that the 
medicine can harm an unborn baby through the sperm. At the same time it is also important that 
you do not become pregnant while your partner is taking the medication. Therefore, you should 
use a highly effective method of birth control (contraception) during the time your male partner 
receives the study treatment and thereafter for another 3 months. Highly effective methods of 
contraception are those  methods of birth control that have less than 1% of unwanted pregnancy 
during one year, if used appropriately according to the instructions of the manufacturer. 
Those methods are the following: 
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) 
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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 any two of the following (a+b): 
a)   Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
b) Barrier methods 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, for 5 T1/2 (8 days) after stopping treatment and 
for additional 12 weeks (3 months in total after study drug discontinuation) and 
should not father a child in this period.  
 
For details on the most appropriate contraception you may talk to your regular doctor, or if check 
that your male partner agrees with the study doctor. 
 
If you get pregnant despite taking the birth control precautions, please ask your partner to inform 
the study doctor as soon as possible. The study doctor will ask your permission to collect 
information about you, your pregnancy and your child. 
4 
Protocol amendments, or changes in study conduct 
Any change or addition to this protocol requires a written protocol amendment that must be 
approved by the PRC and the CHR prior to implementation.   
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator in the interests of preserving the safety of all patients included in the 
trial.  If an immediate change to the protocol is implemented for safety reasons the CHR will be 
informed immediately. 
5 
Statistical methods 
 
5.1 
 Study Design/Endpoints 
 
This is a phase 1/2 clinical trial designed to determine the recommended phase 2 dose of PI3K 
inhibitor BKM120 in combination with BRAF inhibitor vemurafenib (phase 1) followed by a 
determination of 6 month progression-free survival rate (phase 2) in patients with BRAF mutant 
melanoma. 
 
 


 
 
 
 
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For Phase 1, Part A 
This is a single-arm, open-label phase 1 clinical trial. The primary endpoint for phase I, part A is 
the RP2D of vemurafenib twice daily and BKM120 daily in BRAF mutant melanoma patients 
with no prior exposure to potent BRAF inhibitorsand the primary safety endpoint is DLT. 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.   
 
For Phase 1, Part B 
The primary endpoint for phase 1, part B is the RP2D of vemurafenib twice daily in BRAF 
mutant melanoma patients with prior progression of disease on potent BRAF inhibitors and 
BKM120 daily and the primary safety endpoint is DLT.  
 
For the Phase 2 portion 
The primary endpoint of the Phase 2 portion is the progression-free survival rate at 6 months. 
Imaging assessments will be made by a radiologist, and final assessment using Response 
Evaluation Criteria in Solid Tumors (RECIST, version 1.1) will be made by the PI. Any 
documentation of a PR or CR in a target or non-target lesion must be confirmed by a repeat scan 
at least 4 weeks after the initial scan indicating the PR or CR. Disease response will be assessed 
at scheduled visits by diagnostic anatomic imaging, and clinical exam. All patients will be 
followed for 6 months and proportion of patients that are progression free at 6 months will be 
calculated.  
 
Secondary Endpoints 
Median PFS and OS defined by the Kaplan-Meier method.  Tumor progression will be defined 
using RECIST version 1.1.Analysis of tolerability will be descriptive with reporting of all events 
by grade that are thought to be possibly, probably, and definitely attributable to study drug.  
Correlative assessments for PTEN expression, changes in pS6, and gene expression analysis are 
described in section 3.4.7 along with statistical analysis plans for these assessments. 
 
5.2. 
Sample Size/Accrual Rate 
This study will use the standard 3+3 dose escalation design to determine the RP2D of BKM120 
in combination with vemurafenib (phase 1) followed by a single-stage binomial phase 2 design 
of 37 evaluable patients (any patient receiving at least 75% of prescribed cohort dose during the 
DLT period) to determine the PFS rate at 6 months. 
 
For the Phase 1 portion 
A Phase 1 dose escalation design using the standard 3+3 scheme will be followed and the sample 
size is not predetermined. We estimate the phase 1 portion of this trial will require a minimum of 
2 patients from four predefined dose levels (see Table 5) to determine the phase 2 dose (MTD). 
The estimated maximum number of patients is 24.  The final sample size of the study depends 
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For the Phase 2 portion 
The sample size for the phase 2 portion of this study is determined using single-stage binomial 
design for phase 2 studies. Preliminary data from trials of vemurafenibmonotherapy in advanced 
melanoma suggest a median PFS of approximately 6 months4,5,17.  The proposed design will be 
used to test the null hypothesis that the 6 month PFS rate of the study combination is 50% or less 
(which would not be clinically desirable) versus the alternative hypothesis that the true 6 month 
PFS rate is greater 70%, which would be considered clinically meaningful. The maximum total 
sample size will be 37 in Phase 2 including patients in the phase 1 portion of the study treated at 
the RP2D.  
 
5.3 
Analysis Plan 
All patients who received at least 75% of prescribed cohort dose during the DLT period will be 
considered evaluable.  Patients not evaluable will be replaced.   
Phase 1 portion of the study 
Safety and tolerability will also be assessed by clinical review of all relevant parameters 
including adverse experiences (AEs), laboratory tests, and physical exam.  Adverse experiences 
will be summarized as counts and frequencies for each dose level.  Other safety endpoints will be 
summarized as appropriate.  These data are descriptive in nature and statistical analysis tools will 
not be required. The recommended phase 2 dose will be determined using safety data including 
DLTs and post-DLT toxicity, the dose-response relationship, and PK data.   
 
Pharmacokinetic data will be acquired as described in section 3.4.6 and average values and 
standard deviations at each time point will be reported. 
 
Phase 2 portion of the study 
The PFS duration is defined as the time from the date of start of protocol therapy to the date of 
the first documented progression or death due to any cause. A patient who has not progressed or 
died by the date of the analysis cut-off or when the patient received any further anticancer 
therapy would have the PFS censored at the time of the last adequate tumor assessment before 
the first of the cut-off date or of the anticancer therapy date. All patients will be followed for 6 
months and proportion of patients that are progression free at 6 months will be calculated. We 
assume that combination treatment will have at least 70% PFS rate versus the undesirable PFS of 
<50% at 6 months. The phase 2portion is designed based single stage binomial design with the 
type I alpha of 5% and the power of 80%. If ≥ 23 patients ultimately achieve 6 months PFS, then 
further investigation of the drug is warranted.   
 
As secondary efficacy endpoints, the median PFSand OS will be estimated using exact binomial 
distribution; time to progression will be estimated using Kaplan-Meier methods. The 6-month 
PFS and 95% confidence intervals will be reported. ORR will be reported as frequencies and 
proportions with exact 95% confidence intervals from the Binomial distribution. The frequencies 
of individual toxicities thought to be probably, possible, or definitely related to study drug will 
be reported as well as the incidence of any grade 3, 4, and 5 toxicities regardless of attribution. 
 


 
 
 
 
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Correlative assessments for PTEN expression, changes in pS6, and gene expression analysis are 
described in section 3.4.7 along with statistical analysis plans. 
6 
Procedures and instructions 
6.1.1 
Publication of results 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Novartis and prior to any outside submission.  Novartis must receive copies of any 
intended communication in advance of publication (at least fifteen working days for 
presentational materials and abstracts and thirty working days for manuscripts).   These 
requirements acknowledge Novartis‟ responsibility to provide peer input regarding the scientific 
content and conclusions of such publications or presentations.  Principal Investigation/Institution 
shall have the final authority to determine the scope and content of its publications, provided 
such authority shall be exercised with reasonable regard for the interests of Novartis and, in 
accord with the trial contract and shall not permit disclosure of Novartis confidential or 
proprietary information. 
6.1.2 
Disclosure and confidentiality 
The investigator agrees to keep all information provided by Novartis in strict confidence and to 
request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents 
provided by Novartis (investigators' brochures and other material) will be stored appropriately to 
ensure their confidentiality. The information provided by Novartis to the investigator may not be 
disclosed to others without direct written authorization from Novartis, except to the extent 
necessary to obtain informed consent from patients who wish to participate in the trial. 
6.1.3 
Discontinuation of study 
Novartis reserves the right to discontinue any study under the conditions specified in the clinical 
trial agreement. 
6.2 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice and: 
 ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 
91/507/EEC, The Rules Governing Medicinal Products in the European Community 
 US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations) 
 Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects) 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice that it conforms to. 


 
 
 
 
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6.2.1 
Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, will be reviewed by the Committee on Human Research (CHR) (UCSF‟s 
Institutional Review Board [IRB]). A signed and dated statement that the protocol and informed 
consent have been approved by the CHR will be providedto Novartis before study initiation. Any 
amendments to the protocol will be approved by the CHR prior to implementation. 
6.2.2 
Informed consent 
The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject‟s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient 
could not read or sign the documents. No patient can enter the study before his/her informed 
consent has been obtained. 
The informed consent form is considered to be part of the protocol, and willbe submitted by the 
investigator to the CHR for approval. 
6.2.3 
Multicenter communication 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate, at minimum, biweekly conference calls with the 
participating sites for Phase I dose escalation studies prior to each cohort escalation and at the 
completion of each cohort or more frequently as needed to discuss risk assessment.  The 
following issues will be discussed as appropriate: 
 Enrollment information  
 Cohort updates (i.e. DLTs) 
 Adverse events (i.e. new adverse events and updates on unresolved adverse events and new 
safety information) 
 Protocol violations 
 Other issues affecting the conduct of the study 
6.2.4 
Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by subjects, as well as written records of the disposition of the 
drug when the study ends.   


 
 
 
 
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The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 
6.2.5 
Coordinating Center Documentation of Distribution 
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that the 
Study Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, 
drug manufacturer, participating sites, etc.). 
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt. 
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received. 
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed. 
6.2.6 
Regulatory Documentation 
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved by 
the UCSF Committee on Human Research (CHR). Prior to implementing this protocol at the 
participating sites, approval for the UCSF CHR approved protocol must be obtained from the 
participating site‟s IRB.  
The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants:  
 Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization  
 Participating Site IRB approved consent form  


 
 
 
 
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 Participating Site IRB membership list  
 Participating Site IRB‟s Federal Wide Assurance number and OHRP Registration number  
 Curriculum vitae and medical license for each investigator and consenting professional  
 Documentation of Human Subject Research Certification training for investigators and key 
staff members at the Participating Site  
 Participating site laboratory certifications and normals 
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment. 


 
 
 
 
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References 
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18. Weinstein, I.B. & Joe, A. Oncogene addiction. Cancer Res68, 3077-3080; discussion 3080 
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development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol17, 615-675 (2001). 
20. Kim, H.H., Sierke, S.L. & Koland, J.G. Epidermal growth factor-dependent association of 
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21. Ram, T.G. & Ethier, S.P. Phosphatidylinositol 3-kinase recruitment by p185erbB-2 and 
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constitutively elevated in growth factor-independent breast carcinoma cells with c-erbB-2 
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23. Fry, M.J. Phosphoinositide 3-kinase signalling in breast cancer: how big a role might it play? 
Breast Cancer Res3, 304-312 (2001). 
24. Roymans, D. & Slegers, H. Phosphatidylinositol 3-kinases in tumor progression. Eur. J. 
Biochem268, 487-498 (2001). 
25. Bachman, K.E. et al. The PIK3CA gene is mutated with high frequency in human breast 
cancers. Cancer Biol. Ther3, 772-775 (2004). 
26. Broderick, D.K. et al. Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade 
astrocytomas, and medulloblastomas. Cancer Res64, 5048-5050 (2004). 
27. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. 
Science304, 554 (2004). 
28. Ohgaki, H. Genetic pathways to glioblastomas. Neuropathology25, 1-7 (2005). 
29. Zeng, Z. et al. Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 
signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in 
acute myelogenous leukemia. Cancer Res66, 3737-3746 (2006). 
30. Chow, L.M.L. & Baker, S.J. PTEN function in normal and neoplastic growth. Cancer 
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32. Kwiatkowski, D.J. Rhebbing up mTOR: new insights on TSC1 and TSC2, and the 
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34. Polter, A. et al. Forkhead box, class O transcription factors in brain: regulation and 
behavioral manifestation. Biol. Psychiatry65, 150-159 (2009). 
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psychotropic drugs. Annu. Rev. Pharmacol. Toxicol49, 327-347 (2009). 
36. Riddle, M.C., Rosenstock, J. & Gerich, J. The treat-to-target trial: randomized addition of 
glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care26, 
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37. Tsuchida, Y. & Therasse, P. Response evaluation criteria in solid tumors (RECIST): new 
guidelines. Med. Pediatr. Oncol37, 1-3 (2001). 
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40. Armstrong, A.J. et al. A pharmacodynamic study of rapamycin in men with intermediate- to 
high-risk localized prostate cancer. Clin. Cancer Res16, 3057-3066 (2010). 
41. Nazarian, R. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-
RAS upregulation. Nature468, 973-977 (2010). 
 


 
 
 
 
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Appendix 1 Questionnaires 
 
Table A1.  Toxicity grading based on mood questionnaire scores 
 
PHQ-9 
GAD-7 
Score 
Severity 
CTCAE grading 
Score 
Severity 
CTCAE grading 
0-4 
None 
Normal 
0-4 
None 
Normal 
5-9 
Mild 
Grade 1 
5-9 
Mild  
Grade 1 
10-19 
Moderate 
Grade 2 
10-14 
Moderate 
Grade 2 
20-27 
Severe 
Grade 3 
≥ 15 
Severe 
Grade 3 
 
At Screening, a patient as judged by the investigator or who meets the cut-off score of ≥ 10 inthe 
PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, respectively, will be excluded fromthe 
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 
twice weekly bypatient 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).  
 
 
 


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Appendix 2 Prohibited medications 
Table A4. List of prohibited CYP3A Inhibitors and Inducers 
Strong CYP3A4,5,7 inhibitors 
Moderate CYP3A4,5,7 
inhibitors 
CYP3A4 inducers 
Clarithromycin 
aprepitant 
Barbiturates 
Conivaptan 
atazanavir 
Carbamazepine 
grapefruit juice 
cimetidine 
Efavirenz 
Indinavir 
ciprofloxacin 
Modafenil 
Itraconazole 
darunavir 
Nevirapine 
Ketoconazole 
diltiazem 
Oxcarbazepine 
Lopinavir 
erythromycin 
Phenobarbital 
Mibefradil 
fluconazole 
Phenytoin 
Nefazodone 
tofisopam 
pioglitazone  
Nelfinavir 
verapamil 
Rifabutin 
Posaconazole 
amprenavir 
Rifampin 
Ritonavir 
fosamprenavir 
St. John's wort 
Saquinavir 
 
Topiramate 
Telithromycin 
 
troglitazone 
troleandomycin 
 
 
Voriconazole 
 
 
This database of CYP inhibitors was compiled from the Indiana University School of Medicine‟s “Clinically Relevant” Table and 
from the University of Washington‟s Drug Interaction Database based on in vitro studies. Strong inhibitors are predicted to 
increase BKM120 AUC > 5-fold, and moderate inhibitors are predicted to increase BKM120 AUC ≥ 2-fold but < 5-fold.  
This database of CYP inducers was compiled from the FDA‟s “Guidance for Industry, Drug Interaction Studies;” from the Indiana 
University School of Medicine‟s “Clinically Relevant” Table; and from (Pursche et al. 2008). 
 
 
 


 
 
 
 
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Table A5. List of CYP450 Substrates to be used with caution 
CYP2C8 
CYP2C9 
CYP2C19 
CYP3A** 
amodiaquine 
celecoxib 
amitriptyline 
Adinazolam 
felodipine1 
cerivastatin 
diclofenac 
citalopram 
alfentanil1,2 
fentanyl2 
pioglitazone 
flurbiprofen 
clobazam 
alpha-
dihydroergocryptine1 
flunitrazepam 
repaglinide 
fluvastatin 
clomipramine 
Alprazolam 
fluticasone1 
rosiglitazone 
glibenclamide 
(glyburide) 
clopidogrel 
Amlodipine 
lovastatin1 
torasemide 
gliclazide 
diazepam 
Aripiprazole 
maraviroc1 
troglitazone 
glimepiride 
fluoxetine 
Atorvastatin 
midazolam1 
 
glipizide 
imipramine 
Brecanavir 
nifedipine 
 
indomethacin 
lansoprazole 
brotizolam1 
nisoldipine 
 
irbesartan 
mephobarbital 
budesonide1 
nitrendipine 
 
ketobemidone 
moclobemide 
buspirone1 
perospirone1 
 
lornoxicam 
omeprazole 
Capravirine 
quinine 
 
losartan 
pantoprazole 
Cerivastatin 
sildenafil1 
 
meloxicam 
progesterone 
Chlorpheniramine 
simvastatin1 
 
naproxen 
quazepam 
cyclosporine2 
sirolimus1,2 
 
nateglinide 
rabeprazole 
darifenacin1 
tolvaptan 
 
piroxicam 
sertraline 
Diazepam 
trazodone 
 
rosiglitazone 
S-mephenytoin 
diergotamine2 
triazolam1 
 
S-ibuprofen 
 
ebastine1 
 
 
sulfamethoxazole  
eletriptan1 
 
 
tenoxicam 
 
eplerenone1 
 
 
tolbutamide 
 
ergotamine2 
 
 
torasemide 
 
Estazolam 
 
 
valdecoxib 
 
everolimus1 
 
* This database of CYP substrates was compiled from the Indiana University School of Medicine‟s “Clinically Relevant” 
Table, and from (Zhou et al. 2009) 
** CYP3A substrates were compiled from the Indiana University School of Medicine‟s “Clinically Relevant” Table; and 
supplemented by the FDA‟s “Guidance for Industry, Drug Interaction Studies” and the University of Washington‟s Drug 
Interaction Database. 
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-administered 
with a potent inhibitor of the respective enzyme. 
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their exposure 
levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes). 
 
 


 
 
 
 
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Appendix 3 QT prolonging drugs 
Note: If a patient, PRIOR to enrollment, is on a chronic treatment with any medication listed in 
Table A6, AND the treatment cannot be discontinued or switched to a different medication prior 
to starting study drug, then the patient cannot enter the trial (see exclusion criteria). 
If a patient, AFTER she/he has been enrolled, requires the concomitant use of any medication 
listed in Table A6, then investigators, at their discretion, may co-administer such medications. 
Patients receiving such medications must however be monitored. 
 
Table A6. QT prolonging drugs with risk of Torsades de Pointes to avoid 
Drug 
QT risk(*) 
Comment 
Amiodarone 
known risk for TdP 
Females>Males, TdP risk regarded as low 
Arsenic trioxide 
known risk for TdP 
 
Astemizole 
known risk for TdP 
No longer available in US.  
CYP3A4 substrate with narrow therapeutic index. 
Bepridil 
known risk for TdP 
Females>Males 
Chloroquine 
known risk for TdP 
 
Chlorpromazine 
known risk for TdP 
 
Cisapride 
known risk for TdP 
Restricted availability; Females>Males. 
CYP3A substrate with narrow therapeutic index. 
Disopyramide 
known risk for TdP 
Females>Males 
Dofetilide 
known risk for TdP 
 
Domperidone 
known risk for TdP 
Not available in the US. 
Droperidol 
known risk for TdP 
 
Halofantrine 
known risk for TdP 
Females>Males 
Haloperidol 
known risk for TdP 
When given intravenously or at higher-than- 
recommended doses, risk of sudden death, QT 
prolongation and torsades increases. 
Ibutilide 
known risk for TdP 
Females>Males 
Levomethadyl 
known risk for TdP 
Sensitive CYP3A substrate 
Mesoridazine 
known risk for TdP 
 
Methadone 
known risk for TdP 
Females>Males 
Pentamidine 
known risk for TdP 
Females>Males 
Pimozide 
known risk for TdP 
Females>Males. Sensitive CYP3A substrate with 
narrow therapeutic index 
Probucol 
known risk for TdP 
No longer available in U.S. 
Procainamide 
known risk for TdP 
 
Quetiapine 
possible risk for TdP 
Sensitive CYP3A substrate 
Quinidine 
known risk for TdP 
Females>Males. Sensitive CYP3A substrate  
Sotalol 
known risk for TdP 
Females>Males 
Sparfloxacin 
known risk for TdP 
 
 
 


 
 
 
 
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Table A6. QT prolonging drugs with risk of Torsades de Pointes to avoid 
Drug 
QT risk(*) 
Comment 
Tacrolimus 
possible risk for TdP 
Sensitive CYP3A substrate with narrow therapeutic 
index 
Terfenadine 
known risk for TdP 
No longer available in U.S. Sensitive CYP3A 
substrate with narrow therapeutic index 
Thioridazine 
Known risk for TdP 
 
Vardenafil 
possible risk for TdP 
Sensitive CYP3A substrate 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-administered 
with a potent inhibitor of the respective enzyme. 
 
 
 


 
 
 
 
Version date: June 24, 2013 
 
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Table A7. List of QT prolonging drugs to be used with caution 
(Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT) 
Drug 
QT Risk 
Alfuzosin 
possible risk for Torsades de Pointes 
Amantadine 
possible risk for Torsades de Pointes 
Amitriptyline 
conditional risk for Torsades de Pointes 
Azithromycin 
possible risk for Torsades de Pointes 
Chloral hydrate 
possible risk for Torsades de Pointes 
Citalopram 
conditional risk for Torsades de Pointes 
Clomipramine 
conditional risk for Torsades de Pointes 
Clozapine 
possible risk for Torsades de Pointes 
Desipramine 
conditional risk for Torsades de Pointes 
Diphenhydramine 
conditional risk for Torsades de Pointes 
Dolasetron 
possible risk for Torsades de Pointes 
Doxepin 
conditional risk for Torsades de Pointes 
Dronedarone 
possible risk for Torsades de Pointes 
Felbamate 
possible risk for Torsades de Pointes 
Flecainide 
possible risk for Torsades de Pointes 
Fluoxetine 
conditional risk for Torsades de Pointes 
Foscarnet 
possible risk for Torsades de Pointes 
Fosphenytoin 
possible risk for Torsades de Pointes 
Galantamine 
conditional risk for Torsades de Pointes 
Gatifloxacin 
possible risk for Torsades de Pointes 
Gemifloxacin 
possible risk for Torsades de Pointes 
Granisetron 
possible risk for Torsades de Pointes 
Imipramine 
conditional risk for Torsades de Pointes 
Indapamide 
possible risk for Torsades de Pointes 
Isradipine 
possible risk for Torsades de Pointes 
Levofloxacin 
possible risk for Torsades de Pointes 
Lithium 
possible risk for Torsades de Pointes 
Mexiletine 
conditional risk for Torsades de Pointes 
Moexipril/HCTZ 
possible risk for Torsades de Pointes 
Moxifloxacin 
possible risk for Torsades de Pointes 
Nicardipine 
possible risk for Torsades de Pointes 
Nortriptyline 
conditional risk for Torsades de Pointes 
Octreotide 
possible risk for Torsades de Pointes 
Ofloxacin 
possible risk for Torsades de Pointes 


 
 
 
 
Version date: June 24, 2013 
 
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Page 83 of 92 
Table A7. List of QT prolonging drugs to be used with caution 
(Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT) 
Drug 
QT Risk 
Ondansetron 
possible risk for Torsades de Pointes 
Oxytocin 
possible risk for Torsades de Pointes 
Paliperidone 
possible risk for Torsades de Pointes 
Paroxetine 
conditional risk for Torsades de Pointes 
Perflutren lipid 
microspheres 
possible risk for Torsades de Pointes 
Protriptyline 
conditional risk for Torsades de Pointes 
Ranolazine 
possible risk for Torsades de Pointes 
Risperidone 
possible risk for Torsades de Pointes 
Roxithromycin* 
possible risk for Torsades de Pointes 
Sertindole 
possible risk for Torsades de Pointes 
Sertraline 
conditional risk for Torsades de Pointes 
Solifenacin 
conditional risk for Torsades de Pointes 
Tizanidine 
possible risk for Torsades de Pointes 
Trazodone 
conditional risk for Torsades de Pointes 
Trimethoprim-Sulfa 
conditional risk for Torsades de Pointes 
Trimipramine 
conditional risk for Torsades de Pointes 
Venlafaxine 
possible risk for Torsades de Pointes 
Ziprasidone 
possible risk for Torsades de Pointes 
* Not available in the United States 
 


 
 
 
 
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Appendix 4 BKM120 pharmacokinetic analysis 
BKM120 sampling and shipping information 
 Draw 2 mL into a 5 mL EDTA (K3) coated tube 
 Invert the tube gently several times to avoid clotting 
 Place the tube into an ice bath at approximately 4°C during the sampling period 
 Within 30 min after collection, centrifuge the tube at 3-5°C for 15 min at 1500 to 2000g 
 Transfer the plasma into uniquely labeled 2ML SMART SCAN TUBES from Thermo 
(Reference for rack/48 tubes: Nr. AB1411 or Reference for only 100 tubes: AB-1389) and 
frozen immediately over solid carbon dioxide (dry ice) or in a freezer at approximately -70°C 
or below. 
 Ship frozen on dry ice to Central Lab  
Sample shipment instructions 
For each shipment, an inventory of the samples should accompany the shipment. This inventory 
should include the study ID, subject ID, sample number, visit number scheduled time of 
collection. 
Clearly indicate any missing specimens. The original inventory will be retained at the site in the 
Investigator‟s file. 
All samples will be kept at the temperature specified up to and during the shipment. Unless 
instructed otherwise, the samples will be packed carefully with suitable packing material and dry 
ice to keep them frozen. 
All shipments should be sent (Monday through Wednesday only) by a carrier guaranteeing 
overnight delivery. The following items should be considered: 
 Advise the carrier of the type of service desired, need for personalized door-to-door pickup, 
and delivery guaranteed within 24 hours. 
 Advise the carrier of the nature of the shipment's contents (human biological specimens) and 
label the package accordingly. 
 Indicate Novartis drug code and Study No. on the face of the parcel to be shipped. The parcel 
also must carry a "dangerous goods" label because of the dry ice (labels supplied by the 
courier). 
 The carrier must be asked to store the parcel(s) in a freezer if shipment is delayed and to 
replace exhausted dry ice before transportation continues. 
 Shipping reservations should be made to allow delivery to Novartis before 16:00 (4 pm) local 
time Monday to Thursday and before 11:00 (11 am) local time on Friday. Shipments should 
not be sent between Thursday and Sunday, to prevent arrival over the weekend. 
Instructions for shipment of biological samples to Basel 
All pharmacokinetic specimens will be kept at the temperature specified in the PK collection and 
processing section until shipment. 


 
 
 
 
Version date: June 24, 2013 
 
Protocol CC#: 11952 
Phase 1/2 – BKM120 
Page 85 of 92 
Samples have to be packed according to the ICAO/IATA-Packing-Instructions in an insulated 
box. To guarantee that the samples remain deep frozen during transport, use about 10 kg of dry 
ice per box which will keep the samples frozen during the whole duration of the transport (air 
freight). Send the parcel to the following. 
A shipping log must be included with the shipment. 
Ship to: 
Novartis Pharma AG 
Gerardo de Pierro for WalidElbast 
Fabrikstrasse 14 – 3.28.2 
CH-4002 Basel,Switzerland 
Telephone: +41-79-535 96 32 
Fax: +41-61-696 85 84 
Email:  ts-dmpk.sample-management@novartis.com 
 
Please notify the addressee in advance of the shipment and indicate: 
 Number of the airbill, 
 The time and date of shipping and approximate time of arrival, 
 Flight Number, 
 To whom the shipment is addressed, the study number, carrier and the shipping form number 
(or equivalent airbill number), 
 The sender‟s name, telephone number and alternative contact personnel, 
 The total number of cartons and unit weight of each carton, 
Also notify the Clinical Trial Leader at Novartis when a shipment has been scheduled. 
The samples should be sent at the beginning of a week in order to arrive not later than 
Thursday. 


 
 
 
 
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Protocol CC#: 11952 
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Page 86 of 92 
Appendix 5Vemurafenib pharmacokinetics and correlative studies assessments 
 
Vemurafenib pharmacokinetics 
Under the supervision of Drs. Yong Huang and Leslie Floren, vemurafenib analysis will be 
performed at UCSF. 
Vemurafenib sampling and shipping information 
 Draw 2 mL into a 5 mL EDTA (K3) coated tube 
 Invert the tube gently several times to avoid clotting 
 Place the tube into an ice bath at approximately 4°C during the sampling period 
 Within 30 min after collection, centrifuge the tube at 3-5°C for 15 min at 1500 to 2000g 
 Transfer the plasma into uniquely labeled 2ML SMART SCAN TUBES from Thermo 
(Reference for rack/48 tubes: Nr. AB1411 or Reference for only 100 tubes: AB-1389) and 
frozen immediately over solid carbon dioxide (dry ice) or in a freezer at approximately -70°C 
or below. 
 Ship frozen on dry ice to: 
Yong Huang, Ph. D. 
296 Lawrence Street  
University of California, San Francisco 
San Francisco, CA. 94143 – 0912 
Email: yong.huang@ucsf.edu 
Phone: 415-476-5220 
 
Correlative studies assessments 
Portions of all new tumor biopsy specimens will be immediately immersed in formalin and 
subsequently embedded in paraffin and additional tissue will be flash-frozen and stored at  
-70ºC until the time of analysis 
 
The primary contact for acquisition and processing of these specimens at UCSF is: 
Kim Chong, MD 
UCSF Melanoma Fellow 
Phone: 353-9986 
Email: chongk@derm.ucsf.edu 
 
 
 


 
 
 
 
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Appendix 6 
Multicenter Institutional Studies 
 
6.1 
Data and Safety Monitoring Plan* for Multicenter Institutional Study 
(Phase 1 Dose Escalation) 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study 
includes:  
 Review of subject data in each cohort 
 Review of suspected adverse reactions considered “serious” 
 Approval of dose escalation by DSMC Chair (or qualified alternate) 
 Monthly monitoring (depending on study accrual) 
 Minimum of a yearly regulatory audit 
Monitoring and Reporting Guidelines 
All institutional Phase 1 therapeutic studies are designated with a high risk assessment.  The data 
is monitored monthly as subjects are enrolled and includes all visits monitored up through the 
Dose Limiting Toxicity (DLT) period.  At the time of dose escalation, a written report will be 
submitted to the DSMC Chair outlining the cohort dose, all adverse events and suspected adverse 
reactions considered “serious,” and any Dose Limiting Toxicity as described in the protocol.  
The report will be reviewed by the DSMC Chair or qualified alternate and written authorization 
to proceed or a request for more information will be issued within 2 business days of the request.  
The report is then reviewed at the subsequent DSMC meeting.  In the event that the committee 
does not concur with the DSMC Chair‟s decision, further study accrual is held while further 
investigation takes place.   
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair.  
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites.  The Study Chair will conduct continuous review of data 
and subject safety and discuss each subject‟s treatment at weekly UCSF Site Committee 
meetings.  The discussions are documented in the UCSF Site Committee meeting minutes.  For 
each dose level, the discussion will include the number of patients, significant toxicities in 
accordance with the protocol, doses adjustments, and observed responses. 
Multicenter communication 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate, at minimum, monthly conference calls with the 
participating sites at the completion of each cohort or more frequently as needed to discuss risk 
assessment.  The following issues will be discussed as appropriate: 
 Enrollment information  
 Cohort updates (i.e. DLTs) 
 Adverse events (i.e. new adverse events and updates on unresolved adverse events and new 
safety information) 


 
 
 
 
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 Protocol violations 
 Other issues affecting the conduct of the study 
Dose Level Considerations 
The PI/Study Chair, participating investigators, and research coordinators from each site will 
review enrollment for each dose level cohort during the regularly scheduled conference calls.  
The dose level for ongoing enrollment will be confirmed for each subject scheduled to be 
enrolled at a site.  Dose level assignments for any subject scheduled to begin treatment must be 
confirmed by the UCSF Coordinating Center via fax or e-mail. 
If a Dose Limiting Toxicity (DLT) arises in a subject treated at a study site, all sites must be 
notified immediately by the UCSF Coordinating Center.  The Study Chair has 1 business day 
(after first becoming aware of the event at either the UCSF Coordinating Center or the 
participating site) in which to report the information to all participating sites.  If the DLT occurs 
at a participating site, the local investigator must report it to the UCSF Coordinating Center 
within1 business day, after which the UCSF Coordinating Center will notify the other 
participating sites. 
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The DSMC will be responsible for monitoring all data 
entered in OnCore® at the UCSF Coordinating Center and the participating sites.  The data (i.e. 
copies of source documents) from the participating sites will be sent electronically or faxed over 
to the UCSF Coordinating Center prior to the monitoring visits in order for the DSMC to monitor 
the participating site‟s compliance with the protocol, patient safety, and to verify data entry. 
Review and Oversight Requirements 
Adverse Event Monitoring 
All clinically significant adverse events (AEs), whether or not unexpected, and whether or not 
considered to be associated with the use of study drug, will be entered into OnCore®, UCSF‟s 
Clinical Trial Management System.   
All clinically significant adverse events entered into OnCore® will be reviewed on a weekly basis 
at the UCSF Coordinating Center‟s Site Committee.  All clinically significant adverse events 
must be reported to the UCSF Coordinating Center by the participating sites within 10 business 
days of becoming aware of the event.  The Site Committee will review and discuss the selected 
toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the 
administration of the study drug(s). 
In addition, all suspected adverse reactions considered “serious” are entered into OnCore® and 
will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing 
basis and discussed at the DSMC meetings, which take place every six (6) weeks. 
All suspected adverse reactions considered “serious” should be reported to the UCSF 
Coordinating Center within 1 business day of becoming aware of the event or during the next 
scheduled conference call, whichever is sooner.   
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the investigational 
drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or the 


 
 
 
 
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assigned designee must be notified within 1 business day from the participating site(s) and the 
Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of 
this notification.  The contact may be by phone or e-mail. 
Increase in Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating Center is 
responsible for notifying the DSMC at the time the increased rate is identified.  The report will 
indicate if the incidence of adverse events observed in the study is above the range stated in the 
Investigator Brochure or package insert. 
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the DSMC 
Chair and DSMC Manager must be notified within 1 business day via e-mail.  The DSMC must 
receive a formal letter within 10 business days and the CHR must be notified. 
Data and Safety Monitoring Committee Contacts: 
DSMC Chair:  Alan Venook, MD 
DSMC Monitors  
Phone:  
Email: 
Address:  
415-353-2745 
venook@cc.ucsf.edu 
Box 1705 
UCSF 
San Francisco, CA 94115 
Box 1297 
UCSF Helen Diller Family 
Comprehensive Cancer Center 
San Francisco, CA 94115 
* DSMP approved by NCI 09/February2012 
 
6.2 
UCSF Policy/Procedure for Required Regulatory Documents for a UCSF 
Multicenter Investigator-Initiated Oncology Clinical Trials with an Investigator 
held Investigational New Drug (IND) 
Purpose 
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer 
Center (HDFCCC) where the Principal Investigator (PI) holds the IND. 
Background 
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) 
Guidelines define Essential Regulatory Documents as those documents which individually and 
collectively permit evaluation of the conduct of a trial and the quality of data produced. These 
documents serve to demonstrate compliance with standards of GCP and with all applicable 
regulatory requirements. Filing essential documents in a timely manner can greatly assist in the 
successful management of a clinical trial. 
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as 
well as paper files in the Regulatory Binders for both the Coordinating Site and the Participating 
Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials. 
 
 


 
 
 
 
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Protocol CC#: 11952 
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Procedures 
1.   HDFCCC Essential Regulatory Documents 
Documents Filed in iMedRIS: 
 CHR approvals for initial submission of application, all modifications, and continuing 
annual renewals 
 Current and prior approved protocol versions with signed protocol signature page(s) 
 Committee for Human Research (CHR) approval letters and Informed Consent Form(s) 
(ICF) 
 Current and prior versions of the Investigator Brochure (IB). 
 Serious Adverse Event Reporting 
 Protocol Violations and Single Patient Exception (SPE) Reports to CHR with supporting 
fax documentation 
Documents Filed in OnCore®: 
 Package Insert (if the study drug is commercial) or Investigator Brochure 
 Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC) 
 Patient handouts 
 Screening/enrollment log 
 Data and Safety Monitoring Committee (DSMC) monitoring reports 
 DSMC dose escalation approvals with study status summary forms 
 OnCore® Case Report Form (CRF) completion manual 
Documents Filed in Regulatory Binder: 
 Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator‟s signature 
 For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) 
Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative 
(CITI), etc.) 
 Site Initiation Visit (SIV) minutes and correspondence with participating site(s). 
 As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center 
 Serious Adverse Event (SAE) reports to CHR and sponsor. 
 MedWatch reporting to FDA and sponsor 
 Delegation of Authority Form 
 Drug Destruction Standard Operating Procedure (SOP) 
 For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges 
2.  Additional Essential Documents for Multicenter Trials for the Coordinating Center (filed 
in Regulatory Binder or OnCore) 


 
 
 
 
Version date: June 24, 2013 
 
Protocol CC#: 11952 
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Page 91 of 92 
 Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent Form 
(ICF), and Health Insurance Portability and Accountability Act (HIPAA) Consent Form 
for the Participating Site(s) 
 For all Principal Investigators and Sub-Investigators listed on the 1572 at the 
Participating Site(s) – Financial Disclosure Forms, CVs, MD Licenses, and Staff Training 
documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for Investigational 
New Drug Application 
 Site Initiation Visit (SIV) minutes and correspondence with Participating Site(s). 
 As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center for the Participating Site(s) 
 Protocol Violations and Single Patient Exception (SPE) reports to IRB with supporting 
fax documentation for Participating Site(s) 
 Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s) 
 Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating 
Site(s) 
 For all laboratories listed on FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges for the 
Participating Site(s) 
 Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all 
participating site(s) in Multicenter studies or Contract Research Organization (CRO) 
Monitoring Plan (if an outside CRO is used for the study) 
 Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor for the 
Participating Site(s) 
 
27 April 2012 


 
 
 
 
Version date: June 24, 2013 
 
Protocol CC#: 11952 
Phase 1/2 – BKM120 
Page 92 of 92 
6.3 
Required Regulatory Documents for Sub-sites Participating in a UCSF Investigator 
Initiated Multicenter Trial (Checklist) 
Directions:  
1)  Fax the documents listed below to the UCSF Coordinating center at 415-514-6955or 
2)  Scan the documents and upload to OnCore® and create a Note to File for the on-site 
Regulatory binder to indicate where these documents may be found 
1572 
  PI and Sub investigators: 
CV and Medical license  
Financial disclosure form 
NIH or CITI human subject protection training certification 
  Laboratories   
CLIA and CAP 
CV of Lab Director and Lab Licenses 
Laboratory reference ranges 
Local Institutional Review Board  
  IRB Approval letter 
  Reviewed/Approved documents 
 Protocol version date:   
___________ 
 Informed consent version date:  ___________ 
 Investigator Brochure version date:  ___________ 
 HIPAA  
  Current IRB Roster 
Other  
  Delegation of Authority Log  
 Include NIH or CITI human subject protection training certificates or GCP training 
certification 
  Pharmacy 
 Drug destruction SOP and Policy 
  Protocol signature page  
  Executed sub contract 

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IRB NUMBER: 11-07615
IRB APPROVAL DATE: 10/22/2013
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IRB APPROVAL DATE: 10/22/2013
IRB EXPIRATION DATE: 10/31/2014
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IRB APPROVAL DATE: 10/22/2013
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IRB APPROVAL DATE: 10/22/2013
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IRB APPROVAL DATE: 10/22/2013
IRB EXPIRATION DATE: 10/31/2014
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IRB NUMBER: 11-07615
IRB APPROVAL DATE: 10/22/2013
IRB EXPIRATION DATE: 10/31/2014
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