Clinical trial NCT02128724
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Lung cancer BKM120 Hypoxia Misonidazole Radiotherapy Buparlisib
Sponsor: University of Oxford
Start date: 2013-04-01; Completion date: 2017-10-17
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will test whether a drug called BKM120/buparlisib is a safe and effective treatment when given to lung cancer patients having radiotherapy treatment. The trial will identify which of three possible doses of buparlisib is best to give with lung radiotherapy.

Detailed description:
This study will be a single-centre, open-label, 3+3 cohort, dose escalation phase I study of the use of buparlisib in combination with thoracic radiotherapy. Patients with incurable NSCLC requiring palliative thoracic radiotherapy will be eligible for entry.

The first three cohorts of patients will be treated with escalating doses of BKM120. These patients will be treated with buparlisib for a total of fourteen days. One week after commencing buparlisib, patients will start palliative radiotherapy treatment. Radiotherapy treatment will be delivered as 20Gy in 5 fractions over a one week period. Maximum tolerated dose (MTD) will be determined and a further 6 patients will be treated at this dose. Response to buparlisib treatment will be based upon changes in tumour hypoxia and perfusion as detected by 18F-Miso PET-CT scans and perfusion CT scans respectively.

In the event that no changes are detected in tumour hypoxia or perfusion in cohorts 1-3, an optional group of patients (cohort 4) will be recruited. These patients will receive buparlisib treatment for a total of 28 days. Three weeks after commencing buparlisib, this cohort will receive palliative radiotherapy with 20Gy in 5 fractions over a one week period.

Samples from the patients will also be analysed:

Phosphorylation Status of Akt in Peripheral Blood Mononuclear Cells (PBMCs) Tumour Phosphatase and tensin homolog (PTEN) gene levels Tumour PRAS40 Levels

Arms: arm 1: Three cohorts of patients will be treated with escalating doses of oral buparlisib. The doses will be 50mg, 80mg and 100mg, once daily. Patients will be treated with buparlisib for a total of fourteen days. One week after commencing buparlisib, patients will start palliative radiotherapy treatment. Radiotherapy treatment will be delivered as 20Gy in 5 fractions over a one week period. There will be an expansion cohort at the MTD. Patients in an optional fourth cohort will take buparlisib for 4 weeks at the MTD.
Interventions: intervention 1: BKM120
Intervention descriptions: intervention 1: Buparlisib is a highly specific inhibitor of phosphatidylinositol 3-kinase (PI3K). Buparlisib is supplied as 10mg and 50mg hard gelatin capsules.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
BKM120  
 
Full title: A CR-UK phase I study of BKM120 in patients with non-small cell lung 
cancer (NSCLC) receiving thoracic radiotherapy 
Short title: Palliative thoracic radiotherapy plus BKM120 
 
Protocol Version & date: 
Version 7.0 12Jan2017 
Protocol Number: 
OCTO_031 
Ethics Number: 
12/SC/0674 
EudraCT Number: 
2012-003762-40 
NIHR Portfolio Number: 
13615 
Clintrials.gov. No. 
NCT02128724 
ISRCTN: 
ISRCTN04813360 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsored by Oxford University 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the Sponsor, the 
Trials Office, the Investigator Team, host NHS Trust(s), regulatory authorities, and members of the Research Ethics 
Committee.   
 
 
  
 
 
 
 


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GENERAL CONTACT INFORMATION 
 
Chief Investigator 
Dr Geoff Higgins 
Consultant Clinical Oncologist and Clinician Scientist 
Gray Institute for Radiation Oncology and Biology 
University of Oxford 
 
Old Road Campus Research Building 
Oxford OX3 7DQ 
 
Tel.:    01865 617355 
 
Email: geoffrey.higgins@oncology.ox.ac.uk 
 
 
Trial Office (OCTO) 
BKM120  Trial Office 
 
Oncology Clinical Trials Office (OCTO) 
 
Department of Oncology, The University of Oxford 
 
Old Road Campus Research Building 
 
Oxford OX3 7DQ, UK 
 
Tel:+44 (0)1865 617083 
 
Email: octo-BKM120@oncology.ox.ac.uk  
 
Website:  http://www.oncology.ox.ac.uk/trial/bkm120 
 
 
Clinical Trial Coordinator (acting) 
Ms Stasya Ng 
 
Tel.: +44 (0)1865 617083    
 
Fax:  +44 (0)1865 617010     
 
Email: octo-BKM120@oncology.ox.ac.uk 
 
 
Sponsor 
Ms Heather House 
 
 
The University of Oxford Clinical Trials and Research Governance Team 
 
Joint Research Office Block 60 
 
Churchill Hospital 
 
Oxford OX3 7LE 
 
Tel: +44 (0)1865 572245 
 
Fax: +44 (0)1865 572242 
 
E-mail: heather.house@admin.ox.ac.uk 
 
 
Lead NHS Trust 
Ms Heather House 
 
 
R&D Department, Oxford University Hospitals NHS Trust 
 
Joint Research Department, Block 60, Churchill Hospital 
 
Oxford OX3 7LE 
 
Tel: +44 (0) 1865 572245 
 
E-mail: heather.house@ouh.nhs.uk 
 
 
Statistician 
Ms Sharon Love 
 
Senior Medical Statistician 
 
Oxford Clinical Trials Research Unit (OCTRU) 
 
Centre for Statistics in Medicine, The University of Oxford 
 
Wolfson College Annexe 
 
Linton Road 
 
Oxford OX2 6UD 
 
Tel : +44 (0)1865 284411 
 
Fax: +44 (0)1865 284424 
 
Email: sharon.love@csm.ox.ac.uk 
 
Mr Pradeep Virdee 
Medical Statistician  
Centre for Statistics in Medicine 
University of Oxford  
Botnar Research Centre 
Windmill Road 


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Oxford OX3 7LD 
Tel: +44 (0)1865 737950 
 
 
Central Laboratory  
BKM120 Sample Handling Laboratory 
 
Level 1, Oxford Cancer Centre 
 
Old Road 
 
Headington 
 
Oxford 
 
OX3 7LE  
 
Tel: +44(0)1865 220557  
 
Email: labchurchill@oncology.ox.ac.uk 
 
 
Phospho-AKT Expression 
Dr Kevin Myers 
 
Department of Oncology, The University of Oxford 
 
 
Old Road Campus Research Building  
 
Oxford OX3 7DQ, UK 
 
Tel: +44 (0)1865 617050 
 
Clinical Queries 
 
During office hours: Clinical queries should be directed to the BKM120 Trial Office - contact the Clinical Trial 
Coordinator.  The call will be passed on to the Chief Investigator, Clinical Coordinator or an appropriate member of 
the Trial Management Group. 
 
Out of office hours: call the Churchill Hospital switchboard on Tel: 01865 741 841 and ask to speak to the Clinical 
Oncology on-call doctor. 
 
Patient Screening: To obtain a screening number please email/fax the Screening Form to the BKM120 Trial Office at 
octo-BKM120@oncology.ox.ac.uk /01865 617010 
 
Patient Registration: To register a patient on the trial please email/fax the Registration Form to the BKM120 Trial 
Office at octo-BKM120@oncology.ox.ac.uk/01865 617010 
  
 


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TABLE OF CONTENTS 
GENERAL CONTACT INFORMATION ............................................................................................................................ 2 
PROTOCOL SYNOPSIS ................................................................................................................................................. 7 
SUMMARY SCHEDULE OF EVENTS ................................................................................................................................ 12 
COHORTS 1-3 PLUS THE EXPANSION COHORT - SCHEDULE OF EVENTS .......................................................................................... 12 
COHORT 4 - SCHEDULE OF EVENTS ....................................................................................................................................... 13 
STUDY FLOW CHART .......................................................................................................................................................... 14 
ABBREVIATIONS ....................................................................................................................................................... 15 
1 
INTRODUCTION ..................................................................................................................................... 15 
1.1 
BACKGROUND .................................................................................................................................................... 15 
1.2 
OVERVIEW OF BKM120 ...................................................................................................................................... 16 
1.3 
OTHER RESEARCH INTERVENTIONS .......................................................................................................................... 17 
1.4 
RATIONALE FOR THE STUDY ................................................................................................................................... 18 
2 
TRIAL DESIGN......................................................................................................................................... 19 
2.1 
DURATION OF PATIENT PARTICIPATION .................................................................................................................... 19 
2.2 
POST-TRIAL CARE AND FOLLOW-UP......................................................................................................................... 19 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 20 
4 
PATIENT SELECTION ............................................................................................................................... 20 
4.1 
ELIGIBILITY CRITERIA ............................................................................................................................................ 20 
4.2 
PRE-TRIAL SCREENING AND RE-SCREENING (DAY -28 TO DAY -2) .................................................................................. 22 
4.3 
PATIENT REGISTRATION PROCEDURE ....................................................................................................................... 22 
5 
TRIAL ASSESSMENTS AND PROCEDURES ................................................................................................ 23 
5.1 
INFORMED CONSENT FOR SCREENING AND MAIN STUDY .............................................................................................. 23 
5.2 
PRE-DOSING EVALUATIONS FOR ALL COHORTS .......................................................................................................... 24 
5.3 
EVALUATIONS DURING THE STUDY FOR COHORTS 1-3 PLUS THE EXPANSION COHORT ........................................................ 24 
5.4 
EVALUATIONS DURING THE STUDY FOR COHORT 4 ..................................................................................................... 26 
5.5 
END OF STUDY EVALUATIONS ................................................................................................................................ 28 
5.6 
EVALUATIONS ON EARLY WITHDRAWAL ................................................................................................................... 28 
6 
EARLY PATIENT WITHDRAWAL .............................................................................................................. 28 
6.1 
PATIENT EVALUABILITY AND REPLACEMENT .............................................................................................................. 28 
7 
SAMPLES FOR LABORATORY ANALYSIS .................................................................................................. 29 
7.1 
SAMPLES TO BE ANALYSED IN LOCAL TRUST’S LABORATORIES ....................................................................................... 29 
7.2 
SAMPLES TO BE SENT TO AND ANALYSED IN A CENTRAL LABORATORY ............................................................................ 29 
7.3 
SUMMARY OF RESEARCH SAMPLES TO BE TAKEN DURING THE STUDY ............................................................................. 29 
7.4 
PHARMACODYNAMIC ASSAYS ................................................................................................................................ 29 
7.5 
MOLECULAR STUDIES .......................................................................................................................................... 29 
7.6 
LABELLING AND CONFIDENTIALITY OF SAMPLES SENT TO CENTRAL LABORATORIES ............................................................. 29 
7.7 
CLINICAL REPORTING OF RESEARCH ASSAY RESULTS .................................................................................................... 29 
7.8 
TRIAL SAMPLE RETENTION AT END OF STUDY ............................................................................................................. 29 
7.9 
WITHDRAWAL OF CONSENT FOR SAMPLE COLLECTION AND/OR RETENTION .................................................................... 30 
8 
INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS) ................................................................................. 30 
8.1 
DOSING SCHEDULES: DOSE LEVELS AND BKM120 DOSE ESCALATION PLAN ..................................................................... 30 
8.2 
MANAGEMENT OF DRUG ADMINISTRATION .............................................................................................................. 31 
8.3 
SPECIAL PRECAUTIONS ......................................................................................................................................... 32 
8.4 
DOSE MODIFICATION ........................................................................................................................................... 34 
8.5 
COMPLIANCE ..................................................................................................................................................... 34 
8.6 
MANAGEMENT OF OVERDOSE ............................................................................................................................... 34 
8.7 
DOSE ESCALATION REVIEW .................................................................................................................................... 34 
9 
OTHER TREATMENTS ............................................................................................................................. 34 


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9.1 
BACKGROUND SYSTEMIC  THERAPY ......................................................................................................................... 34 
9.2 
SUPPORT MEDICATION ......................................................................................................................................... 34 
9.3 
CONCOMITANT MEDICATION AND NON-DRUG THERAPIES ........................................................................................... 35 
9.4 
PROHIBITED THERAPIES ........................................................................................................................................ 35 
10 
RADIOTHERAPY ..................................................................................................................................... 36 
10.1 
RADIOTHERAPY SIMULATION AND PLANNING ............................................................................................................ 36 
10.2 
RADIOTHERAPY FIELD ARRANGEMENT AND PRESCRIPTION ........................................................................................... 36 
10.3 
RADIOTHERAPY TREATMENT DELIVERY ..................................................................................................................... 36 
10.4 
RADIOTHERAPY DOSE CONSTRAINTS ........................................................................................................................ 36 
11 
DRUG MANAGEMENT ............................................................................................................................ 37 
11.1 
DRUG SUPPLIES .................................................................................................................................................. 37 
11.2 
DRUG ORDERING ................................................................................................................................................ 37 
11.3 
IMP RECEIPT ..................................................................................................................................................... 37 
11.4 
HANDLING AND STORAGE ..................................................................................................................................... 37 
11.5 
LABELLING ......................................................................................................................................................... 37 
11.6 
DOSING DISPENSING ............................................................................................................................................ 37 
11.7 
DRUG ACCOUNTABILITY........................................................................................................................................ 37 
11.8 
DRUG RETURNS FROM PATIENTS ............................................................................................................................ 38 
11.9 
DRUG DESTRUCTION ............................................................................................................................................ 38 
11.10 
OCCUPATIONAL SAFETY ........................................................................................................................................ 38 
12 
EVALUATION OF RESPONSE TO BKM120 ................................................................................................ 38 
12.1 
TUMOUR ASSESSMENT ......................................................................................................................................... 38 
12.2 
TUMOUR RESPONSE ............................................................................................................................................ 39 
12.3 
OTHER DEFINITIONS OF OUTCOME: ........................................................................................................................ 39 
13 
ASSESSMENT OF SAFETY ........................................................................................................................ 39 
13.1 
ADVERSE EVENT DEFINITIONS ............................................................................................................................... 39 
13.2 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS AES AND SAES ...................................... 40 
13.3 
DETERMINING ADVERSE EVENT CAUSALITY ............................................................................................................... 40 
13.4 
EXPECTED ADVERSE EVENTS .................................................................................................................................. 41 
13.5 
SUSPECTED UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS (SUSARS) .................................................................... 41 
13.6 
EXPEDITED REPORTING OF SAES ............................................................................................................................ 41 
13.7 
FOLLOW-UP OF SERIOUS ADVERSE EVENTS .............................................................................................................. 41 
13.8 
REPORTING ADVERSE EVENTS ON THE CRF .............................................................................................................. 42 
13.9 
EVENTS EXEMPT FROM BEING REPORTED AS AE/ SAES............................................................................................... 42 
13.10 
INFORMING INVESTIGATORS OF NEW SAFETY INFORMATION ........................................................................................ 42 
14 
PREGNANCY ........................................................................................................................................... 42 
15 
DEFINING THE END OF TRIAL ................................................................................................................. 43 
16 
STATISTICAL CONSIDERATIONS .............................................................................................................. 43 
16.1 
SAMPLE SIZE DETERMINATION ............................................................................................................................... 43 
16.2 
DEFINITION OF PRIMARY AND SECONDARY ENDPOINTS ............................................................................................... 43 
16.3 
RANDOMISATION ................................................................................................................................................ 44 
17 
STATISTICAL ANALYSIS PLAN ................................................................................................................. 44 
17.1 
INCLUSION IN ANALYSIS ........................................................................................................................................ 44 
17.2 
SUBGROUP ANALYSIS ........................................................................................................................................... 44 
17.3 
INTERIM ANALYSES ............................................................................................................................................. 44 
17.4 
PROCEDURES FOR REPORTING ANY DEVIATION(S) FROM THE ORIGINAL STATISTICAL PLAN .................................................. 44 
17.5 
ANALYSIS OF SAFETY ............................................................................................................................................ 45 
17.6 
FINAL ANALYSIS .................................................................................................................................................. 45 
18 
TRIAL COMMITTEES ............................................................................................................................... 45 
18.1 
TRIAL MANAGEMENT GROUP (TMG) .................................................................................................................... 45 
18.2 
DATA AND SAFETY MONITORING ........................................................................................................................... 45 


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18.3 
TRIAL STEERING COMMITTEE ................................................................................................................................ 45 
19 
DATA MANAGEMENT ............................................................................................................................ 45 
19.1 
DATABASE CONSIDERATIONS ................................................................................................................................. 45 
19.2 
ELECTRONIC CASE REPORTS FORMS (ECRFS) ............................................................................................................ 46 
19.3 
ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS DATA. .......................................................................................... 46 
20 
CLINICAL STUDY REPORT ....................................................................................................................... 46 
21 
STUDY SITE MANAGEMENT ................................................................................................................... 46 
21.1 
STUDY SITE RESPONSIBILITIES ................................................................................................................................ 46 
21.2 
STUDY SITE SET UP AND ACTIVATION ....................................................................................................................... 46 
21.3 
STUDY DOCUMENTATION ..................................................................................................................................... 46 
22 
REGULATORY AND ETHICAL CONSIDERATIONS ...................................................................................... 47 
22.1 
ETHICAL CONDUCT OF THE TRIAL AND ETHICS APPROVAL ............................................................................................. 47 
22.2 
REGULATORY AUTHORITY APPROVAL ...................................................................................................................... 47 
22.3 
NHS RESEARCH GOVERNANCE .............................................................................................................................. 47 
22.4 
PROTOCOL AMENDMENTS .................................................................................................................................... 47 
22.5 
URGENT SAFETY MEASURES .................................................................................................................................. 47 
22.6 
TEMPORARY HALT ............................................................................................................................................... 48 
22.7 
SERIOUS BREACHES ............................................................................................................................................. 48 
22.8 
PROGRESS, END OF STUDY AND OTHER REPORTS........................................................................................................ 48 
23 
EXPENSES AND BENEFITS ....................................................................................................................... 48 
24 
QUALITY ASSURANCE ............................................................................................................................ 48 
24.1 
RISK ASSESSMENT AND SITE MONITORING ................................................................................................................ 48 
24.2 
CENTRAL MONITORING ........................................................................................................................................ 48 
24.3 
AUDIT AND REGULATORY INSPECTION ..................................................................................................................... 49 
25 
RECORDS RETENTION & ARCHIVING ...................................................................................................... 49 
26 
PATIENT CONFIDENTIALITY .................................................................................................................... 49 
27 
STUDY FUNDING .................................................................................................................................... 49 
28 
SPONSORSHIP AND INDEMNITY ............................................................................................................ 49 
28.1 
SPONSORSHIP .................................................................................................................................................... 49 
28.2 
INDEMNITY ........................................................................................................................................................ 49 
28.3 
CONTRACTS/AGREEMENTS ................................................................................................................................... 50 
29 
PUBLICATION POLICY ............................................................................................................................. 50 
30 
REFERENCES ........................................................................................................................................... 50 
APPENDIX 1: ECOG  PERFORMANCE SCALE ............................................................................................................... 51 
APPENDIX 2: LIST OF CYP450 SUBSTRATES TO BE USED WITH CAUTION ................................................................... 52 
APPENDIX 3: LIST OF PROHIBITED QT PROLONGING DRUGS ..................................................................................... 53 
APPENDIX 4: LIST OF QT PROLONGING DRUGS TO BE USED WITH CAUTION ............................................................ 53 
APPENDIX 5: LIST OF PROHIBITED CYP3A INHIBITORS (STRONG AND MODERATE) AND INDUCERS .......................... 54 
APPENDIX 6: PATIENT SELF REPORTED MOOD QUESTIONNAIRES............................................................................. 55 
APPENDIX 7: AMENDMENT HISTORY ........................................................................................................................ 57 
  
 
 


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PROTOCOL SYNOPSIS 
 
Full Title of study: 
A phase I dose escalation study of the PI3K inhibitor BKM120, given concomitantly with 
palliative radiotherapy for the treatment of Non-Small Cell Lung Cancer (NSCLC). 
Short Title: 
Palliative thoracic radiotherapy plus BKM120. 
Trial Acronym: 
BKM120 
Objectives: 
To determine the safety, dose-limiting toxicity (DLT) and maximum tolerated dose 
(MTD) of BKM120 when administered concomitantly with thoracic radiotherapy in 
patients with metastatic NSCLC. 
Scientific rationale: 
The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway controls tumour cell 
proliferation, growth, and survival after DNA damage (4). Activation of this pathway is 
common in NSCLC and many other cancers and can occur through diverse mechanisms 
such as amplification of the epidermal growth factor receptor (EGFR) gene, mutations of 
the Ras oncogene, PI3K mutations and loss of phosphatase and tensin homologue 
deleted in chromosome 10 (PTEN) (4-7).  
 
Pre-clinical experiments with BKM120 (PI3K inhibitor) have shown that in addition to 
inducing tumour cell radiosensitisation in vitro, it has a profound effect on the tumour 
microenvironment and physiology. 
 
Using xenograft models, it has been shown that BKM120 causes a marked reduction in 
tumour hypoxia after seven days of treatment. The doses of drug used in these 
experiments resulted in almost complete reduction of pAKT staining, demonstrating the 
efficacy of these drugs. Furthermore, power Doppler ultrasound scans showed that 
seven days of treatment with BKM120 resulted in a significant increase in tumour 
perfusion. 
 
The tumour vasculature was significantly altered in animals treated with BKM120 at 
doses that altered tumour hypoxia and perfusion. These agents induced ‘vascular 
normalisation’ by causing the vessels to become longer, wider and less tortuous. 
    
Importantly it was shown that all of these changes in the tumour microenvironment 
were associated with marked prolongation in tumour regrowth in the xenografts of 
animals treated with a combination of radiation and drug treatment compared with 
treatment with either modality alone. 
 
Tumours typically have grossly abnormal blood vessels resulting in the tumours 
becoming hypoxic and poorly perfused. Since poor vascular perfusion and tumour 
hypoxia significantly reduce the effectiveness of both chemotherapy and radiotherapy 
respectively, it is possible that treatment with BKM120 may be able to improve the 
outcomes of NSCLC patients treated with chemotherapy and radiotherapy (8). 
 
Clinical rationale: 
BKM120 has previously been used in a single-agent phase I study. It is currently being 
used in clinical trials in combination with both chemotherapies (e.g. paclitaxel and 
carboplatin) and biological therapies (trastuzumab). There are currently no trials 
combining BKM120 with radiotherapy treatment. 
 
Potential risks to participants include the following: 
 
Exposure to an investigational agent with corresponding side effects. In 
addition to the main toxicities associated with this treatment (see table in 
Section 1.4) it is possible that BKM120 may increase the side-effects associated 
with radiotherapy. 
 
Adding BKM120 to radiotherapy may not be as effective as standard 
radiotherapy alone. This risk is very small as there is no laboratory evidence to 
suggest this might happen. 
 
Exposure to ionising radiation from the additional research scans. However, 
this dose is minimal in comparison with the radiotherapy dose. Additionally, 


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the patients in this study have a limited life expectancy due to their advanced 
cancer and are therefore unlikely to be harmed by the long-term effects of 
radiation exposure. These scans are purely for research purposes and clinical 
management is unlikely to be altered as a result of this imaging. 
 
Discomfort and bruising due to the additional research blood tests. 
 
Potential benefits to participants include: 
 
Access to a novel drug which is not available outside of a clinical trial. BKM120 
has shown evidence of clinical activity when used as a single-agent. However, it 
is not clear whether such responses are likely when the drug is used for shorter 
periods, as in this trial.  
 
BKM120 may increase the efficacy of radiotherapy. This may result in improved 
local disease control, with a greater improvement in patient’s symptoms. 
 
Primary Endpoint: 
Analysis of safety and identification of the maximum tolerated dose (MTD), which is 
defined as the highest dose at which no more than 1 of 6 evaluable patients or 0 of 3 
evaluable patients experience a DLT. DLTs will be defined as per NCI CTCAE v 4.0. The 
following will be considered DLT if they occur at any point whilst the patient is on study: 
1) Any ≥ grade 3 non-haematological toxicity (excluding nausea, vomiting or diarrhoea) 
that requires hospital admission or which does not resolve to ≤ grade 2 within 7 
consecutive days of optimal treatment.  
2) Any ≥ grade 3 nausea, vomiting or diarrhoea will be considered DLT only if any of 
them persist for >48 hours despite maximum supportive care. 
3) ≥ Grade 3 pneumonitis 
4) Any ≥ grade 4 haematological toxicity. 
5) Mood deterioration from baseline (BL). DLT will be any grade ≥3 mood change if BL 
score of 2. DLT will be any grade ≥2 mood change if BL score of ≤ 1. 
 
Secondary Endpoints: 
Changes in 18F-Misonidazole uptake as detected by PET-CT scans.  Changes in blood flow 
as detected by perfusion CT. 
Other investigations: 
Determine phosphorylation status of Akt in PBMC at baseline, during BKM120 
treatment and following BKM120 + RT treatment. Measure tumour pAkt and PTEN 
levels and then identify mutation status of RAS, PI3K and EGFR by PCR. 
Study Design: 
Single-centre, open-label, 3+3 cohort, dose escalation phase I study of the use of 
BKM120 in combination with thoracic radiotherapy. 
Patient Numbers: 
2-30 evaluable 
Target Population: 
Patients with incurable NSCLC requiring palliative thoracic radiotherapy. 
Inclusion and exclusion 
criteria 
Inclusion criteria:  
A patient will be eligible for inclusion in this study if all of the following criteria apply.  
1. Evidence of histologically confirmed NSCLC of any stage  
2. Thoracic lesion requiring palliative radiotherapy and which has been identified 
on a scan within eight weeks of starting the trial. 
3. Male or female, age  18 years at the day of consenting to the study. 
4. Life expectancy of at least 16 weeks. 
5. ECOG performance score of 0-2.  
6. Patient is able to swallow and retain oral medication. 
7. The patient is willing to provide written informed consent and is likely to 
comply with the protocol for the duration of the study, and scheduled follow-
up visits and examinations. 
8. Haematological and biochemical indices within the ranges shown below: 
 
Haemoglobin (Hb) ≥ 9.0 g/dL 
 
Absolute neutrophil count ≥ 1.5 x 109/L 
 
Platelet count ≥100 x 109/L 
 
International Normalised Ratio (INR) ≤ 1.5 
 
Potassium, calcium and Magnesium within normal range 
 
ALT and AST not above normal range or ≤3.0 times ULN if liver metastases 


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are present 
 
Total serum bilirubin not above normal range, or ≤1.5 times ULN if liver 
metastases are present or total bilirubin ≤3.0 times ULN if the patient has 
well documented Gilbert’s disease and absence of other contributing 
disease process at the time of diagnosis 
 
Creatinine ≤ 1.5 x ULN 
 
Fasting plasma glucose (FPG) ≤ 120mg/dL [6.7 mmol/L] 
Exclusion criteria:  
 
A patient will not be eligible for the trial if any of the following apply: 
1. Previous chemotherapy or biological therapy within four weeks of starting 
study treatment. 
2. Treatment with any other investigational agent, or participation in another 
interventional clinical trial within 28 days prior to enrolment. 
3. Patient has not recovered to grade 1 or better (except alopecia) from related 
side effects of any prior antineoplastic therapy. 
4. Treatment at the start of study treatment with any drugs known to be 
moderate or strong inhibitors or inducers of isoenzyme CYP3A4, and the 
treatment cannot be discontinued or switched to a different medication prior 
to starting study drug. 
5. Presence of active uncontrolled or symptomatic CNS metastases. Patients with 
asymptomatic CNS metastases may participate in this trial. Any prior local 
treatment for CNS metastases must have been completed treatment  28 days 
prior to enrolment in the trial (including surgery and radiotherapy). 
6. Patient has poorly controlled diabetes mellitus (HbA1c > 8 %) 
7. Previous exposure to PI3K, mTOR, or AKT inhibitor 
8. Patient has a known hypersensitivity to any of the excipients of BKM120 
9. Previous thoracic radiotherapy treatment 
10. Any previous extra-thoracic radiotherapy within 28 days prior to enrolment 
11. Medically documented history of or active major depressive episode, bipolar 
disorder, obsessive-compulsive disorder, schizophrenia, a history of suicidal 
attempt or ideation, or risk of doing harm to others 
12. Patient meets the cut-off score of ≥ 12 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 ideation in the 
PHQ-9 (independent of the total score of the PHQ-9) 
13. Patient has ≥CTCAE grade 3 anxiety 
14. Other psychological, social or medical condition, physical examination finding 
or a laboratory abnormality that the Investigator considers would make the 
patient a poor trial candidate or could interfere with protocol compliance or 
the interpretation of trial results. 
15. Patient has a concurrent malignancy or has had any malignancy (other than 
NSCLC) in the last 3 years prior to start of study treatment (with the exception 
of adequately treated basal or squamous cell carcinoma or cervical carcinoma 
in situ) 
16. Patient has had major surgery within 14 days of starting the study drug. 
17. Patient has any other concurrent severe, and/or uncontrolled medical 
condition that would, in the investigator’s judgement contraindicate patient 
participation in the clinical study (e.g. chronic pancreatitis, chronic active 
hepatitis). 
18. Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of BKM120. 
19. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C 
or HIV. 
20. 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) 
 
Patient is taking a medication that has a known risk of causing QT interval 


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prolongation or inducing Torsades de Pointes, and the treatment cannot 
be discontinued or switched to an alternative medication. 
 
Angina pectoris that requires the use of anti-anginal medication 
 
Ventricular arrhythmias except for benign premature ventricular 
contractions 
 
Any other cardiac arrhythmia not controlled with medication 
 
Supraventricular and nodal arrhythmias requiring a pacemaker or not 
controlled with medication 
 
Conduction abnormality requiring a pacemaker 
 
Valvular disease with documented compromise in cardiac function 
 
Symptomatic pericarditis 
 
History of myocardial infarction within 6 months of entering the trial 
 
History of congestive heart failure( New York Heart Association functional 
classification III-IV) 
 
Documented cardiomyopathy 
21. Pregnant or breast-feeding women, or women of childbearing potential unless 
effective methods of contraception are used. Oral contraception, injected or 
implanted hormonal methods are not allowed as BKM120 potentially decreases 
the effectiveness of hormonal contraceptives. Acceptable methods of 
contraception are either: 
 
True abstinence  
 
Surgical sterilization 
 
Male partner sterilization 
 
Or 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 
Women of child-bearing potential must have a negative serum pregnancy test 
≤ 72 hours prior to initiating treatment. 
Trial dose and 
administration: 
BKM120 will be administered orally to all cohorts. The trial doses are as below 
Cohort  1: 50mg od for a total of two weeks 
Cohort 2: 80mg od for a total of two weeks 
Cohort 3: 100mg od for a total of two weeks 
Expansion cohort: Two weeks of BKM120 at MTD determined by cohorts 1-3. 
Cohort 4: Four weeks of BKM120 at the MTD determined by cohorts 1-3. 
Radiotherapy schedule 
All patients will receive 20Gy in 5 fractions over one week. 
Duration on study: 
Patients in cohorts 1-3 will be on study for 8 weeks. 
Patients in cohort 4 will be on study for 10 weeks 
Study Procedures and 
frequency: 
Evaluations at screening day -28 to day -2 (all cohorts) 
Written informed consent for Screening and for  Main Study,  demography, 
inclusion/exclusion criteria, medical history, diagnosis of cancer, ECOG performance 
status, patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7), ECG, 
concomitant medications, haematology, biochemistry, research blood sample for PBMC 
pAkt level, urinalysis. 
 
Evaluations on day -1 (all cohorts)  
On the day before the first dose of BKM120 is given: 
Physical examination including weight, ECOG performance status, patient self-rating 
mood scales for depression (PHQ-9) and anxiety (GAD-7), evaluation of toxicity, 18F-Miso 
PET-CT and perfusion CT scans. Pregnancy test (if applicable). Patients will be supplied 
with BKM120 to start on day 1. 
 
Evaluations on day 8 and day 14  (cohorts 1-3 and expansion cohort) 
Haematology, biochemistry, research blood sample for PBMC pAkt level, physical 
examination including weight, ECOG performance status, patient self-rating mood scales 
for depression (PHQ-9) and anxiety (GAD-7), evaluation of toxicity, 18F-Miso PET-CT and 
perfusion CT scans, urinalysis (day 14 only). Patients will commence radiotherapy 
treatment on day 8 after the imaging investigations have been completed. Patients will 


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complete both radiotherapy and BKM120 on day 14. 
 
Evaluations from day 8 – 28  (cohort 4 only) 
Patients will undergo evaluations on an approximately weekly basis whilst receiving 
BKM120 (at days 8, 15, 22, 28). Haematology, biochemistry, research blood sample for 
PBMC pAkt level, physical examination including weight, ECOG performance status, 
patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7), evaluation 
of toxicity.  On day 22 patients will also undergo 18F-Miso PET-CT and perfusion CT scans, 
urinalysis. Commence radiotherapy treatment after the imaging investigations have 
been completed. Patients will complete treatment on day 28. 
 
Evaluations on day 28 (cohorts 1-3 and expansion cohort), day 42 (cohort 4 only) 
Two weeks after completion of treatment, patients will undergo: 
Haematology, biochemistry, research blood sample for PBMC pAkt level, physical 
examination including weight, ECOG performance status, patient self-rating mood scales 
for depression (PHQ-9) and anxiety (GAD-7), evaluation of toxicity. 
 
Evaluations on day 56 (cohorts 1-3 and expansion cohort), day 70 (cohort 4 only) 
 
Six weeks after completion of treatment, patients will undergo: 
Haematology, biochemistry, research blood sample for PBMC pAkt level, physical 
examination including weight, ECOG performance status, patient self-rating mood scales 
for depression (PHQ-9) and anxiety (GAD-7), evaluation of toxicity. 
 
The end of study visit will occur six weeks after completion of treatment and will involve 
assessments as described for day 56 (cohorts 1-3 and expansion cohort) or day 70 
(cohort 4) above. 
Patient care post-trial: 
Following the end of study visit, patients will receive standard care. Following discharge 
to standard clinical care, the responsible healthcare team will be asked to report any 
clinically significant late radiotherapy effects to the BKM120 Trial Office. 
Criteria for evaluation: 
 
Efficacy: 
Response to BKM120 treatment will be based upon changes in tumour hypoxia and 
perfusion as detected by 18F-Miso PET-CT scans and perfusion CT scans respectively 
Safety: 
Safety and toxicity will be reported using CTCAE (version 4.0).  
Pharmacokinetic 
assays: 
N/A 
Pharmacodynamic 
assays: 
The levels of phospho-Akt expression in normal tissues may reflect the efficacy of 
BKM120. Changes in phospho-Akt expression will be monitored during the trial using 
PBMCs taken at the timepoints indicated in Sections 5.3 and 5.4. Reductions in phospho-
Akt expression of PBMC’s following BKM120 treatment will be correlated with changes 
observed with the functional imaging investigations.  
Histopathology: 
Histological confirmation of NSCLC  
No. of Study Site(s) 
Single centre: Oxford, UK 
End of study 
Last Patient Last Visit. Patients should be on study for a maximum of 10 weeks. 
Publication policy 
The results of this study will be published in a peer-reviewed scientific journal and 
presented for other academic research purposes as agreed by the Investigators. 
 


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SUMMARY SCHEDULE OF EVENTS 
Cohorts 1-3 plus the expansion cohort - Schedule of Events 
 
 
Day-28 to 
day -2 
Day -1 
Day 1 
Day 8 
Day 14 
Day 28 
Day 56 
Written Informed Consent Screening 
X 
 
 
 
 
 
 
Written Informed Consent Main Study 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Relevant medical history/current medical conditions 
X 
 
 
 
 
 
 
Diagnosis and extent of cancer 
X 
 
 
 
 
 
 
Prior antineoplastic therapy 
X 
 
 
 
 
 
 
18F-Miso PET-CT and Perfusion CT scans 
 
X 
 
X 
 
 
 
Blood samples from 18F-Miso PET-CT 
 
X 
 
X 
 
 
 
Vital signs 
 
X 
 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
Weight 
 
X 
 
X 
X 
X 
X 
Physical examination 
 
X 
 
X 
X 
X 
X 
ECOG performance status 
X 
X 
 
X 
X 
X 
X 
Patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-
7) 
X 
X 
 
X 
X 
X 
X 
ECG 
X 
 
 
 
X 
 
X 
Prior/concomitant medications 
X 
 
 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Haematology 
X 
 
 
X 
X 
X 
X 
Clinical chemistry 
X 
 
 
X 
X 
X 
X 
Lipase 
X 
 
 
 
X 
 
X 
Fasting plasma glucose (FPG)  
X 
 
 
X 
X 
X 
X 
HbA1C 
X 
 
 
 
 
 
 
Liver Function Tests 
X 
 
 
X 
X 
X 
X 
Blood test for pAkt measurement 
X 
 
 
X 
X 
X 
X 
Coagulation (INR) 
X 
 
 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
X 
 
X 
Dispensing of BKM120 
 
X 
 
 
 
 
 
BKM120a 
 
 
Once daily 
 
 
Radiotherapy 
 
 
 
20 Gy in 5 fractions 
 
 
Pregnancy test (if applicable) 
 
X 
If clinically indicated 
 
aBKM120 taken at 50mg,  80mg, 100mg (cohorts 1-3 respectively) or MTD (expansion cohort) once daily continuously on days 1-14 


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Cohort 4 - Schedule of Events 
 
aBKM120 taken at MTD once daily continuously on days 1-28 
 
Day-28 to 
day -2 
Day -1 
Day 1 
Day 8 
Day 15 
Day 22 
Day 28 
Day 42 
Day 70 
Written Informed Consent Screening 
X 
 
 
 
 
 
 
 
 
Written Informed Consent Main Study 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Relevant medical history/current medical 
conditions 
X 
 
 
 
 
 
 
 
 
Diagnosis and extent of cancer 
X 
 
 
 
 
 
 
 
 
Prior antineoplastic therapy 
X 
 
 
 
 
 
 
 
 
18F-Miso PET-CT and Perfusion CT scans 
 
X 
 
 
 
X 
 
 
 
Blood samples from 18F-Miso PET-CT 
 
X 
 
 
 
X 
 
 
 
Vital signs 
 
X 
 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
X 
X 
X 
X 
X 
Physical examination 
 
X 
 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
 
X 
X 
X 
X 
X 
X 
Patient self-rating mood scales for 
depression (PHQ-9) and anxiety (GAD-7) 
X 
X 
 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
X 
 
X 
 
X 
Prior/concomitant medications 
X 
 
 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology 
X 
 
 
X 
X 
X 
X 
X 
X 
Clinical chemistry 
X 
 
 
X 
X 
X 
X 
X 
X 
Lipase 
X 
 
 
 
X 
 
X 
 
X 
Fasting plasma glucose (FPG)  
X 
 
 
X 
X 
X 
X 
X 
X 
HbA1C 
X 
 
 
 
 
 
 
 
 
Liver Function Tests 
X 
 
 
X 
X 
X 
X 
X 
X 
Blood test for pAkt measurement 
X 
 
 
X 
X 
X 
X 
X 
X 
Coagulation (INR) 
X 
 
 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
X 
 
X 
 
X 
Dispensing of BKM120 
 
X 
 
 
 
 
 
 
 
BKM120a 
 
 
Once daily 
 
 
Radiotherapy 
 
 
 
 
 
20 Gy in 5 fractions 
 
 
Pregnancy test (if applicable) 
 
X 
If clinically indicated 


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Study Flow Chart 
 
Schematic Trial Design of Dose Escalation 
 
 


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ABBREVIATIONS 
 
 
 
 
AE 
 
Adverse event 
CNS 
 
Central Nervous System 
 
 
 
 
CRF 
 
Case report form  
 
CT 
 
Computed tomography 
 
 
 
 
 
DL 
 
Dose level 
DLT 
 
Dose limiting toxicity 
eCRF 
 
Electronic case report form 
Gy 
 
Gray 
FPG 
 
Fasting plasma glucose 
FPFV 
 
First patient, first visit 
IEPTOC  
Independent Early Phase Trial Oversight Committee  
 
 
 
 
ITSC 
 
Independent Trial Steering Committee 
IR 
 
Ionising Radiation 
LFT 
 
Liver function test 
LPLV 
 
Last patient, last visit 
MTD  
 
Maximum tolerated dose  
NSCLC   
Non-small cell lung cancer  
 
OD 
 
Once daily 
pAKT 
 
Phosphorlyated AKT 
PBMC 
 
Peripheral Blood Mononuclear Cell 
PET 
 
Positron emission tomography 
PI3K 
 
Phosphatidylinositol 3-kinase 
PTEN 
 
Phosphatase and tensin homologue 
RPTD 
 
Recommended phase two dose 
RT 
 
Radiotherapy 
SAE 
 
Serious adverse event 
SUSAR  
Suspected unexpected serious adverse event 
SUV 
 
Standardised uptake value 
TMG 
 
Trial management group 
ULN 
 
Upper limit of normal 
 
1 
INTRODUCTION 
1.1 
Background  
Lung cancer is the most common malignancy in industrialised countries. In 2008 approximately 41000 people in the 
UK were diagnosed with lung cancer, of which approximately 80% were due to NSCLC. In the same year there were 
over 35000 deaths due to lung cancer, reflecting the poor prognosis associated with the disease. Radiotherapy plays 
an important role in the management of patients with NSCLC. Patients with non-metastatic disease may be treated 
with radical radiotherapy alone (Stage I-II), or with combination radical chemo-radiotherapy treatment (Stage III). 
Patients with metastatic disease (Stage IV) or with disease not amenable to radical radiotherapy treatment, often 
receive palliative thoracic radiotherapy in order to alleviate their symptoms. 
 
The overall prognosis associated with NSCLC remains very poor despite improvements associated with combined 
modality treatment and with technical advances enabling the delivery of more accurate radiotherapy treatment. 
 
Pre-clinical data suggests that BKM120 renders tumour cells more sensitive to ionising radiation and reduces tumour 
hypoxia and increases perfusion. All of these effects may enhance the efficacy of radiotherapy treatment.  
 
This trial will therefore assess whether BKM120 can be safely combined with thoracic radiotherapy treatment and 
whether it alters the tumour microenvironment in a way that is likely to improve radiotherapy. 
 


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1.2 
Overview of BKM120 
 
The investigational agent used in this trial, BKM120 is a potent and highly specific oral, pan class-1 PI3K inhibitor, 
belonging to the 2,6 dimorpholino pyrimidine derivatives, currently being tested in clinical trials. BKM120 does not 
have a marketing authorisation. A summary of BKM120 is given below. More detailed information is provided in the 
BKM120 Investigator’s Brochure. 
 
Pharmacodynamics 
 
BKM120 inhibits wild-type PI3Kα (IC50: 35 nM), with at least 50 fold selectivity toward protein kinases (i.e., a panel of 
cytosolic tyrosine-, cytosolic Serin/Threonin- and receptor tyrosine 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 and Vps34, nor 
does it inhibit (IC50 >10 μM) other receptors and ion channels profiled. 
 
Non-Clinical pharmacokinetics and metabolism 
 
BKM120 showed favourable pharmacokinetic properties in all animal species tested. The absorption of [14C]-BKM120- 
related radioactivity was >84% in the rat. Oral bioavailability was high in rats (73%), was complete in dogs, and was 
moderate in monkeys (42%). The estimated steady state plasma volume of distribution (Vss) was high (3.0-3.5L/kg) in 
all species tested, suggesting a wide tissue distribution. BKM120 was found to cross the blood brain barriers in rats 
with a tissue-to-plasma ratio of approximately 2 (Novartis internal data). BKM120 is moderately bound to plasma 
protein in all species examined (about 80%).  
 
In vitro metabolism studies using human liver microsomes showed that oxidative phase I metabolism of BKM120 was 
predominantly mediated by CYP3A4 (estimated fm>0.9). Formation of a BKM120N-glucoronide conjugate (Phase II 
metabolism) via the UDP glucuronosyltransferase-1 family, polypeptide A4 (UGT1A4) was also observed in human liver 
microsomes supplemented with uridine 5’-diphosph-glucuronic acid (UDPGA). BKM120 and metabolites have a low 
potential for covalent binding to protein.  
 
BKM120 was determined to be a weak reversible inhibitor of CYP3A4 at concentrations reached in patients. BKM120 
did not show time-dependent inhibition of CYP450 enzymes. In GLP toxicology studies, BKM120 exposure in terms of 
AUC0-24 hour and Cmax increased in a dose proportional manner in rat and dog. Results from the rat ADME study 
showed that radioactivity was mainly excreted into the faeces. Renal excretion was minor. There was no noticeable 
drug accumulation in dog or male rats after 13 weeks of daily dosing. There was a slight accumulation in female rat 
(<2 fold).  
 
Non-clinical safety pharmacology and toxicology 
 
Safety pharmacology studies in rats revealed no effects on neuronal (behaviour) or respiratory functions. Cardiac 
safety studies, conducted in vitro and in vivo did not indicate a prominent electrophysiological risk. No relevant 
electrophysiological effect was seen in dogs. The only effect considered relevant was a trend toward an increase in 
systolic and diastolic blood pressure, which was observed in two dog telemetry studies. In rats and dogs, clinical 
pathology and histopathology findings showed quantitative reductions of lymphoid and erythroid counts and 
lymphoid tissue hypoplasia. 
 
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. At higher doses in the 2-week dose-range-finding study in rats, there were 
histopathological findings in both 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 dogs, there was no effect on female sexual organs. 
 
Glucose homeostasis was affected in various species (mice, rats, dogs), as expected from the mode of action of 
BKM120. However, these effects were minimal in both rats and dogs at the doses used in the 4-week studies. 


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Other safety considerations include: 
 
After up to 2 weeks of treatment with up to .5mg/kg/day of BKM120, alterations in the levels of multiple 
brain neurotransmitters were seen in rats. 
 
No evidence for a direct DNA interaction was found in an Ames test and two chromosome aberration tests in 
vitro with BKM120. However, evidence of a genotoxic potential with BKM120 has been seen in vitro and in 
vivo and is likely due to an aneugenic effect. 
 
No phototoxic potential or any effect on wound healing has been identified with BKM120 in pre-clinical 
studies. 
 
In conclusion, pre-clinical data found that the majority of observed effects were related to the pharmacological 
activity of BKM120 as an inhibitor of PI3K, such as a potential influence on glucose homeostasis and the risk of 
increased blood pressure. 
 
Pharmacodynamic biomarkers 
 
The preclinical in vivo studies with xenografted tumours in mice indicate that detectable inhibition of AKT 
phosphorylation, which is an accurate readout of PI3K activity, as well as further suppression of downstream signaling 
(eg phosphorylation of S6) was obtained soon after BKM120 administration.  
 
Clinical pharmacokinetics 
 
Preliminary review of the available pharmacokinetic data showed that BKM120 is rapidly absorbed after oral 
administration with mean peak plasma concentrations (Cmax) obtained 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. At the MTD dose (100 mg daily), mean Cmax and drug exposure within a dosing interval 
(AUC0-24) was ~1600 ng/ml (CV=45%) and ~ 20,000 ng.hr/ml (CV=40%), respectively. 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 Cmax and 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%. 
 
Clinical experience with BKM120 
 
As of September 2012, over 500 patients have been entered into clinical studies with BKM120. Overall the treatment 
has been well tolerated. The most common adverse events associated with BKM120 are anorexia, nausea, 
constipation, diarrhoea, fatigue, rash, hyperglycaemia, asthenia, abdominal pain, vomiting, liver toxicity, anxiety and 
depression. Potential adverse events requiring special precaution are mentioned in Section 8.3. 
 
It has previously been recommended that the recommended phase two dose (RPTD) for single agent BKM120 should 
be 100mg once daily (od) (1). Since it is conceivable that BKM120 may increase the side-effects associated with 
radiotherapy treatment, the initial cohorts of patients will be treated with lower doses of BKM120. The first cohort 
will be treated with 50mg od, escalating to 80mg od and then 100mg od for subsequent cohorts if no safety issues 
emerge.  
 
The first three cohorts of patients will be treated with BKM120 for one week prior to commencing radiotherapy 
treatment. This is based on pre-clinical experiments which showed that one week of BKM120 treatment significantly 
reduced tumour hypoxia and increased tumour perfusion. Since it may take longer in humans to affect the 
microenvironment in this way, an optional cohort of patients will receive 3 weeks of BKM120 prior to radiotherapy 
(cohort 4) if no functional imaging changes are detected in the one week pre-treatment cohorts. 
1.3 
Other research interventions  
 
This trial will use functional imaging investigations to identify changes in tumour physiology caused by BKM120. 18F-
Misonidazole (18F-Miso) PET-CT scans and perfusion CT scans will be used to measure tumour hypoxia and perfusion 
respectively. They will be conducted prior to commencing BKM120 and repeated prior to commencing radiotherapy 
treatment. 


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18F-Miso is a radiotracer that selectively accumulates in hypoxic tissues. 18F-Miso PET-CT scans are therefore able to 
non-invasively image tumour hypoxia and have been shown to be capable of detecting changes in tumour hypoxia due 
to therapeutic drug treatment (2).  
 
Perfusion CT is a technique used to study the vasculature within tumours and other tissues (3). It is non-invasive and 
readily incorporated into existing CT protocols using conventional contrast agents. 
 
If BKM120 increases the efficacy of radiotherapy treatment, it is likely that it will do so largely by reversing tumour 
hypoxia and increasing tumour perfusion. These functional imaging investigations are therefore extremely important 
in determining whether BKM120 causes these changes in tumour physiology and at what doses these changes are 
apparent. 
1.4 
Rationale for the study 
Non-clinical  
 
The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway controls tumour cell proliferation, growth, and survival 
after DNA damage (4). Activation of this pathway is common in NSCLC and many other cancers and can occur through 
diverse mechanisms such as amplification of the epidermal growth factor receptor (EGFR) gene, mutations of the Ras 
oncogene, PI3K mutations and loss of phosphatase and tensin homologue deleted in chromosome 10 (PTEN) (4-7).  
 
Pre-clinical experiments with BKM120 have shown that in addition to inducing tumour cell radiosensitisation in vitro, 
they have a profound effect on the tumour microenvironment and physiology. 
 
Using xenograft models, it has been shown that BKM120 causes a marked reduction in tumour hypoxia after seven 
days of treatment. The doses of drugs used in these experiments resulted in almost complete reduction of pAKT 
staining, demonstrating the efficacy of these drugs. Furthermore, power Doppler ultrasound scans showed that seven 
days of treatment with BKM120 resulted in a significant increase in tumour perfusion. 
 
The tumour vasculature was significantly altered in animals treated with BKM120 at doses that altered tumour 
hypoxia and perfusion. These agents induced ‘vascular normalisation’ by causing the vessels to become longer, wider 
and less tortuous. 
 
Importantly it was shown that all of these changes in the tumour microenvironment were associated with marked 
prolongation in tumour regrowth in the xenografts of animals treated with a combination of radiation and drug 
treatment compared with treatment with either modality alone. 
 
Tumours typically have grossly abnormal blood vessels resulting in the tumours becoming hypoxic and poorly 
perfused. Since poor vascular perfusion and tumour hypoxia significantly reduce the effectiveness of both 
chemotherapy and radiotherapy respectively, it is possible that treatment with BKM120 may be able to improve the 
outcomes of NSCLC patients treated with chemotherapy and radiotherapy (8). 
 
Clinical 
 
BKM120 has previously been used in a single-agent phase I study (summarised in the table below). It is currently being 
used in clinical trials in combination with both chemotherapies (e.g. paclitaxel and carboplatin) and biological 
therapies (trastuzumab). There are currently no trials combining BKM120 with radiotherapy treatment. 
 
Potential risks to participants include the following: 
 
Exposure to an investigational agent with corresponding side effects. In addition to the main toxicities 
associated with this treatment (see table below) it is possible that BKM120 may increase the side-effects 
associated with radiotherapy. 
 
Adding BKM120 to radiotherapy may not be as effective as standard radiotherapy alone. This risk is very 
small as there is no laboratory evidence to suggest this might happen. 
 
Exposure to ionising radiation from the additional research scans. However, this dose is minimal in 
comparison with the radiotherapy dose. Additionally, the patients in this study have a limited life expectancy 
due to their advanced cancer and are therefore unlikely to be harmed by the long-term effects of radiation 


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exposure. These scans are purely for research purposes and clinical management is unlikely to be altered as a 
result of this imaging. 
 
Discomfort and bruising due to the additional research blood tests. 
 
Potential benefits to participants include: 
 
Access to a novel drug which is not available outside of a clinical trial. BKM120 has shown evidence of clinical 
activity when used as a single-agent. However, it is not clear whether such responses are likely when the drug 
is used for shorter periods, as in this trial.  
 
BKM120 may increase the efficacy of radiotherapy. This may result in improved local disease control, with a 
greater improvement in patient’s symptoms. 
 
Table of relevant clinical studies 
 
Trial name/ 
researcher/ 
Pub. Ref. 
Phase 
Disease type 
No. of 
patients 
Main 
Toxicities 
Outcome 
Bendell et al 
(1) 
I 
All advanced 
solid tumours 
35 
Hyperglycaemia, 
upper abdominal 
pain, rash, mood 
alteration, nausea 
MTD of 
BKM120 
established 
(100mg od) 
 
 
2 
TRIAL DESIGN 
 
This study will be a single-centre, open-label, 3+3 cohort, dose escalation phase I study of the use of BKM120 in 
combination with thoracic radiotherapy. Patients with incurable NSCLC requiring palliative thoracic radiotherapy will 
be eligible for entry. Potential patients will be initially screened to determine eligibility for the main study. For the 
main study, the first three cohorts of patients will be treated with escalating doses of BKM120. These patients will be 
treated with BKM120 for a total of fourteen days. One week after commencing BKM120, patients will start palliative 
radiotherapy treatment. Radiotherapy treatment will be delivered as 20Gy in 5 fractions over a one week period. The 
delay for radiotherapy, compared to not participating in the trial, for cohorts 1-3 and the expansion cohort will only be 
a few days and the delay for cohort 4 will be approximately 2 weeks. However since the effects of radiotherapy 
typically take several weeks to show any benefit the delays are unlikely to change the effect of the radiotherapy. 
 
The MTD will be determined as described in Section 8.1. An additional expansion cohort of a further six patients will 
be treated with BKM120 in combination with radiotherapy at whichever cohort (1-3) corresponds to the MTD. 
 
In the event that no changes are detected in tumour hypoxia or perfusion in cohorts 1-3, an optional group of patients 
(cohort 4) will be recruited. These patients will receive BKM120 treatment for a total of 28 days. Three weeks after 
commencing BKM120, this cohort will receive palliative radiotherapy with 20Gy in 5 fractions over a one week period. 
 
The trial will recruit 2-30 evaluable patients presenting with any stage of NSCLC, requiring palliative radiotherapy 
treatment. 
 
Refer to the schedule of events and flow chart for details of the study visits and procedures. 
 
2.1 
Duration of patient participation 
 
Participants in cohorts 1-3 and the expansion cohort will be in the study for approximately 8 weeks, and participants 
in cohort 4, will be in the study for approximately 10 weeks from the start of BKM120 treatment.  
 
2.2 
Post-trial care and follow-up 
 
Following the end of study visit, patients will receive standard care. Following discharge to standard clinical care, the 
responsible healthcare team will be asked to report any clinically significant late radiotherapy effects to the trial office 
for up to 1 year following the end of treatment. 
 


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3 
OBJECTIVES AND ENDPOINTS 
 
Primary Objective 
Endpoints/ Outcome measures 
 To determine the safety, dose-limiting 
toxicity (DLT) and MTD of BKM120 when 
administered concomitantly with thoracic 
radiotherapy  in patients with incurable 
NSCLC 
Analysis of safety and find the MTD of BKM120. 
DLTs will be defined per NCI CTCAE v 4.0. The following will 
be considered DLT if they occur at any point whilst the 
patient is on study:  
1) Any ≥ grade 3 non-haematological toxicity (excluding 
nausea, vomiting or diarrhoea) that requires hospital 
admission or which does not resolve to ≤ grade 2 within 7 
consecutive days of optimal treatment.  
2) Any ≥ grade 3 nausea, vomiting or diarrhoea will be 
considered DLT only if any of them persist for >48 hours 
despite maximum supportive care. 
3) ≥ Grade 3 pneumonitis   
4) Any ≥ grade 4 haematological toxicity. 
5) Mood deterioration from baseline. DLT will be any grade 
≥3 mood change if BL score of 2. DLT will be any grade ≥2 
mood change if BL score of ≤ 1.The maximum tolerated dose 
(MTD) is defined as the highest dose at which no more than 1 
of 6 evaluable patients or 0 of 3 evaluable patients 
experience a DLT (see section 6.1).  
 
 
Secondary Objectives 
Endpoints 
 To investigate whether BKM120 alters 
tumour hypoxia and perfusion 
 Changes in 18F-Misonidazole uptake as detected by PET-
CT scans.  
 Changes in blood flow as detected by perfusion CT. 
 
 
Tertiary/Exploratory Objectives 
Endpoints 
 To evaluate Akt phosphorylation as a 
predictive marker of response to BKM120 
 Determine phosphorylation status of Akt in PBMC at 
baseline, during BKM120 treatment and following 
BKM120 + RT treatment. 
 To investigate potential biomarkers that 
correlate with response to BKM120 
 Measure tumour pAkt and PTEN levels and then identify 
mutation status of RAS, PI3K and EGFR by PCR. 
 
 
4 
PATIENT SELECTION 
All patients will be screened for inclusion and exclusion criteria within 4 weeks prior to the first dose of BKM120. 
Baseline evaluations should be performed within 4 weeks of the first dose of BKM120. See Section 5.2 for a 
description of the baseline evaluations required. Written informed consent must be obtained before any study 
specific procedures are performed. The Investigator will determine patient eligibility based on the following criteria.  
4.1 
Eligibility criteria 
Inclusion criteria:  
A patient will be eligible for inclusion in this study if all of the following criteria apply.  
1. Evidence of histologically confirmed NSCLC of any stage  
2. Thoracic lesion requiring palliative radiotherapy and which has been identified on a scan within eight weeks 
of starting the trial. 
3. Male or female, age  18 years at the day of consenting to the study. 
4. Life expectancy of at least 16 weeks. 
5. ECOG performance score of 0-2.  
6. Patient is able to swallow and retain oral medication. 


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7. The patient is willing to provide written informed consent and is likely to comply with the protocol for the 
duration of the study, and scheduled follow-up visits and examinations. 
8. Haematological and biochemical indices within the ranges shown below: 
 
Lab Test 
Value required 
Haemoglobin (Hb) 
≥ 9.0 g/dL 
Absolute neutrophil count 
≥ 1.5 x 109/L 
Platelet count 
≥100 x 109/L 
International Normalised Ratio (INR) 
≤ 1.5 
Potassium, calcium and Magnesium 
Within normal range 
ALT and AST 
Not above normal range or ≤3.0 times ULN if liver 
metastases are present 
Total serum bilirubin 
Not above normal range, or ≤1.5 times ULN if liver 
metastases are present or total bilirubin ≤3.0 times 
ULN if the chief investigator is satisfied that the 
patient has well documented Gilbert’s disease and 
absence of other contributing disease process at 
the time of diagnosis 
Creatinine  
≤ 1.5 x ULN 
Fasting plasma glucose (FPG)  
≤ 120mg/dL [6.7 mmol/L] 
Exclusion criteria:  
A patient will not be eligible for the trial if any of the following apply: 
 
1. Previous chemotherapy or biological therapy within four weeks of starting study treatment. 
2. Treatment with any other investigational agent, or participation in another interventional clinical trial within 
28 days prior to enrolment. 
3. Patient has not recovered to grade 1 or better (except alopecia) from related side effects of any prior 
antineoplastic therapy. 
4. Treatment at the start of study treatment with any drugs known to be moderate or strong inhibitors or 
inducers of isoenzyme CYP3A4, and the treatment cannot be discontinued or switched to a different 
medication prior to starting study drug. 
5. Presence of active uncontrolled or symptomatic CNS metastases. Patients with asymptomatic CNS 
metastases may participate in this trial. Any prior local treatment for CNS metastases must have been 
completed treatment  28 days prior to enrolment in the trial (including surgery and radiotherapy). 
6. Patient has poorly controlled diabetes mellitus (HbA1c > 8 %) 
7. Previous exposure to PI3K, mTOR, or AKT inhibitor 
8. Patient has a known hypersensitivity to any of the excipients of BKM120 
9. Previous thoracic radiotherapy treatment 
10. Any previous extra-thoracic radiotherapy within 28 days prior to enrolment 
11. Medically documented history of or active major depressive episode, bipolar disorder, obsessive-compulsive 
disorder, schizophrenia, a history of suicidal attempt or ideation, or risk of doing harm to others 
12. Patient meets the cut-off score of ≥ 12 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 ideation in the PHQ-9 (independent of the total score of the PHQ-9) 
13. Patient has ≥CTCAE grade 3 anxiety 
14. Other psychological, social or medical condition, physical examination finding or a laboratory abnormality 
that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol 
compliance or the interpretation of trial results. 
15. Patient has a concurrent malignancy or has had any malignancy (other than NSCLC) in the last 3 years prior to 
start of study treatment (with the exception of adequately treated basal or squamous cell carcinoma or 
cervical carcinoma in situ) 
16. Patient has had major surgery within 14 days of starting the study drug. 
17. Patient has any other concurrent severe, and/or uncontrolled medical condition that would, in the 
investigator’s judgement contraindicate patient participation in the clinical study (e.g. chronic pancreatitis, 
chronic active hepatitis). 
18. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of BKM120. 


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19. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV. 
20. 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) 
 
Patient is taking a medication that has a known risk of causing QT interval prolongation or inducing 
Torsades de Pointes, and the treatment cannot be discontinued or switched to an alternative 
medication. 
 
Angina pectoris that requires the use of anti-anginal medication 
 
Ventricular arrhythmias except for benign premature ventricular contractions 
 
Any other cardiac arrhythmia not controlled with medication 
 
Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication 
 
Conduction abnormality requiring a pacemaker 
 
Valvular disease with documented compromise in cardiac function 
 
Symptomatic pericarditis 
 
History of myocardial infarction within 6 months of entering the trial 
 
History of congestive heart failure( New York Heart Association functional classification III-IV) 
 
Documented cardiomyopathy 
21. Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of 
contraception are used. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, must use highly effective methods of contraception. Oral contraception, injected or 
implanted hormonal methods are not allowed as BKM120 potentially decreases the effectiveness of 
hormonal contraceptives. Acceptable methods of contraception are either: 
 
True abstinence: When this is in line with the preferred and usual lifestyle of the patient. [Periodic 
abstinence (eg calendar, ovulation, sympotothermal, post ovulation methods) and withdrawal are not 
acceptable methods of contraception]. 
 
Surgical sterilization: Have had bilateral oophorectomy (with or without hysterectomy) or tubal ligation 
at least six weeks before taking BKM120. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment. 
 
Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm 
in the ejaculate). [For female study patients, the vasectomised male partner should be the sole partner 
for that patient] 
 
Or 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 
Female patients must use acceptable methods of contraception must continue to use contraception for at 
least 4 weeks after completing BKM120. Male patients (and their female partners) will need to continue to 
use contraception for at least 16 weeks after completing BKM120. 
Women of child-bearing potential must have a negative serum pregnancy test ≤ 72 hours prior to initiating 
treatment 
4.2 
Pre-trial screening and re-screening (day -28 to day -2)  
Patients will be eligible for screening provided that: 
 
They give separate written informed consent for completing the self-rating mood questionnaires. 
 
The Investigator anticipates that there is a reasonable expectation that they will satisfy the remaining 
inclusion criteria see section 4.1 above (NB formal screening for the main study should not be performed 
until the outcome of the mood questionnaires of the patient is known). 
 
To obtain a screening number, complete a Screening Form and fax/email it to the BKM120 Trial Office.  
 
Patients who do not meet the inclusion/exclusion criteria first time round will not be re-screened. 
4.3 
Patient registration procedure 
Potential participants will have been referred to oncology services for management of NSCLC and be considered 
suitable for palliative radiotherapy treatment by their multidisciplinary team. The study team will maintain screening 


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and study enrolment logs for all patients approached concerning the study. The log will include details of patients 
subsequently excluded along with the reason for the exclusion. 
 
Protocol waivers to deviate from the entry criteria will not be granted. 
 
A patient registration/eligibility check-list must be completed and passed to the BKM120 Trial Office. 
 
Before entering a patient onto the study the Principal Investigator or designee will confirm eligibility. If in any doubt 
the Chief Investigator must be consulted before entering the patient. Details of the query and outcome of the decision 
must be documented on the registration/eligibility checklist. 
 
After completing suitability checks, the Informed Consent Form for trial participation and the Registration Form for 
the patient, site staff will email/fax the Registration Form to the BKM120 Trial Office to confirm the patient’s 
eligibility. The patient will then be registered, where applicable, to one of the cohorts. 
Once the investigator / research nurse has a study number for the patient, they will be asked to provide the original 
Registration Form and a copy of the patient’s histology report (which will identify the patient by study number only) to 
the Trials office.  This will allow the Trial Office to confirm the disease stage of patients entering the study. 
 
5 
TRIAL ASSESSMENTS AND PROCEDURES 
 
Please refer to the Schedule of Events given at the front of this protocol. Details of all protocol evaluations and 
investigations must be recorded in the patient’s medical record for extraction onto the CRF. 
5.1 
Informed consent for screening and main study 
 
Informed consent will be a two stage process. Firstly potential participants will be asked to provide consent for 
screening. If the potential patients are successfully screened they will be asked to consent to the main study. 
 
Potential participants will be given a current, approved version of the patient information sheet. They will also receive 
clear verbal information about the study detailing no less than: the nature of the study; the implications and 
constraints of the protocol; the known side effects and any risks involved in taking part.  It will be explained that they 
will be free to withdraw from the study at any time, for any reason, without prejudice to future care, and with no 
obligation to give a reason for withdrawal. 
 
They will have at least 24 hours to consider the information provided and the opportunity to question the 
Investigator, their GP or other independent parties before deciding whether to participate.  The Investigator or 
designee who obtains consent must be suitably qualified and experienced, and be authorised to do so by the 
Chief/Principal Investigator.  The Investigator is responsible for ensuring that the trial consent procedures comply with 
current applicable GCP Regulatory and ethical requirements. Informed consent discussions and outcomes must be 
well documented in the medical record. The Investigator or designee must be satisfied that the patient has made an 
informed decision before taking consent.  The patient and the Investigator or designee must personally sign and date 
the current approved version of the informed consent form in each other’s presence. A copy of the information and 
signed consent form will be given to the participant. The original signed form will be retained at the study site. A copy 
must be held in the Investigator Site File if retaining the original in the medical record. 
 
Contraceptive/ Pregnancy counselling 
All participants must be advised on the need to use reliable methods of contraception during the study. The advice 
should include:  
(1) The acceptable methods, including: male or female sterilization, some intrauterine devices (IUDs), and 
abstinence.  
(2) The recommendation that a barrier method should be used in addition to another form of contraception. 
(3) Males should continue to take these precautions for a minimum of 16 weeks after the last dose of study 
drug. Female partners of men enrolled in the study should continue to use acceptable methods of 
contraception for 16 weeks after the final dose of BKM120. 
(4) Female patients in the study should continue to take these precautions for a minimum of 4 weeks after the 
last dose of study drug. 


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(5) That any pregnancy that occurs during administration of the study drug will be followed up and the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital abnormality) 
will be reported and followed up even if the participant is discontinued from the study.  
 
Evaluations at screening (day -28 to day -2) for all cohorts 
 
 
Written informed consent for Screening. 
 
Patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7). 
5.2 
Pre-dosing evaluations for all cohorts 
The following must be performed/obtained within 4 weeks before the patient receives the first study dose.  
 
Written informed consent for Main Study. 
 
Demographic details. 
 
Medical History including prior diagnosis, prior treatment and concomitant diseases.  
 
Concomitant medications. 
 
ECOG performance status. 
 
Patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7). 
 
Haematology – Hb, white blood cells (WBC) with differential count (neutrophils and lymphocytes), platelets 
and INR. 
 
Biochemistry – sodium, potassium, calcium, magnesium, phosphate, urea, creatinine, albumin, bilirubin, 
alkaline phosphatase (alk phos), AST, ALT, LDH, HbA1c and lipase. 
    Fasting plasma glucose (FPG) ≤ 120mg/dL [6.7 mmol/L]. 
 
Research blood sample for PBMC pAkt level.  
 
Urinalysis (Blood, White Cells, Protein and Nitrites) &/or dipstick for proteinuria. 
 
Electrocardiogram (ECG). 
 
Histological confirmation of NSCLC. 
5.3 
Evaluations during the study for cohorts 1-3 plus the expansion cohort 
 
An illustration of the schedule for patients in cohorts 1-3 is shown below.   Treatment with BKM120 starts on Day 1 
and continues until day 14. Radiotherapy treatment starts on day 8 and continues until day 14. 
 
The MTD will be determined as described in Section 8.1. An additional expansion cohort of a further six patients will 
be treated with BKM120 in combination with radiotherapy at whichever cohort (1-3) corresponds to the MTD. 
 
 
 
 
 
 


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The breakdown of the investigations performed at each visit for patients in cohorts 1-3 are summarised below: 
 
Evaluations on day -1   
 
On the day before the first dose of BKM120 is given: 
 
Physical examination including height and weight.  
 
ECOG performance status. 
 
Patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7). 
 
Vital signs: systolic / diastolic blood pressure (BP), pulse rate. 
 
Evaluation of toxicity (NCI CTCAE v 4.0). 
 
Patients will undergo 18F-Miso PET-CT and perfusion CT scans. 
 
Blood samples from 18F-Miso PET-CT. 
 
Pregnancy test: serum or urine Human Chorionic Gonadotropin (HCG) test to rule out pregnancy at study 
entry; results must be obtained and reviewed before the first dose of BKM120 is administered. 
 
Patients will be supplied with BKM120 and will commence treatment on day 1. 
 
Evaluations on day 8 
 
Haematology – Hb, white blood cells (WBC) with differential count (neutrophils and lymphocytes), platelets 
and INR. 
 
Biochemistry – sodium, potassium, calcium, magnesium, phosphate, urea, creatinine, albumin, bilirubin, 
alkaline phosphatase (alk phos), AST, ALT and LDH. 
 
FPG. 
 
Research blood sample for PBMC pAkt level.  
 
Physical examination including weight.  
 
Concomitant medications. 
 
ECOG performance status. 
 
Patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7). 
 
Vital signs: systolic / diastolic blood pressure (BP), pulse rate. 
 
Evaluation of toxicity (NCI CTCAE v 4.0). 
 
Patients will undergo 18F-Miso PET-CT and perfusion CT scans. 
 
Blood samples from 18F-Miso PET-CT. 
 
Patients will commence radiotherapy treatment after the imaging investigations have been completed. 
 
Evaluations on day 14 
 
Haematology – Hb, white blood cells (WBC) with differential count (neutrophils and lymphocytes), platelets 
and INR. 
 
Biochemistry – sodium, potassium, calcium, magnesium, phosphate, urea, creatinine, albumin, bilirubin, 
alkaline phosphatase (alk phos), AST, ALT, LDH and lipase. 
 
FPG. 
 
Urinalysis (Blood, White Cells, Protein and Nitrites) &/or dipstick for proteinuria. 
 
Electrocardiogram (ECG). 
 
Research blood sample for PBMC pAkt level.  
 
Physical examination including weight.  
 
Concomitant medications. 
 
ECOG performance status. 
 
Patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7). 
 
Vital signs: systolic / diastolic blood pressure (BP), pulse rate. 
 
Evaluation of toxicity (NCI CTCAE v 4.0). 
 
Patients will complete both radiotherapy and BKM120. 
 
Evaluations on day 28 
Two weeks after completion of treatment, patients will undergo: 
 
Haematology – Hb, white blood cells (WBC) with differential count (neutrophils and lymphocytes), platelets 
and INR. 
 
Biochemistry – sodium, potassium, calcium, magnesium, phosphate, urea, creatinine, albumin, bilirubin, 
alkaline phosphatase (alk phos), AST, ALT and LDH. 
 
FPG. 


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 
Research blood sample for PBMC pAkt level.  
 
Physical examination including weight.  
 
Concomitant medications. 
 
ECOG performance status. 
 
Patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7). 
 
Vital signs: systolic / diastolic blood pressure (BP), pulse rate. 
 
Evaluation of toxicity (NCI CTCAE v 4.0). 
 
Evaluations on day 56 
Six weeks after completion of treatment, patients will undergo: 
 
Haematology – Hb, white blood cells (WBC) with differential count (neutrophils and lymphocytes), platelets 
and INR. 
 
Biochemistry – sodium, potassium, calcium, magnesium, phosphate, urea, creatinine, albumin, bilirubin, 
alkaline phosphatase (alk phos), AST, ALT, LDH and lipase. 
 
FPG. 
 
Urinalysis (Blood, White Cells, Protein and Nitrites) &/or dipstick for proteinuria. 
 
Electrocardiogram (ECG). 
 
Research blood sample for PBMC pAkt level.  
 
Physical examination including weight.  
 
Concomitant medications. 
 
ECOG performance status. 
 
Patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7). 
 
Vital signs: systolic / diastolic blood pressure (BP), pulse rate. 
 
Evaluation of toxicity (NCI CTCAE v 4.0). 
 
A dose escalation decision will be made after the last patient in each cohort has completed day 56 evaluation. The 
dose escalation will be based on the prevalence of dose limiting toxicities as defined in Section 8.1.  
5.4 
Evaluations during the study for cohort 4 
 
An illustration of the schedule for patients in cohorts 4 is shown below.   Treatment with BKM120 starts on Day 1 and 
continues until day 28. Radiotherapy treatment starts on day 22 and continues until day 28. 
 
 
 
 
 
 
The breakdown of the investigations performed at each visit for patients in cohort 4 are summarised below: 
 
 
 
 


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Evaluations on day -1   
On the day before the first dose of BKM120 is given 
 
Physical examination including height and weight.  
 
ECOG performance status. 
 
Patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7). 
 
Vital signs: systolic / diastolic blood pressure (BP), pulse rate. 
 
Evaluation of toxicity (NCI CTCAE v 4.0). 
 
Patients will undergo 18F-Miso PET-CT and perfusion CT scans. 
 
Blood samples from 18F-Miso PET-CT. 
 
Pregnancy test: serum or urine Human Chorionic Gonadotropin (HCG) test to rule out pregnancy at study 
entry; results must be obtained and reviewed before the first dose of BKM120 is administered. 
 
Patients will be supplied with BKM120 and will commence treatment on day 1. 
 
Evaluations from day 8 – 28 
Patients will undergo evaluations on an approximately weekly basis whilst receiving BKM120 (at days 8, 15, 22, 28). 
 
Haematology – Hb, white blood cells (WBC) with differential count (neutrophils and lymphocytes), platelets 
and INR. 
 
Biochemistry – sodium, potassium, calcium, magnesium, phosphate, urea, creatinine, albumin, bilirubin, 
alkaline phosphatase (alk phos), AST, ALT and LDH. Lipase (days 15 and 28 only). 
 
FPG. 
 
Urinalysis (Blood, White Cells, Protein and Nitrites) &/or dipstick for proteinuria (days 15 and 28 only). 
 
Electrocardiogram (ECG) (days 15 and 28 only). 
 
Research blood sample for PBMC pAkt level.  
 
Physical examination including weight. 
 
Concomitant medications. 
 
ECOG performance status. 
 
Patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7). 
 
Vital signs: systolic / diastolic blood pressure (BP), pulse rate. 
 
Evaluation of toxicity (NCI CTCAE v 4.0). 
 
Patients will complete treatment on day 37. 
 
On day 22 patients will also: 
 
Undergo 18F-Miso PET-CT and perfusion CT scans. 
 
Blood samples from 18F-Miso PET-CT. 
 
Commence radiotherapy treatment after the imaging investigations have been completed. 
 
Evaluations on day 42 
Two weeks after completion of treatment, patients will undergo: 
 
Haematology – Hb, white blood cells (WBC) with differential count (neutrophils and lymphocytes), platelets 
and INR. 
 
Biochemistry – sodium, potassium, calcium, magnesium, phosphate, urea, creatinine,  albumin, bilirubin, 
alkaline phosphatase (alk phos), AST, ALT and LDH. 
 
FPG. 
 
Research blood sample for PBMC pAkt level.  
 
Physical examination including weight.  
 
Concomitant medications. 
 
ECOG performance status. 
 
Patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7). 
 
Vital signs: systolic / diastolic blood pressure (BP), pulse rate. 
 
Evaluation of toxicity (NCI CTCAE v 4.0). 
 
Evaluations on day 70 
Six weeks after completion of treatment, patients will undergo: 
 
Haematology – Hb, white blood cells (WBC) with differential count (neutrophils and lymphocytes), platelets 
and INR. 
 
Biochemistry – sodium, potassium, calcium, magnesium, phosphate, urea, creatinine, albumin, bilirubin, 
alkaline phosphatase (alk phos), AST, ALT, LDH and lipase. 


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 
FPG. 
 
Urinalysis (Blood, White Cells, Protein and Nitrites) &/or dipstick for proteinuria. 
 
Electrocardiogram (ECG). 
 
Research blood sample for PBMC pAkt level.  
 
Physical examination including weight.  
 
Concomitant medications. 
 
ECOG performance status. 
 
Patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7). 
 
Vital signs: systolic / diastolic blood pressure (BP), pulse rate. 
 
Evaluation of toxicity (NCI CTCAE v 4.0). 
5.5 
End of study evaluations 
The end of study visit will occur six weeks after completion of treatment and will involve assessments as described in 
Sections 5.3 and 5.4. 
5.6 
Evaluations on early withdrawal 
Where possible, patients who withdraw early from the study will be evaluated as described in the ‘End of study 
evaluations’ section above.  
 
6 
EARLY PATIENT WITHDRAWAL 
Treatment Withdrawal 
During the course of the trial, a patient may withdraw early from treatment.  This may happen for a number of 
reasons, including: 
 
Unacceptable toxicity 
AE/SAEs requiring discontinuation 
Clinical decision 
Patient decision 
 
When the patient stops treatment early, the End of Study Form needs to be completed, along with any other relevant 
CRFs (e.g. a SAE Form).  The reason for withdrawing early from treatment should be clearly documented in the 
medical records. 
 
Consent Withdrawal 
Consent withdrawal means that a patient has expressed a wish to withdraw from the study altogether.  Under these 
circumstances, the site needs to document all relevant discussions in the patient notes and notify the Trials Office, 
which will allow the office to mark all future CRFs as not applicable.  
 
Under these conditions, investigators are still responsible to follow up any SAEs till resolution. 
6.1 
Patient evaluability and replacement 
Dose escalation 
The MTD will be based on DLTs observed within 6 weeks of completion of BKM120 treatment. DLTs will be assessed 
whilst the patient is on treatment and for up to 6 weeks after completion of treatment in all patients. Patients 
completing 14 days of BKM120 treatment who either complete the follow up period or withdraw early fromor 
experiencing DLT will be evaluable for dose escalation decisions. Patients who withdraw early for reasons other than 
experiencing DLT (e.g. progression) will be considered non-evaluable for dose escalation and replaced as necessary to 
complete each cohort. Patients replaced for dose escalation earlier than the 14 days will be followed up and 
considered evaluable for toxicity analysis. 
 
Expansion cohort and cohort 4 
Secondary endpoints of changes in 18F-Misonidazole and in blood flow will be based on 18F-Miso PET-CT and perfusion 
CT scans prior to commencing BKM120 treatment and on the day that radiotherapy treatment commences. Patients 
who have data available from both scans will be considered evaluable for secondary endpoints. Patients withdrawn 
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complete each cohort. All patients who receive at least one dose of BKM120 will be followed up and will be 
considered evaluable for toxicity analysis. 
 
7 
SAMPLES FOR LABORATORY ANALYSIS 
7.1 
Samples to be analysed in local Trust’s laboratories 
Diagnostic Laboratories 
Samples for haematology and biochemistry analysis will be labelled with standard patient identifiers and sent to the 
local hospital diagnostic laboratory. Results will be processed in the standard way and entered into the routine 
hospital reporting system. Samples will be stored, held reported and subsequently destroyed in accordance with 
standard local laboratory practice.  
7.2 
Samples to be sent to and analysed in a Central Laboratory 
Research blood samples will be collected, processed and stored by the clinical study site in accordance with written 
instructions that will be provided in a separate sample handling manual. For phospho-Akt expression 20ml blood 
samples will be taken at the timepoints indicated in Sections 5.3 and 5.4. Samples will be retained and dispatched to a 
central laboratory for analysis.  
 
The Chief Investigator or designee will apply for access to archival pathology material from the relevant Pathology 
Department. Any available specimens will be sent to a designated laboratory for central analysis. Separate shipping 
instructions will be provided. 
7.3 
Summary of research samples to be taken during the study 
Assay/sample handling and storage will be managed according to separate written instructions in the Sample Handling 
Manual. Research assays will be performed according to separate laboratory SOPs. 
7.4 
Pharmacodynamic assays  
The levels of phospho-Akt expression in normal tissues may reflect the efficacy of BKM120. Changes in phospho-Akt 
expression will be monitored during the trial using PBMCs taken at the timepoints indicated in Sections 5.3 and 5.4. 
Reductions in phospho-Akt expression of PBMC’s following BKM120 treatment will be correlated with changes 
observed with the functional imaging investigations.  
7.5 
Molecular studies 
Exploratory studies will aim to correlate response to BKM120 with activation of specific molecular pathways present 
in the archived, diagnostic, tumour biopsy sample.  In cases where there is sufficient tumour tissue available, we will 
assess pAkt and PTEN levels and then the mutation status of RAS, PI3K and EGFR by PCR. In cases where there is 
insufficient tissue available to perform these investigations we will prioritise the assessment of pAkt levels. 
7.6 
Labelling and confidentiality of samples sent to central laboratories 
All samples sent to analytical Laboratories will be labelled with the trial code, trial patient number, dosing cohort and 
date taken.  Should a laboratory receive any samples carrying unique patient identifiers the recipient must 
immediately obliterate this information and re-label. The study site will be informed of their error. 
7.7 
Clinical reporting of research assay results 
The results of the molecular assays are exploratory and are not intended to influence the individual patient's medical 
care. Findings will not be reported routinely to the responsible clinician except in the unlikely event that the result 
might be beneficial to the patient's clinical management. 
7.8 
Trial sample retention at end of study 
The Chief Investigator has overall responsibility for custodianship of the trial samples. Laboratories are instructed to 
retain any surplus tumour samples pending instruction from the Chief Investigator on use, storage or destruction.  It is 
possible that new or alternative assays may be of future scientific interest. At the end of the research study any 
surplus tumour samples may be retained for use in other projects that have received ethical approval.  Hence, any 
surplus tumour samples may be transferred to a licensed tissue bank where they will be managed in accordance with 


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applicable host institution policies and the Human Tissue Act (HTA) requirements. Any excess blood samples will be 
destroyed once the study has been completed. 
7.9 
Withdrawal of consent for sample collection and/or retention 
A patient may withdraw consent to take samples for research and/ or to retain and use their samples for research at 
any time without giving a reason. The Investigator must ensure that their wishes are recorded in the medical record 
and will inform the trials office accordingly. No further samples will be taken and any unused samples will be 
destroyed as per host institution policy. 
 
8 
INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS) 
 
Patients will be assigned to the appropriate BKM120 dose level according to the dose escalation scheme given below. 
BKM120 will not be dose escalated above 100mg od, as this dose has previously been established as the RPTD for 
future single agent studies (1). BKM120 will be supplied by Novartis and packaged, labelled and distributed by Fisher 
Clinical Services. 
8.1 
Dosing schedules: dose levels and BKM120 dose escalation plan 
 
In this study, DLT is defined as the presence of the following: 
 
1. Any ≥ grade 3 non-haematological toxicity (excluding nausea, vomiting or diarrhoea) that requires hospital 
admission or which does not resolve to ≤ grade 2 within 7 consecutive days of optimal treatment.  
2. Any ≥ grade 3 nausea, vomiting or diarrhoea will be considered DLT only if any of them persist for >48 hours 
despite maximum supportive care. 
3. ≥ Grade 3 pneumonitis 
4. Any ≥ grade 4 haematological toxicity. 
5. Mood deterioration from baseline DLT will be any grade ≥3 mood change if BL score of 2. DLT will be any 
grade ≥2 mood change if BL score of ≤ 1.  
 
DLT will be considered to occur if the toxicity is attributed either to BKM120 or to its interaction with radiotherapy. 
Cohort 4 will only be opened if there is inadequate evidence that BKM120 alters tumour hypoxia or perfusion (see 
Section 12.1) 
 


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DL 
RT 
BKM120 
BKM120 dose escalation plan 
1 
20Gy in 5 
fractions 
(days 8 - 14) 
50 mg od 
(days 1 to 14) 
Three patients will be entered 
If 0/3 have DLT proceed to DL2  
If 1/3 have DLT expand dose level to a total of 6 patients. 
If none of the additional 3 patients develop DLT, proceed 
to DL2. 
If any further patient(s) develop DLT (≥ 2/6) the MTD is 
exceeded and the trial will be terminated. 
2 
20Gy in 5 
fractions 
(days 8 - 14) 
80 mg od 
(days 1 to 14) 
Three patients will be entered  
If 0/3 have DLT proceed to DL3. 
If 1/3 have DLT expand dose level to a total of 6 patients. 
If none of the additional 3 patients develop DLT, proceed 
to DL3. 
If any further patient(s) develop DLT (≥ 2/6) the MTD will 
be defined as 50mg od. 
3 
20Gy in 5 
fractions 
(days 8 - 14) 
100 mg od 
(days 1 to 14) 
Three patients will be entered 
If 0/3 have DLT then the MTD is 100 mg od. 
If 1/3 have DLT expand dose level to a total of 6 patients. 
 If none of the additional 3 patients develop DLT, the 
RPTD is 100 mg bd. 
If any further patient(s) develop DLT (≥ 2/6) the MTD will 
be defined as 80mg od. 
Expanded 
cohort at 
RPTD 
20Gy in 5 
fractions 
(days 8 - 14) 
MTD dose 
(days 1 to 14) 
Once the MTD has been reached a further 6 patients will 
be treated at the MTD of BKM120 with palliative RT. 
 
4 
20 Gy in 5 
fractions 
(days 22 – 28) 
At MTD 
(days 1 to 28) 
This cohort will only be used if there is no evidence of 
BKM120 induced changes in the tumour 
microenvironment on functional imaging in cohorts 1-3. A 
total of six patients will be entered into this cohort. 
 
8.2 
Management of drug administration 
BKM120 will be supplied as 10mg and 50mg hard gelatin capsules. BKM120 will be administered on a continuous daily 
dosing from the morning of day 1, until the morning of the final RT treatment. A flat scale of mg/day will be used and 
the dose will not be adjusted to body weight or surface area. The dose levels and total number of days of BKM120 
treatment for cohorts 1-3 and for cohort 4 are given in section 8.1. 
The potential CYP3A4 interaction associated with BKM120 means that patients must avoid consumption of Seville 
orange (and juice), grapefruit (and juice), and exotic citrus fruits from 7 days prior to the first dose of study drug and 
during the entire study period. Regular orange juice is allowed. 
The following general guidelines should be followed for BKM120 administration: 
 
Patients should be instructed to take the dose of BKM120 once daily in the morning at approximately the 
same time each day 
 
BKM120 should be taken one hour following a light breakfast 
 
Patients should not eat for 2 hours after the administration of each BKM120 dose 
 
BKM120 should be taken with a glass of water. Patients should swallow the capsules as a whole and not chew 
them 
 
Patients taking medicinal products that may alter the pH of the upper GI tract should follow guidance in 
section 9.3 
If vomiting occurs during the course of treatment, re-dosing is not permitted. Missed doses will not be made up. The 
next dose must be taken as scheduled. 


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8.3 
Special precautions 
 
Non-infectious pneumonitis 
 
Lung changes compatible with pneumonitis have not been observed in the preclinical setting. 
Based on the literature, this class of PI3K inhibitors has not previously been associated with the development of 
pneumonitis.  
 
In ongoing clinical trials with BKM120 in the single agent setting, two cases of pneumonitis have been reported. In 
study BKM120X2101 one patient experienced Pneumonitis grade 2 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 has been reported in one patient after one month of 
treatment with 100 mg of BKM120. The patient experienced pneumonitis grade 5 which was concomitant with 
progression of the underlying malignancy including the progression of existing lesions as well as the appearance of 
new lesions in combination with increasing pleural effusion (please see current IB for more details). The data currently 
available does not enable a clear assessment about the causal relationship of pneumonitis with BKM120 treatment. 
 
Pneumonitis is a common side effect associated with thoracic radiotherapy treatment. The palliative dose of radiation 
used in this study may be associated with grade 1 or 2 pneumonitis but would not be expected to cause more severe 
pneumonitis. The development of grade 3 pneumonitis would be unusual, and will be considered to reflect a dose 
limiting toxicity of BKM120 resulting in the patient discontinuing BKM120 treatment.  
 
Patients will be asked about new respiratory symptoms at each visit. Patients with suspected pneumonitis will be 
investigated as deemed appropriate by the investigator. This may involve chest CT scans and lung function tests as 
well as referral to a respiratory physician. Symptomatic management with steroids and oxygen will be initiated as 
required. 
 
Mood alteration 
 
There is some pre-clinical evidence that modulation of the AKT/GSK3 signalling pathway by neurotransmitters is 
important for the regulation of behaviour. Preclinical studies conducted in rats to investigate the effect of BKM120 of 
different neurotransmitters have shown that repeated administration of BKM120 resulted in an enhanced decrease in 
glutamate, dopamine, serotonin, and epinephrine as well as in an enhanced increase in GABA and HIAA. 
 
As of September 2012, approximately 4% of patients treated with BKM120 at 100mg od developed G3/4 mood 
alteration. In order to lower the risk of BKM120 induced mood alteration, patients with a past or current history of 
significant psychiatric disorders will be excluded from the study. Patients will also have to satisfactorily complete two 
different mood questionnaires (PHQ-9 and GAD-7) in order to be eligible for entry. Patient’s mood will be carefully 
monitored throughout the study using these questionnaires at each visit.  
 
The following grading system will be used for this study:  
 
 
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 
* Note: The grading guidance above may be overruled at the discretion of the Chief Investigator following a 
psychiatric review. 
 
At Screening, a patient as judged by the investigator or a psychiatrist to be ineligible or who meets the cut-off score of 
≥ 12 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 ideation in the PHQ-9 (independent of the total 
score of the PHQ-9) or who otherwise exhibit any suicidal ideation regardless of the question 9 scoring will be 
excluded from the study. 


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During the study, patients who develop mood alteration that constitutes a DLT, or who indicate a positive response by 
selecting ‘1, 2, or 3’ to question number 9 on the PHQ-9 or who otherwise exhibit any suicidal ideation regardless of 
the question 9 scoring must see a psychiatrist for diagnosis and determination of most appropriate medical 
treatment. Patients will then be followed twice weekly by patient self-rating mood scale and will be seen weekly by 
the psychiatrist until the symptoms have resolved to ≤ grade 1 or baseline.  
 
Hyperglycaemia 
 
The PI3K/Akt pathway plays a significant role in regulating glucose metabolism, particularly by regulating glucose 
transport into adipocytes and muscle tissue. Hyperglycaemia is therefore considered an ‘on target’ effect of BKM120. 
Transient increases in plasma glucose levels have been commonly reported in patients taking BKM120. 
 
Patients with poorly controlled diabetes (HbA1c > 8 %) or a fasting plasma glucose (FPG) ≤ 120 mg/dL or ≤ 6.7 mmol/L 
at baseline will be ineligible for trial entry. FPG will be assessed at each subsequent visit. Hyperglycaemia will be 
managed with appropriate diabetic medication in consultation with endocrinology advice. Since in vitro studies have 
shown that BKM120 may inhibit insulin-stimulated glucose uptake, treatment is likely to involve the use of oral anti-
diabetic medication such as metformin which increases muscle and fat glucose uptake. BKM120 will be continued 
unless grade 3 hyperglycaemia develops (FPG > 250 - 500 mg/dL) [> 13.9 - 27.8 mmol/L]) at which point it will be 
discontinued. If grade 3 hyperglycaemia lasts for longer than 7 days despite optimal treatment it will be considered a 
DLT. 
 
Cardiac 
 
Cardiac safety studies, conducted in vitro and in vivo, indicate a minimal risk of an electrophysiological effect of 
BKM120. As of September 2012 adverse cardiac events following BKM120 treatment were rare. Nevertheless, cardiac 
monitoring will be undertaken with an ECG prior to commencing BKM120 and repeated during the trial. Concomitant 
use of any medications known to cause QT prolongation is prohibited (a list of such medications is provided in 
Appendix 3). 
 
Liver 
 
Liver function test (LFT) alterations have been observed in patients taking BKM120. These have mostly involved 
temporary increases in transaminase enzymes (ALT and/or AST). Transaminase elevations typically occur during the 
first 6 to 8 weeks of treatment start. Only a few of the patients with LFT alterations had other simultaneous 
observations like bilirubin increase or clinical symptoms related to impaired hepatic function. A recent safety review 
across Novartis-sponsored trials has identified several potentially drug-induced liver toxicity (DILI) cases in the 
absence of cholestasis and other explanatory causes. This protocol has applied a conservative selection criteria to 
restrict the inclusion of patients with abnormal LFTs. Liver function will be monitored throughout the study and 
BKM120 discontinued if bilirubin >2.0 x ULN or AST/ALT >3.0 x ULN occurs and hepatology advice will be sought and 
appropriate follow-up assessments will be carried out to event resolution or stabilization (for patients with Gilbert 
Syndrome these dose modifications apply to changes in direct bilirubin only).  
 
Follow-up assessments may include (as clinically indicated): 
 
Evaluate if associated with the appearance or worsening of clinical symptoms of hepatitis or hypersensitivity such 
as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia, or other organ 
involvement. 
 
Obtain bilirubin, serum Alkaline Phosphatase (ALP), creatine phosphokinase (CPK), lactate dehydrogenase (LDH), 
and blood count with differential to assess eosinophilia. 
 
Perform liver imaging (ultrasound, MRI, or CT) to evaluate liver disease including metastasis or new lesions, 
obstruction/compression, etc. 
 
Perform viral hepatitis and other serology tests: 
 
Hepatitis C (HCV) serology and viral RNA, Hepatitis B (HBV) serology and viral DNA, Hepatitis A (HAV) 
Immunoglobulin M (IgM) and HAV total 
 
Hepatitis E (HEV) serology: IgM and IgG, viral RNA 
 
Herpes Simplex Virus (HSV), Cytomegalovirus (CMV), Epstein-Barr viral (EBV) serology  
 
Verify and record the use of concomitant medications, acetaminophen, herbal remedies, and other over the 
counter medications, or putative hepatotoxins, on the concomitant medications report form. 


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 
Liver biopsy as clinically indicated to assess pathological change and degree of potential liver injury 
 
LFTs should be followed-up weekly until resolve to ≤ grade 1, baseline or stabilisation (no CTCAE grade change 
over 4 weeks) and outcome documented on the respective AE and lab chemistry pages.  
 
This guidance has been updated since the completion of the escalation phase. During the escalation phase grade 3 
bilirubinaemia or transaminitis events would result in the discontinuation of BKM120 and if the event lasted for longer 
than 7 days qualify as a DLT. 
8.4 
Dose modification  
If a patient is unable to tolerate BKM120 due to side-effects, then BKM120 will be stopped. Scheduled visits and all 
assessments should continue to occur except the dosing of BKM120. The BKM120 dose will not be reduced. For 
replacement of non-evaluable patients see Section 6.1. 
8.5 
Compliance 
Patients will be asked to bring all their unused/remaining supplies of BKM120 to specified clinic visits for checking by 
the research team. 
8.6 
Management of overdose 
There is no specific antidote for BKM120. Patients experiencing toxicities upon miss-dosing or overdosing will be 
treated at the discretion of the investigator with adequate supportive care and followed until recovery. 
8.7 
Dose escalation review 
The Trial Management Group will decide upon dose escalation 6 weeks after the final patient in each cohort has 
completed radiotherapy treatment. All decisions will be documented. Emerging safety data will be reviewed 
throughout the trial and appropriate measures taken to ensure the safety of participants. 
 
9 
OTHER TREATMENTS 
9.1 
Background systemic  therapy  
There will be no background therapy. 
9.2 
Support medication 
The patients recruited to this study will have advanced NSCLC. It is therefore imperative that appropriate palliative 
care treatments are made available to them as per local practice. Additional side-effects associated with either 
BKM120 or radiotherapy treatment will be treated as per local practice.  
BKM120 induced diarrhoea should be considered once other potential causes such as food, comorbidity, or 
concomitant medication have been considered and treated. Patients will be monitored for signs of dehydration and 
instructed to take preventative measures against dehydration. Concomitant medication to treat diarrhoea such as 
loperamide given at a standard dose will be considered for Grade 1-2 diarrhoea along with oral hydration and dietetic 
measures. More severe diarrhoea should be treated appropriately at the investigators discretion and may include IV 
fluid administration. 
Patients will be monitored for skin reactions at each planned visit. Although preclinical experiments with BKM120 
have demonstrated that BKM120 has no potential phototoxic effect, a small number of patients have experienced 
some phototoxicity. Patients will therefore be advised to avoid sun exposure during treatment with BKM120, 
especially when they have already experienced rash or other skin toxicities. Skin rash will be managed at the 
investigators discretion and may include the use of anti-histamines and corticosteroids. 
 
Examples of additional supportive care procedures are outlined below. 
Nausea and vomiting 
Anti-emetic therapy is appropriate to manage treatment related nausea 
and should be given as per local practice. 


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Pneumonitis 
Therapy with steroids and oxygen is appropriate to manage treatment-
related pneumonitis and may be given as per local practice. 
Oesophagitis 
Therapy with antacids, proton pump inhibitors and analgesics is 
appropriate to manage treatment-related oesophagitis and may be 
given as per local practice. 
 
Patients may require IV hydration if they suffer protracted oesophagitis 
resulting in significant dysphagia and odynophagia. 
Rash 
BKM120 induced rash may be managed with anti-histamine and steroid 
treatment as required 
 
9.3 
Concomitant medication and non-drug therapies 
Concomitant therapies may be given as medically indicated. Details (including indication, doses, frequency and start / 
stop dates) of concomitant medication will be documented in the medical record at entry to the trial and at each 
follow-up visit.  
 
BKM120 is characterised by a pH-dependent solubility. Medicinal products that alter the pH of the upper Gastro-
Intestinal (GI) tract may alter the solubility of BKM120 and hence its bioavailability. These agents include, but are not 
limited to, proton-pump inhibitors (e.g. omeprazole), H2 antagonists (e.g. ranitidine) and antacids. BKM120 should be 
dosed in a staggered manner at least 1 hour before or 10 hours after dosing with medicinal products that may alter 
the pH of the upper GI tract. 
 
Prolonged corticosteroid treatment 
 
Prolonged corticosteroid treatment equivalent to dexamethasone 4mg od does not significantly alter the 
pharmacokinetics of BKM120. However, these treatments should be used with caution in order to avoid inducing 
hyperglycaemia. 
9.4 
Prohibited therapies 
Patients must not be prescribed any other anti-cancer or investigational therapies, other than the study treatments, 
whilst participating in this study.  
 
CYP450 metabolised drugs 
BKM120 is a weak, reversible inhibitor of CYP3A4/5, CYP2C8, CYP2C9 and 2C19. With the data available, it is not 
possible to confirm whether such interactions will occur in patients. Therefore, caution will be used in the 
administration of concomitant medications known to be metabolized by CYP3A4/5, CYP2C8, CYP2C9 and CYP2C19. 
Patients receiving such medications must be monitored for potentiation of toxicity due to any individual concomitant 
medications, and may require dose titration or reduction of the drug substrate. A list of CYP3A4 and CYP2C substrates 
to be used with caution is given in Appendix 2. Particularly, caution should be used when BKM120 is co-administered 
with drugs that are sensitive substrates and/or have a narrow therapeutic index. 
 
Patients taking a statin may continue this medication during the trial if it is considered desirable for them to remain on 
an anti-hypercholesterolaemic drug but should be monitored carefully.  
 
QT interval prolonging drugs 
Drugs which may prolong the QT interval and which are prohibited, or which should only be used with caution are 
shown in Appendices 3 and 4 respectively. 
 
Moderate and strong CYP3A inducers and inhibitors 
In vitro metabolism studies suggest that oxidative metabolism of BKM120 is predominantly mediated by CYP3A4, with 
only minor contributions of CYP1A2 and UGT1A4. Coadministration of BKM120 with strong and moderate CYP3A4 


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inhibitors is predicted to increase the systemic exposure to BKM120 by more than 5-fold and more than 2-fold, 
respectively. 
Based on in vitro studies, co-administration of BKM120 with CYP3A4 inducers such as enzyme-inducing anti-epileptic 
medication, is predicted to decrease the systemic exposure to BKM120, thereby increasing the risk of exposing the 
patient to subtherapeutic drug levels.  
 
A list of prohibited drugs is given in Appendix 5. 
 
Herbal Medications 
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), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, ginseng. Patients should stop using these herbal medications 7 days prior to first dose of study drug. 
 
 
Warfarin and coumarin derivatives  
Therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative anticoagulants are not 
permitted. Treatment with heparin, low molecular weight heparin, or fondaparinux is allowed. 
10 RADIOTHERAPY 
 
Patients will be treated with palliative radiotherapy using 20Gy in 5 fractions. This dose and fractionation scheme 
reflects current local practice. 
 
Radiotherapy planning, delivery and treatment verification will be carried out as per local policy. Participation in the 
trial will not involve any additional imaging relating to treatment planning or delivery. 
 
10.1 Radiotherapy simulation and planning 
Patients will be positioned on an immobilisation couch in the supine position and a planning CT scan performed as per 
departmental protocol. Treatment will be planned using 6 to 15 MV photons. The photon energy which results in the 
optimal RT dose distribution within the target volume and which minimises dose to non-target tissues will be selected. 
 
The radiotherapy treatment volume will be planned as per local protocol. The treatment will be planned so that the 
disease considered to be responsible for the patients’ symptoms will be encompassed. An adequate margin (typically 
2cm) will be added to allow for set-up variations and tumour movement. 
10.2 Radiotherapy field arrangement and prescription 
The radiotherapy treatment fields will usually be arranged as a parallel opposed pair. Multileaf collimators will be 
used to shield normal tissue as required.  The maximum field area will not exceed 200cm2. 
 
Radiotherapy doses of 20Gy in 5 fractions will be prescribed for all patients in the study. The radiotherapy will be 
prescribed according to ICRU guidance and local practice. 
10.3 Radiotherapy treatment delivery 
To ensure that the radiotherapy treatment is targeted accurately, verification imaging will be performed in 
accordance with local practice. Radiotherapy quality assurance will be as per local policy. 
10.4 Radiotherapy dose constraints 
The radiotherapy doses used within this study are within the tolerance doses of all critical normal tissues such as the 
lung and spinal cord. Therefore no specific dose constraints will be applied for the purposes of radiotherapy planning. 
 


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11 DRUG MANAGEMENT 
11.1 Drug supplies 
BKM120 will be supplied by Novartis as 10mg and 50mg hard gelatine capsules, packaged as 35 capsules per bottle in 
unlabelled HDPE bottles. The bottles will be appropriately labelled in accordance with all applicable regulatory 
requirements, by Fisher Clinical Services. 
11.2  Drug ordering 
Initial supplies of BKM120 are sent out by Fisher Clinical Services after they have been informed by OCTO that all 
approvals are in place. Subsequent supplies will be ordered by OCTO. Pharmacy should request additional shipments 
by contacting the BKM120 trial office.  
11.3 IMP Receipt 
Study drug must be received by a designated person at the study site, handled and stored safely and properly, and 
kept in a secured location to which only the investigator and designated assistants have access.  
11.4 Handling and storage 
Upon receipt, BKM120 should be stored according to the instructions specified on the drug labels. It will be stored & 
handled in pharmacy in accordance with local procedures. 
11.5 Labelling  
BKM120 will be supplied, appropriately labelled in accordance with all applicable regulatory requirements, by Fisher 
Clinical Services to the study site. 
11.6 Dosing dispensing 
BKM120 will be dispensed as 35 x 10mg and 35 x 50mg hard gelatin capsules in HDPE bottles In accordance with local 
procedures for dispensing IMPs. For all cohorts sufficient drug will be dispensed at day -1 for the duration of the trial. 
See table below: 
 
 
Cohort 
No. 10mg 
Bottles/pt 
No. 50mg 
Bottles/pt 
1 (50mg) 
0 
1 
2 (80mg) 
2 
1 
3 (100mg) 
0 
1 
Expanded dose (50mg) 
0 
1 
Expanded dose (80mg) 
2 
1 
Expanded dose (100mg) 
0 
1 
4 (50mg) 
0 
1 
4 (80mg) 
3 
1 
4 (100mg) 
0 
2 
11.7 Drug accountability 
Full drug accountability records must be maintained for BKM120 using the Drug Dispensing Log provided. The hospital 
may amend the Drug Dispensing Log provided or use their own documentation if it captures all the information 
requested on the Drug Dispensing Log. This must be approved by the trials office prior to use. 
The Drug Dispensing Logs must be available for inspection by the monitor at every monitoring visit. At the conclusion 
of the study the overall numbers of drug shipped to the centre, the number dispensed and the number destroyed or 
returned will be provided by the pharmacy. An account must be given of any discrepancy. 


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11.8 Drug returns from patients 
Patient returns of BKM120 should be returned to pharmacy for counting and recording in the patient’s Dispensing 
Log. Returns may then be destroyed on site according to local practice (verification by monitor not required). 
11.9 Drug destruction 
At the end of the study, once authorised to do so, any unused drug should be disposed of at site according to local 
hospital policy. A dated certificate of disposal should be completed. The original should be placed in the Pharmacy File 
and a copy emailed/faxed to the Trials Unit. Any patient returns should be disposed of at site according to local 
hospital policy  
11.10 Occupational safety 
The product is not expected to pose an occupational safety risk to site staff under normal conditions of use and 
administration. 
 
12 EVALUATION OF RESPONSE TO BKM120 
Imaging investigations will be aimed at identifying changes in tumour physiology following BKM120 treatment rather 
than assessing morphological changes in the tumour following radiotherapy treatment. Patients’ will undergo 18F-Miso 
PET-CT and perfusion CT scans as per departmental protocol. The 18F-Miso PET-CT imaging procedure will involve 
three scans to be performed after injection and then at approximately 2 and 4 hours after injection. During this time, 
up to 4 blood samples will be obtained from a venous cannula. Less than 5ml of blood is generally required for each 
test and it is unlikely that more than 15ml of blood will be required in total. 
12.1 Tumour assessment 
Response to BKM120 treatment will be based upon changes in tumour hypoxia and perfusion as detected by 18F-Miso 
PET-CT scans and perfusion CT scans respectively. These imaging investigations will be performed the day prior to 
commencing BKM120 treatment, and on the day that radiotherapy treatment commences. The imaging investigations 
will be repeated prior to the patient receiving their first fraction of radiotherapy.  
The rationale for this timing is to observe whether BKM120 can reduce tumour hypoxia and increase tumour 
perfusion, since both of these changes would be likely to increase the efficacy of radiotherapy treatment.  
Establishing the appropriate method for analysis of both imaging techniques is part of the research question. Once 
established the same method of assessment and the same technique will be used throughout the trial. Changes in 
tumour-to-blood ratio (TBR) mean and volume will be identified with 18F-Miso PET-CT imaging and changes in tumour 
blood flow, blood volume, and mean transit time assessed with perfusion CT imaging.  
If there is no change in tumour hypoxia or perfusion following one week of BKM120 treatment, patients will be 
recruited to cohort 4 where they will receive three weeks of BKM120 at the MTD prior to commencing radiotherapy. 
Perfusion CT and dynamic 18F-Misonidazole PET-CT scans will be performed as summarised in Sections 5.3 and 5.4. 
Each patient will be classified as a ‘responder’ or ‘non-responder’ on the basis or their pre- and post- BKM120 
imaging. Those patients whose imaging demonstrates the presence of a physiological response on either perfusion CT 
and/or 18F-Misonidazole PET-CT will be classified as a responder whilst those that do not show a response on either 
imaging modality will be classed as a non-responder.  
Patients will only be recruited to cohort 4 if more than 50% of the patients treated with the MTD of BKM120 (n = 9 to 
12 evaluable) are defined as non-responders. The following is considered guidance and the statistical analysis of the 
imaging endpoints will be detailed in the SAP with approval from the DSMC/TSC.  
Perfusion will be assessed on the basis of perfusion CT. Perfusion parameters including blood flow (BF), blood volume 
(BV) and mean transit time (MTT) will be measured using standard commercially supplied software. Patients will be 
classified as ‘responders’ if the BF is increased and/or MTT is reduced from the baseline measurements by more than 
25%. This is in keeping with published data on the use of BF and MTT to predict response to chemoradiotherapy (10). .  
Recent information from research of F-MISO in head and neck cancer patients (11) has reported a mean (SD) tumour 
to muscle (TMR) volume of 3% (14%). Extrapolating from this data and following discussion with the DSMC/TSC, 
patients will be classified as “responders” using the minimum detectable change (MDC) (12) method if their 
differences are ≥ 10% for at least one of the hypoxia parameters TBR mean or TBR volume.  


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12.2 Tumour response 
Imaging investigations performed in this study will aim to identify changes in tumour physiology rather than tumour 
measurements. Tumour responses will therefore not be expected or formally recorded. 
12.3 Other definitions of outcome: 
Toxic death:  
 
Any death to which drug toxicity is thought to have a major contribution. 
Early death:  
 
Death during the first three weeks of treatment that is not a toxic death. 
 
13 ASSESSMENT OF SAFETY 
The Investigator will monitor each patient for clinical and laboratory evidence of adverse events on a routine basis 
throughout the study. Should an Investigator become aware of any study drug related SAEs following this period these 
must also be reported as stated below. Adverse event monitoring starts from the time the patient receives any of the 
research procedures until they complete the trial. All reportable AEs will be followed to a satisfactory conclusion. Any 
reportable AEs that are unresolved at the patient’s last visit in the study are followed up by the Investigator for as long 
as medically indicated, but without further recording in the CRF. 
 
All AEs reported to the trial office will be processed by the trial office according to internal OCTO standard operating 
procedures. The trial office may request additional information for any AE as judged necessary. 
13.1 Adverse Event Definitions 
An Adverse Event or experience (AE) is any untoward medical occurrence in a patient or research study subject 
temporally associated with the administration of an investigational medicinal product (IMP) or a comparator product, 
whether or not considered related to the IMP or a comparator product. An AE can therefore be any unfavourable and 
unintended sign, symptom, disease (new or exacerbated) and /or significant abnormal laboratory or physiological 
observation temporally associated with the use of a medicinal product.  
 
A Serious Adverse Event (SAE) is any AE, regardless of dose, causality or expectedness, that: 
 
 Results in death 
 
 
 Is life-threatening  
This refers to an event in which the subject was at risk of death at the time 
of the event.  It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
 
 Requires in-patient 
hospitalisation  
or prolongs existing inpatient 
hospitalisation  
 
In general, hospitalisation signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency 
ward for observation and/or treatment that would not have been 
appropriate in the physician’s office or out-patient setting.  Complications 
that occur during hospitalisation are AEs.  If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event is serious.  
When in doubt as to whether hospitalisation occurred or was necessary, 
the AE should be considered serious. 
 Results in persistent or 
significant incapacity or 
disability 
This means a substantial disruption of a person’s ability to conduct normal 
life functions.  It does include experiences of relatively minor medical 
significance or accidental trauma (e.g. sprained ankle), which do not 
constitute a substantial disruption. 
 Is a congenital anomaly or 
birth defect 
 
 Is 
any 
other 
medically  
important event 
Defined as an event that may jeopardise the patient or may require 
intervention to prevent one of the outcomes listed above. Any new 
primary cancer must be reported as an SAE. 


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An Adverse Drug Reaction (ADR) is an AE which is considered to be causally related to any dose of the IMP.  This 
means that a causal relationship between the IMP and the AE is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out. 
 
An Unexpected Drug Reaction is an adverse drug reaction, the nature or severity of which, is not consistent with 
applicable product information. 
 
A Suspected Unexpected Serious Adverse Drug Reaction (SUSAR) is a serious adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (e.g. Investigator’s Brochure for an unapproved 
investigational product or SPC for an approved product). 
13.2 Clinical laboratory abnormalities and other abnormal assessments as AEs and SAEs 
Abnormal laboratory findings (e.g., clinical chemistry, haematology, urinalysis) or other abnormal assessments (e.g., 
ECGs, X-rays and scans) that are judged by the investigator as clinically significant will be recorded as AEs or SAEs if 
they meet the definitions given above. By definition, all clinically significant Grade 3 or 4 laboratory abnormalities 
should be reported as SAEs. 
 
Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study 
or are present at baseline and significantly worsen following the start of the study will be reported as AEs or SAEs.  
However, clinically significant abnormal laboratory findings or other abnormal assessments that are associated with 
the disease being studied, unless judged by the investigator as more severe than expected for the patient’s condition, 
or that are present or detected at the start of the study and do not worsen, will not be reported as AEs or SAEs.  
 
The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory 
finding or other abnormal assessment is clinically significant.  
13.3 Determining adverse event causality 
The Investigator will assess and classify the relationship of an AE to the trial IMP as follows: 
 
Classification 
Relationship 
Definition 
 drug-related 
Almost certainly 
 
 Starts within a time related to the study drug administration 
and 
 No obvious alternative medical explanation. 
 
Probably 
 
 Starts within a time related to the study drug administration 
and 
 Cannot be reasonably explained by known characteristics of 
the patient’s clinical state. 
 
 
Possibly 
 
 Starts within a time related to the study drug administration 
and 
 A causal relationship between the study drug and the 
adverse event is at least a reasonable possibility. 
 
not drug related 
Unlikely 
 
 The time association or the patient’s clinical state is such that 
the study drug is not likely to have had an association with 
the observed effect. 
 
Unrelated 
 
 The AE is definitely not associated with the study drug 
administered. 
 
 


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The Investigator must endeavour to obtain sufficient information to confirm the causality of the adverse event (i.e. 
relation to surgery, study drug, background treatment, other illness, progressive malignancy etc) and give their 
opinion of the causal relationship between each AE and study drug.  This may require instituting supplementary 
investigations of significant AEs based on their clinical judgement of the likely causative factors and/or include seeking 
a further specialist opinion. 
13.4 Expected adverse events 
Section 5 of the IB for BKM120 lists all the expected side effects associated with the use of BKM120. A copy of this 
document must be held in the Site File for reference. 
 
Thoracic radiotherapy treatment is often associated with side effects such as fatigue, oesophagitis, pneumonitis, and 
nausea. However with the palliative doses of radiotherapy that will be used in this trial, these side effects are usually 
mild and resolve within a few weeks of completing treatment. If a patient experiences more severe side effects, the 
Investigator will decide whether these have occurred as a result of BKM120 or its interactions with radiotherapy 
treatment, based on the severity of symptoms and other clinical information such as the radiotherapy volumes. 
13.5 Suspected Unexpected Serious Adverse Drug Reactions (SUSARs) 
A Suspected Unexpected Serious Adverse Drug Reaction (SUSAR) is a serious adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (e.g. Investigator’s Brochure for an unapproved 
investigational product or SPC for an approved product). SUSARS therefore are suspected to be at least possibly 
related to the study agent, fulfil the definition of a SAE, the nature and severity of which are not consistent with the 
applicable product information.  In addition, other safety issues qualify for expedited reporting where they might 
materially alter the current risk assessment of an IMP or be sufficient to change IMP administration or the overall 
conduct of the trial. Responsibility for expedited safety reporting to responsible authorities will be done by the trials 
office using their own internal OCTO SOPs. 
13.6 Expedited reporting of SAEs 
The following SAE reporting requirements apply regardless of the Investigator’s assessment of the causality or 
expectedness of the SAE.  All SAEs should be reported on the trial SAE paper report form (see SAE report form and 
completion guidelines).  
 
SAE reports must be sent within 24 hours of site staff becoming aware of the event to either: 
 
PV Email:  
 
octo-safety@oncology.ox.ac.uk 
OCTO Fax: 
 
   01865 617010 
 
- If the SAE has not been reported within the specified timeframe, a reason for lateness must be provided when 
sending the SAE Report Form. 
 
- Investigators should also adhere to their local Trust policy for incident and SAE reporting in research. 
 
-OCTO will be responsible for reporting all SAEs to Novartis within 24 hours of receiving an SAE report. 
13.7 Follow-up of Serious Adverse Events 
If new or amended information on a reported SAE becomes available, the Investigator should report this on a new SAE 
Report Form using the completion guidelines. Extra annotated information and/or copies of test results may be 
provided separately. If using the original form to notify further information, all new or amended information must be 
initialled and dated so that all changes are clearly identified.  
 
Follow up will continue until all the necessary safety data for the event has been gathered. Follow up information 
must be sent to the trials office within one working day of the site becoming aware. Any SAE that is ongoing when a 
subject completes his/her participation in the trial must be followed until any of the following occurs: 
 
The event resolves or stabilizes; 
 
The event returns to baseline condition or value (if a baseline value is available); 
 
The event is attributed to other agent(s) or to factors unrelated to study conduct. 
 


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SAEs that are considered to be definitely unrelated to the trial intervention will not be followed up and monitored. 
SAEs must be reported until 6 weeks after end of treatment.  
13.8 Reporting Adverse Events on the CRF 
All AEs, including Serious AEs (except those described in section 13.9) must be recorded on the case report forms 
(CRF) for that patient. Please note that AEs are recorded on eCRFs within OpenClinica and SAEs are additionally 
recorded on the paper SAE report form and emailed/faxed to OCTO. The information provided will include date of 
onset, event diagnosis (if known) or sign/symptom, severity, time course, duration and outcome and relationship of 
the AE to study drug.  Any concomitant medications or other any therapy used to treat the event must be listed. The 
Investigator will provide an “other” cause for serious AEs considered to be unrelated to the study drug. Sites should 
ensure data entered into the CRF is consistent with the SAE report information where applicable. 
 
Each separate AE episode must be recorded.  For example, if an AE resolves completely or resolves to baseline and 
then recurs or worsens again, this must be recorded as a separate AE. For AEs to be considered intermittent, the 
events must be of similar nature and severity 
 
The NCI CTCAE Version 4.0 must be used to grade each AE, and the worst grade recorded.  
13.9 Events exempt from being reported as AE/ SAEs 
This section specifies adverse events that do not require reporting providing the Investigator is certain that they are as 
expected given the natural course of the disease under study and /or expected outcomes of any background routine 
standard of care.  The event must be reported if the Investigator cannot exclude the possibility that any trial 
intervention (including tests and other procedures) might be causally implicated or if the frequency, severity or 
pattern of events is not as expected for the patient's condition. 
 
Progression of underlying disease 
Disease progression and resultant death will be captured on the eCRF. Adverse events including hospitalisation and/or 
death that are clearly consistent with disease progression will not be reported as individual AE/SAEs. Clinical 
symptoms of progression will only be reported as adverse events if the symptom cannot be determined as exclusively 
due to the progression of the underlying malignancy, or does not fit the expected pattern of progression. 
 
Every effort should be made to document the objective progression of underlying malignancy.  In some cases, the 
determination of clinical progression may be based on symptomatic deterioration. For example, progression may be 
evident from clinical symptoms, but is not supported by tumour measurements. Or, the disease progression is so 
evident that the investigator may elect not to perform further disease assessments.  
Death on study 
The patients enrolled into this study will have incurable NSCLC which is associated with a poor prognosis. It is 
therefore likely that some patients will die as a result of their underlying malignancy whilst enrolled in this study. 
Death due to NSCLC will be recorded on the Death eCRF form providing no causal relationship with BKM120 is 
suspected. The investigator will state whether the death was expected or unexpected. 
13.10 Informing Investigators of new safety information 
The Chief Investigator will ensure that all investigators are kept informed in a timely manner, as new safety profile 
information becomes available. Investigators are responsible for briefing their study team and onward transmission to 
their local ethics committees and/or R&D office as appropriate. 
14 PREGNANCY  
Pregnancies (in a participant or partner) occurring whilst taking BKM120 treatment must be reported. A pregnancy 
notification form should be completed and emailed/faxed to the trial office within the same timelines as an SAE. All 
reported pregnancies should be followed and the outcome reported using the same form.  
 
 Note: Pregnancy is only considered an AE/SAE if there is reason to believe it may be the result of an interaction 
between the study IMP and the contraceptive used. 
 
Women who become pregnant must be withdrawn from BKM120 treatment at the earliest opportunity.  
 


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All reported pregnancies should be followed up until term.  If the outcome of the pregnancy meets any of the criteria 
for seriousness, it must also be reported as an SAE.  Examples of pregnancy outcomes that are SAEs include reports of: 
 
congenital anomalies or developmental delay, in the foetus or the child. 
 
foetal death and spontaneous abortion  
 
suspected adverse reactions in the neonate that are classified as serious 
15 DEFINING THE END OF TRIAL  
For this study the end of the trial is defined as the last visit of the last patient enrolled in the trial i.e. approximately 6 
weeks post completion of BKM120 plus radiotherapy. 
 
The sponsor and the Chief Investigator reserve the right to terminate the study earlier at any time. In terminating the 
study, they must ensure that adequate consideration is given to the protection of the participants’ best interests. 
 
16 STATISTICAL CONSIDERATIONS  
16.1 Sample size determination 
If a MTD is reached, it is anticipated that between 6 and 18 evaluable patients will be required for the dose escalation 
phase of the study. Once the MTD has been reached an expanded cohort of 6 additional patients will be treated at the 
MTD of BKM120 with palliative RT. Furthermore, an optional cohort of 6 patients will receive 3 weeks of BKM120 prior 
to RT, bringing the total patient number for the study from 18 to 30. 
 
Dose escalation phase 
Between 2 and 18 evaluable patients will be recruited to the dose escalation phase. The aim of this Phase I study is to 
define the MTD of BKM120 when used in combination with palliative thoracic radiotherapy. The starting dose will be 
50mg od. Unless DLT occurs this will be escalated to 80mg od and then 100mg od. There will be no further dose 
escalation beyond 100mg od. The study uses a standard 3+3 cohort design. Three patients will be entered at each 
dose level. At minimum, the criteria for dose escalation will be that if, by 6 weeks after the 3rd patient in each cohort 
has completed treatment there is no DLT, then the study will proceed to the next dose level. There will be a 
continuous evaluation of safety data, and dose escalation will be reviewed in response to any emerging safety 
information, with the Chief Investigator reserving the right to prolong the duration between cohorts as appropriate. 
The first cohort of patients will be given the starting dose of 50mg od, consideration will be given to stopping the 
recruitment early whether 2 or 3 DLTs are observed – consequently the minimum number of patients recruited is 2. If 
no DLT is observed, 3 patients will be entered at the next higher dose level. If 1 DLT is observed, an additional 3 
patients will be entered at the same dose level. This process will be repeated until MTD is reached. This is the dose 
level at which no more than 1 of 6 evaluable patients or 0 of 3 evaluable patients experience a DLT. As a result, the 
maximum number of evaluable patients that could be recruited is 18 (6 evaluable patients by 3 dose levels) 
 
Dose expansion cohort 
To investigate the effect of BKM120 on tumour hypoxia and perfusion, an additional expansion cohort of a further six 
patients will be treated with BKM120 in combination with radiotherapy at whichever cohort (1-3) corresponds to the 
MTD.  
 
Dose cohort 4 
Six patients will be recruited to cohort 4 and will receive 3 weeks of BKM120 at MTD dose prior to RT if cohorts 1-3 
have been unable to demonstrate that BKM120 causes changes in tumour hypoxia and perfusion as described in 
Section 12.1. 
 
The study is planned to include a total of 2-30 patients. All patients will be scheduled to receive the same prescribed 
dose of radiotherapy. 
16.2 Definition of primary and secondary endpoints 
 
Dose escalation phase 


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The maximum tolerated dose (MTD) is defined as the highest dose of BKM120 in combination with radiotherapy at 
which no more than 1 of 6 evaluable patients or 0 of 3 evaluable patients experiences a DLT. 
 
Expansion cohort and cohort 4 
Changes in 18F-Misonidazole retention and in blood flow between pre and post BKM120 treatment are defined as 
response to BKM120 treatment based upon changes in tumour hypoxia and perfusion as detected by 18F-Miso PET-CT 
scans and perfusion CT scans respectively. Each patient will be classified as a ‘responder’ or ‘non-responder’ on the 
basis or their pre- and post- BKM120 imaging. Those patients whose imaging demonstrates the presence of a 
physiological response on either perfusion CT and/or 18F-Misonidazole PET-CT will be classified as a responder whilst 
those that do not show a response on either imaging modality will be classed as a non-responder.  
 
16.3 Randomisation 
None planned. 
 
17 STATISTICAL ANALYSIS PLAN 
A detailed statistical analysis plan will be available from the time the first patient is recruited and will be finalised 
before any analysis is undertaken. The analysis plan will be written in accordance with the current OCTRU standard 
operating procedures and will be finalised and agreed by the trial statistician and the CI.  
17.1 Inclusion in analysis 
All patients enrolled in the study, will be accounted for and included in the analyses. Patients who have completed 56 
days on trial or experience a DLT will be included in the dose escalation analysis. The number of patients who were not 
evaluable, who died or withdrew before treatment began will be recorded. The distribution of follow-up time will be 
described and the number of patients lost to follow-up will be given. 
 
Variables will be analysed to determine whether the criteria for the study conduct are met. This will include a 
description of patients who did not meet all the eligibility criteria, an assessment of protocol violations, study drug 
accountability and other data that impact on the general conduct of the study. 
 
Baseline characteristics will be summarised for all patients who commence BKM120. Patients who do not commence 
BKM120 or do not complete the required safety observations will be described separately. 
 
Patients will be evaluable for safety and tolerability analysis from the time of their first treatment with BKM120 using 
NCIC CTCAE v 4.0 scoring and MedDRA coding. Treatment related toxicity will be tabulated by type and grade of 
toxicity. 
 
Adverse events will be summarised by the number of patients experiencing each type of event. The grades and 
causality will be reported. 
 
The functional imaging investigations will be used to assess whether BKM120 induces changes in tumour hypoxia and 
perfusion and to determine whether to open cohort 4. The criteria on which this decision will be based is summarised 
in Section 12.1. 
17.2 Subgroup analysis 
Nil planned. 
17.3 Interim Analyses 
Interim analyses will only be performed if requested by the Independent Early Phase Trial Oversight Committee 
(IEPTOC). 
17.4 Procedures for reporting any deviation(s) from the original statistical plan 
Any deviations from the original statistical plan will be described and justified in the final report. 


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17.5 Analysis of safety 
 
Dose escalation phase 
The variables that define the DLTs and safety variables will be summarized by descriptive statistics with patients 
grouped according to dose level received. Number (with percentages) of patient with and without DLT will also be 
presented according to dose level. 
 
Expansion cohort and cohort 4 
Safety and toxicity variables will be summarized by descriptive statistics to investigate the safety and feasibility of 
expanded cohort patients at MTD dose and cohort 4 patients at MTD dose for 3 weeks of BKM120. 
 
17.6 Final analysis 
 
The duration of the trial will depend upon whether 3 or 6 evaluable patients are required to complete each of cohorts 
1 to 3, and whether there is a requirement to open cohort 4. Final analysis will be performed at least six weeks after 
the last patient in the trial has completed radiotherapy treatment. However, the analysis of escalation phase will be 
done and could be showed before expansion phase and/or cohort 4 analyses. 
 
Expansion cohort and cohort 4 
The variables related to the secondary endpoints of changes in 18F-Misonidazole PET-CT and in blood flow will be 
summarized by descriptive statistics with patients grouped according to MTD cohort, expansion cohort and cohort 4. 
Number (with percentages) of patients ‘responder’ and ‘non-responder’ will also be presented according to the cohort 
of the patient. 
 
18 TRIAL COMMITTEES 
18.1 Trial Management Group (TMG) 
The Chief Investigator will chair a TMG with responsibility for overseeing the successful conduct and publication of the 
trial in accordance with the protocol. The TMG will review safety and dose escalations with advice from the 
Independent Early Phase Trial Oversight Committee (see section 18.2 below). It will provide regular progress reports 
as required by the applicable steering committees and governance bodies. Members of the TMG are: 
 
Chief Investigator 
 
Clinical Trial Coordinator 
 
Trial management / QA 
 
Trial Statistician 
 
External Member 
18.2 Data and Safety Monitoring 
There is no Data and Safety Monitoring Committee. The IEPTOC will be in place to monitor the safety and progress of 
the trial. 
18.3 Trial Steering Committee  
The role of the Trial Steering Committee will be fulfilled by the IEPTOC. 
 
19 DATA MANAGEMENT 
19.1 Database considerations 
Data management will be performed via a web-based, bespoke trial database (OpenClinica). OpenClinica is a 
dedicated and validated clinical trials database designed for electronic data capture. See: http://www.openclinica.org.   
 
The Chief Investigator will act as Data Custodian for the trial. 


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19.2 Electronic case reports forms (eCRFs) 
The Investigator and study site staff will ensure that data collected on each subject is recorded in the CRF as 
accurately and completely as possible. The CRFs will not contain any source data. All appropriate laboratory data, 
summary reports and Investigator observations will be transcribed into the CRFs from the relevant medical record(s). 
Please ensure that  
 
the relevant CRFs are completed and signed off by the Investigator for each study patient  
 
all CRF data are verifiable in the source documentation or the discrepancies must be explained.  
 
CRF sections are completed in a timely fashion, as close to the visit or event being recorded as possible. 
 
Data queries are resolved and documented by authorised study staff, giving a reason for the change or 
correction where appropriate. 
 
The above considerations also apply to patients who are withdrawn early. If a patient withdraws from the study, the 
reason must be noted on the appropriate form and the patient must be followed-up as per protocol.  
19.3 Accounting for missing, unused, or spurious data. 
Missing data will be chased up and supplemented where possible after consultation with the investigator. The control 
of the correctness of the data is performed with ranking tests, validity tests and consistency checks. Unused data will 
be retained as for used data. 
20 CLINICAL STUDY REPORT  
All clinical data will be presented at the end of the study as data listings. These will be checked to confirm the lists 
accurately represents the data collected during the course of the study.  The trial data will then be locked and a final 
data listing produced. The clinical study report will be based on the final data listings. The locked trial data may then 
be used for analysis and publication.  
21 STUDY SITE MANAGEMENT 
21.1 Study site responsibilities 
The Principal Investigator (the PI or lead clinician for the study site) has overall responsibility for conduct of the study, 
but may delegate responsibility where appropriate to suitably experienced and trained members of the study site 
team.  All members of the study site team must complete the delegation log provided prior to undertaking any study 
duties.  The PI must counter sign and date each entry in a timely manner. Study team members must provide a 
current CV giving evidence of valid and up to date GCP training for inclusion in the study file. Copies of the delegation 
log and CVs will be provided to the trial office on request. Sites must report any unintended deviations/violations to 
OCTO according to the procedure outlined during site initiation training. 
For further information on trial responsibilities, please refer to the ICH GCP guideline (E6).  Copies can be obtained 
from www.ich.org 
21.2 Study site set up and activation 
A Principal Investigator should lead the study at the site, providing the local study office with all core documentation 
and attend ‘Site Training Call’ organised by the trial office before the site becomes activated (usually carried out as a 
telephone conference call or personal visit).  The trial office will call to check that the site has all the required study 
information/documentation and is ready to recruit.  The site will then be notified once they are activated on the 
BKM120 database and able to register. 
21.3 Study documentation 
The trial office will provide an Investigator File and Pharmacy File (where applicable) to each investigational site 
containing the documents needed to initiate and conduct the study.  The trial office must review and approve any 
local changes made to any study documentation including patient information and consent forms prior to use. 
Additional documentation generated during the course of the trial, including relevant communications must be 
retained in the site files as necessary to reconstruct the conduct of the trial. 


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22 REGULATORY AND ETHICAL CONSIDERATIONS 
The Sponsor and Investigators will ensure that this protocol will be conducted in compliance with the UK Clinical Trials 
Regulations1, the principles of GCP and the applicable policies of the sponsoring organisation. Together, these 
implement the ethical principles of the Declaration of Helsinki (1996) and the regulatory requirements for clinical 
trials of an investigational medicinal product under the European Union Clinical Trials Directive. 
22.1 Ethical conduct of the trial and ethics approval 
The protocol, patient information sheet, consent form and any other information that will be presented to potential 
trial patients (e.g. advertisements or information that supports or supplements the informed consent) will be 
reviewed and approved by an appropriately constituted, independent Research Ethics Committee (REC).  
22.2 Regulatory Authority approval 
This study will be conducted under a CTA granted by the MHRA.  
22.3 NHS Research Governance 
Investigators are responsible for ensuring they obtain local Trust management agreement to conduct the trial in 
accordance with local arrangements and policies. 
22.4 Protocol amendments 
Amendments are changes made to the research following initial approval. A ‘substantial amendment’ is an 
amendment to the terms of the Responsible Authority application (if applicable), the REC application, or to the 
protocol or any other supporting documentation, that is likely to affect to a significant degree: 
 
the safety or physical or mental integrity of the subjects of the trial; 
 
the scientific value of the trial; 
 
the conduct or management of the trial; or 
 
the quality or safety of the investigational medicinal product(s) used in the trial.  
Non-substantial amendments are those where the change(s) involve only minor logistical or administrative aspects of 
the study. 
 
All amendments will be generated and managed according to the trial office standard operating procedures to ensure 
compliance with applicable regulation and other requirements. Written confirmation of all applicable REC, regulatory 
and local approvals must be in place prior to implementation by Investigators. The only exceptions are for changes 
necessary to eliminate an immediate hazard to study patients (see below). 
 
It is the Investigator’s responsibility to update patients (or their authorised representatives, if applicable) whenever 
new information (in nature or severity) becomes available that might affect the patient’s willingness to continue in the 
trial.  The Investigator must ensure this is documented in the patient’s medical notes and the patient is re-consented if 
appropriate. 
22.5 Urgent safety measures 
The sponsor or Investigator may take appropriate urgent safety measures to protect trial participants from any 
immediate hazard to their health or safety. Urgent safety measures may be taken without prior authorisation. The 
trial may continue with the urgent safety measures in place. The Investigator must inform the trial office 
IMMEDIATELY if the study site initiates an urgent safety measure: 
 
Contact the BKM120 Trial Office on tel: 01865 617083 or fax: 01865 617010  
or email: octo-BKM120@oncology.ox.ac.uk 
 
The notification must include: 
 
Date of the urgent safety measure; 
 
Who took the decision; and 
 
Why the action was taken. 
 
                                                                
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 


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The Investigator will provide any other information that may be required to enable the trial office to report and 
manage the urgent safety measure in accordance with the current regulatory and ethical requirements for expedited 
reporting and close out. 
22.6 Temporary halt 
The sponsor and Investigators reserve the right to place recruitment to this protocol on hold for short periods for 
administrative reasons or to declare a temporary halt. A temporary halt is defined as a formal decision to: 
 
interrupt the treatment of subjects already in the trial for safety reasons; 
 
stop recruitment on safety grounds; or 
 
stop recruitment for any other reason(s) considered to meet the substantial amendment criteria, including 
possible impact on the feasibility of completing the trial in a timely manner. 
 
The trial office will report the temporary halt via an expedited substantial amendment procedure. The trial may not 
restart after a temporary halt until a further substantial amendment to re-open is in place.  If it is decided not to 
restart the trial this will be reported as an early termination. 
22.7 Serious Breaches 
The Medicines for Human Use (Clinical Trials) Regulations require the Sponsor to notify any "serious breaches" to the 
MHRA within 7 days of the sponsor becoming aware of the breach. A serious breach is defined as “A breach of GCP or 
the trial protocol which is likely to effect to a significant degree:  
 
the safety or physical or mental integrity of the subjects of the trial; or 
 
the scientific value of the trial 
 
Investigators must notify the trials office at once if any serious breach of GCP is suspected.   
22.8 Progress, end of study and other reports 
This protocol will comply with all current applicable Regulatory Authority, Research Ethics Committee and Sponsor 
requirements for the provision of periodic study safety and progress reports. Any additional reports will be provided 
on request. Reporting will be managed by the trials office according to internal Standard Operating Procedures. 
 
Trial reports will be copied to all Principal Investigators as appropriate. Study sites are responsible for forwarding 
these reports to their local Trust as required. 
23 EXPENSES AND BENEFITS 
Reasonable travel expenses for any visits additional to normal care will be reimbursed on production of receipts or a 
mileage allowance provided as appropriate. 
24 QUALITY ASSURANCE 
24.1 Risk assessment and site monitoring 
A risk assessment based monitoring plan will be prepared before the study opens. The risk assessment will be 
repeated if necessary in the light of changes while the study is ongoing or in response to monitoring reports.  The 
Monitoring plan will be amended as appropriate. 
 
Regular monitoring will be performed according to the plan. Data will be evaluated for compliance with the protocol 
and accuracy in relation to source documents. Monitoring visits reports will be sent to the site in a timely fashion. 
24.2 Central monitoring 
The site will be monitored centrally by checking incoming forms for compliance with the protocol, data consistency, 
missing data and timing or the database which validates data against set criteria and ranges. All changes to data that 
could influence the outcome will be queried with and approved by the study site in a timely manner. For all other 
data, where there is no doubt about the source of any errors, clear changes to data will be made internally by OCTO 
staff without referring back to the study site. Study staff will be in regular contact with site personnel (by 
phone/fax/email/letter) to check on progress and deal with any queries that they may have including those arising 
from queries raised by the trials office. 


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24.3 Audit and Regulatory Inspection 
All aspects of the study conduct may be subject to internal or external quality assurance audit to ensure compliance 
with the protocol, GCP requirements and other applicable regulation or standards. It may also be subject to a 
regulatory inspection. Such audits or inspections may occur at any time during or after the completion of the study. 
Investigators and their host Institution(s) should understand that it is necessary to allow auditors/inspectors direct 
access to all relevant documents, study facilities and to allocate their time and the time of their staff to facilitate the 
audit or inspection visit. Anyone receiving notification of a Regulatory Inspection that will (or is likely to) involve this 
trial must inform the trial office without delay. 
25 RECORDS RETENTION & ARCHIVING 
During the clinical trial and after trial closure the Investigator must maintain adequate and accurate records to enable 
the conduct of a clinical trial and the quality of the research data to be evaluated and verified.  All  essential 
documents (as detailed in OCTO’s SOP)  must be stored in such a way that ensures that they are readily available, 
upon request for the minimum period required by national legislation or for longer if needed.  The medical files of trial 
subjects shall be retained in accordance with national legislation and in accordance with the host institution policy. 
 
Retention and storage of laboratory records for clinical trial samples must also follow these guidelines. 
Retention and storage of central laboratory records supporting PK or PD endpoints and the disposition of samples 
donated via the trial must also comply with applicable legislation and Sponsor requirements. 
 
It is the University of Oxford’s policy to store data for a minimum of 5 years. Investigators may not archive or destroy 
study essential documents or samples without written instruction from the trial office. 
 
26 PATIENT CONFIDENTIALITY 
The personal data recorded on all documents will be regarded as confidential, and to preserve each patient’s 
anonymity, only their initials and date of birth will be recorded on the CRFs.  
 
Medical source data or Scans acquired and exported for research purposes will be linked anonymised as per 
Departmental Protocol so that the patient cannot be identified from them. 
 
The Investigator site must maintain the patient’s anonymity in all communications and reports related to the research. 
The Investigator site team must keep a separate log of enrolled patients’ personal identification details as necessary 
to enable them to be tracked. These documents must be retained securely, in strict confidence. They form part of the 
Investigator Site File and are not to be released externally. 
27 STUDY FUNDING 
This study is funded by the Oxford Cancer Imaging Centre, Cancer Research UK and the Experimental Cancer Medicine 
Centre network. Novartis are providing BKM120 and providing funding for packaging and distribution. 
28 SPONSORSHIP AND INDEMNITY 
28.1 Sponsorship 
The Sponsor will provide written confirmation of Sponsorship and authorise the trial commencement once satisfied 
that all arrangements and approvals for the proper conduct of the trial are in place. A separate study delegation 
agreement, setting out the responsibilities of the Chief Investigator and Sponsor will be put in place between the 
parties. 
28.2 Indemnity 
Compensation for Harm 
Arrangements for NEGLIGENT harm 
Indemnity and/or compensation for negligent harm arising specifically from accidental injury for which the University 
is legally liable as the Research Sponsor will be covered by the University of Oxford.  The NHS will owe a duty of care 
to those undergoing clinical treatment, with Trust Indemnity available through the NHS Litigation Authority Scheme. 
 


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Arrangements for NON-NEGLIGENT harm 
Indemnity and/or compensation for harm arising specifically from an accidental injury and occurring as a consequence 
of the research subjects’ participation in the trial for which the University is the research Sponsor may be covered by 
the University of Oxford. 
28.3 Contracts/Agreements 
This trial is subject to the Sponsors policy requiring that written contracts/agreements are agreed formally by the 
participating bodies as appropriate. A Clinical Trial Agreement (CTA) will be placed between the Sponsor and 
participating NHS Trust(s) prior to site activation.   
The Sponsor will also set up written agreements with any other external third parties involved in the conduct of the 
trial as appropriate.  
 
29 PUBLICATION POLICY 
 
The Chief and Co-Investigators (the investigators) will retain ownership of all data arising from this trial. The intention 
is to publish this research in a specialist peer reviewed scientific journal on completion of the study. The results may 
also be presented at scientific meetings and/or used for a thesis.  The Investigators will be involved in reviewing drafts 
of the manuscripts, abstracts, press releases and any other publications arising from the trial and retain final editorial 
control. 
 
Authors will acknowledge that the study was sponsored by and performed with the support of the Sponsor, and with 
funding support from Cancer Research UK, the Oxford Cancer Imaging Centre and the Oxford ECMC. Novartis has a 
right to review each publication and presentation (including, but not limited to, full papers, abstracts, poster 
presentations and oral presentations), prior to submission. Also, trial reports, entries on clinical trial databases, 
publications including abstracts and presentations shall acknowledge Novartis’ support. 
 
30 REFERENCES 
 
1. 
Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, et al. Phase I, Dose-Escalation Study of BKM120, 
an Oral Pan-Class I PI3K Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol. 2011. 
 
2. 
Hugonnet F, Fournier L, Medioni J, Smadja C, Hindie E, Huchet V, et al. Metastatic renal cell carcinoma: 
relationship between initial metastasis hypoxia, change after 1 month's sunitinib, and therapeutic response: an 18F-
fluoromisonidazole PET/CT study. J Nucl Med. 2011;52:1048-55. 
 
3. 
Fraioli F, Anzidei M, Zaccagna F, Mennini ML, Serra G, Gori B, et al. Whole-tumor perfusion CT in patients 
with advanced lung adenocarcinoma treated with conventional and antiangiogenetic chemotherapy: initial 
experience. Radiology. 2011;259:574-82. 
 
4. 
Maity A, Bernhard EJ. Modulating tumor vasculature through signaling inhibition to improve cytotoxic 
therapy. Cancer research. 2010;70:2141-5. 
 
5. 
Begg AC, Stewart FA, Vens C. Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer. 
2011;11:239-53. 
 
6. 
McKenna WG, Muschel RJ, Gupta AK, Hahn SM, Bernhard EJ. The RAS signal transduction pathway and its 
role in radiation sensitivity. Oncogene. 2003;22:5866-75. 
 
7. 
Gupta AK, Soto DE, Feldman MD, Goldsmith JD, Mick R, Hahn SM, et al. Signaling pathways in NSCLC as a 
predictor of outcome and response to therapy. Lung. 2004;182:151-62. 
 
8. 
Vaupel P. Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat 
Oncol. 2004;14:198-206. 
 
9. 
Ray GM. Antiretroviral and statin drug-drug interactions. Cardiol Rev. 2009;17:44-7. 


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10. 
Sahani DV, Kalva SP, Hamberg LM, Hahn PF, Willett CG, Saini S, et al. Assessing tumor perfusion and 
treatment response in rectal cancer with multisection CT: initial observations. Radiology. 2005;234:785-92. 
 
 
11. 
Okamoto S, Shiga T, Yasuda K, Ito YM, Magota K, Kasai K, Kuge Y, Shirato H, Tamaki N. High Reproductibility 
of Tumour Hypoxia Evaluated by 18F-Fluoromisonidazole PET for Head and Neck Cancer. J Nucl Med. 2013; 54:201-
207 
 
12. 
Copay AG, Subach BR, Glassman SD, Polly DW Jr, Schuler TC. Understanding the minimum clinically important 
difference: a review of concepts and methods. The Spine Journal. 2007;7: 541-546. 
 
 
APPENDIX 1: ECOG  PERFORMANCE SCALE 
 
Activity Performance Description 
Score 
 
 
Fully active, able to carry out all on all pre-disease performance without restriction. 
0 
 
 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g. light housework, office work. 
1 
 
 
Ambulatory and capable of all self-care, but unable to carry out any work activities.  Up and about 
more than 50% of waking hours.  
2 
 
 
Capable of only limited self-care.  Confined to bed or chair more than 50% of waking hours.  
3 
 
 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair. 
 
4 
 
 
 


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APPENDIX 2: LIST OF CYP450 SUBSTRATES TO BE USED WITH CAUTION 
 
CYP2C8 
 
CYP2C9 
 
CYP2C19 
 
CYP3A4,5,7** 
 
amodiaquine 
 
celecoxib 
 
amitriptyline 
 
adinazolam 
 
fentanyl2 
 
cerivastatin 
 
diclofenac 
 
citalopram 
 
alfentanil1,2 
 
flunitrazepam 
 
repaglinide 
 
flurbiprofen 
 
clobazam 
 
alphadihydroergocr
yptine1 
 
fluticasone1 
 
R-ibuprofen 
 
fluvastatin 
 
clomipramine 
 
alprazolam 
 
lovastatin1 
 
rosiglitazone 
 
glibenclamide 
(glyburide) 
 
clopidogrel 
 
amlodipine 
 
maraviroc1 
 
 
gliclazide 
 
diazepam 
 
aripiprazole 
 
midazolam1 
 
 
glimepiride 
 
fluoxetine 
 
atorvastatin 
 
nifedipine 
 
 
glipizide 
 
imipramine 
 
brotizolam1 
 
nisoldipine 
 
 
indomethacin 
 
lansoprazole 
 
budesonide1 
 
nitrendipine 
 
 
irbesartan 
 
moclobemide 
 
buspirone1 
 
perospirone1 
 
 
ketobemidone 
 
omeprazole 
 
cerivastatin 
 
quinine 
 
 
lornoxicam 
 
pantoprazole 
 
chlorpheniramine 
 
sildenafil1 
 
 
losartan 
 
progesterone 
 
cyclosporine2 
 
simvastatin1 
 
 
meloxicam 
 
propranolol 
 
darifenacin1 
 
sirolimus1,2 
 
 
naproxen 
 
quazepam 
 
diazepam 
 
tipranavir1 
 
 
nateglinide 
 
rabeprazole 
 
diergotamine2 
 
trazodone 
 
 
piroxicam 
 
sertraline 
 
ebastine1 
 
triazolam1 
 
 
S-ibuprofen 
 
S-mephenytoin 
 
eletriptan1 
 
 
 
sulfamethoxazole 
 
 
eplerenone1 
 
 
 
tenoxicam 
 
 
ergotamine2 
 
 
 
tolbutamide 
 
 
estazolam 
 
 
 
torasemide 
 
 
everolimus1 
 
 
 
valdecoxib 
 
 
felodipine1 
 
 
 
 
 


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APPENDIX 3: LIST OF PROHIBITED QT PROLONGING DRUGS 
 
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 
 
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. 
 
APPENDIX 4: LIST OF QT PROLONGING DRUGS TO BE USED WITH CAUTION 
 
1. Drug 
2. 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 


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1. Drug 
2. QT risk (*) 
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 
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 
 
APPENDIX 5: LIST OF PROHIBITED CYP3A INHIBITORS (STRONG AND MODERATE) AND INDUCERS 
 
Strong CYP3A4,5,7 inhibitors 
 
Moderate CYP3A4,5,7 inhibitors 
 
CYP3A4 inducers 
 
clarithromycin 
 
aprepitant 
 
barbiturates 
 
conivaptan 
 
atazanavir 
 
carbamazepine 
 
grapefruit juice 
 
cimetidine 
 
efavirenz 
 


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Strong CYP3A4,5,7 inhibitors 
 
Moderate CYP3A4,5,7 inhibitors 
 
CYP3A4 inducers 
 
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 
 
 
 
 
APPENDIX 6: PATIENT SELF REPORTED MOOD QUESTIONNAIRES 
 
GAD-7 anxiety scale 
 
Over the last 2 weeks, how often have you 
been bothered by the following problems? 
(Use “✔” to indicate your answer) 
Not at 
all 
Several 
Days 
More than 
half of the 
days 
Nearly every 
day 
1. Feeling nervous, anxious or on edge 
0 
1 
2 
3 
2. Not being able to stop or control worrying 
0 
1 
2 
3 
3. Worrying too much about different things 
0 
1 
2 
3 
4. Trouble relaxing 
0 
1 
2 
3 
5. Being so restless that it is hard to sit still 
0 
1 
2 
3 
6. Becoming easily annoyed or irritable 
0 
1 
2 
3 
7. Feeling afraid as if something awful might 
happen 
0 
1 
2 
3 
Column totals: 
 
______  
+ ______ 
+ ______ 
+ ______ 
 
= Total Score ______ 
 
 
 
 
 
 
 
 
 


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PHQ9 depression scale 
 
Over the last 2 weeks, how often have you been 
bothered by any of the following problems? 
 
Not at 
all 
 
Several 
days 
 
More 
than half 
the days 
 
Nearly 
every 
day 
 
(Use “✔” to indicate your answer) 
 
 
 
 
 
1. Little interest or pleasure in doing things 
 
0 
1 
2 
3 
2. Feeling down, depressed, or hopeless 
 
0 
1 
2 
3 
3. Trouble falling or staying asleep, or sleeping too much 
 
0 
1 
2 
3 
4. Feeling tired or having little energy 
 
0 
1 
2 
3 
5. Poor appetite or overeating 
 
0 
1 
2 
3 
6. Feeling bad about yourself - or that you are a failure or 
have let yourself or your family down 
 
0 
1 
2 
3 
7. Trouble concentrating on things, such as reading the 
newspaper or watching television 
 
0 
1 
2 
3 
8. Moving or speaking so slowly that other people 
Could have noticed? Or the opposite - being so 
fidgety or restless that you have been moving 
around a lot more than usual 
 
0 
1 
2 
3 
9. Thoughts that you would be better off dead or of hurting 
yourself in some way 
 
0 
1 
2 
3 
Column totals: 
_____+ 
_____+ 
_____+ 
_____+ 
 
 
 
 
 
 
= Total Score 
 
 
 
 
 
 
 
If you checked off any problems, how difficult have these problems made it for you to do your work, take care 
of things at home, or get along with other people? 
 
 
Not difficult at 
all 
 
Somewhat 
difficult 
 
Very difficult 
 
Extremely 
difficult 
 
 
  
  
  
 
 
 
 
 
 
 
 
  
  
  


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APPENDIX 7: AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
Version No. 
Date issued 
Author(s) of 
changes 
Details of Changes made 
N/A 
V2.0 
24 Dec 2012 
Linda Collins 
N/A Protocol V2.0 was the protocol 
initially approved for use in the trial 
001 
V3.0 
22 Mar 2013 
Linda Collins 
Change to scan procedure 
003 
V4.0 
16 Sep 2013 
Linda Collins 
Change to scan procedure 
006 
V5.0 
07 Jul 2014 
Naomi McGregor 
DLT definitions  
010 
V6.0 
24 Mar 2016 
Naomi McGregor 
Guidance on management of liver and 
mood alteration toxicity 
011 
V7.0 
12 Jan 2016 
Stasya Ng 
Eligibility criteria (ECOG performance 
score) 
 

SAP_001.pdf: 
 
 
 
 
BKM120 
 
 
A CR-UK phase I study of BKM120 in patients 
with non-small cell lung cancer (NSCLC) 
receiving thoracic radiotherapy  
 
Palliative thoracic radiotherapy plus BKM120 
 
Statistical Analysis Plan 
 
 
Version number 3.0, 18 Oct 2017 
 
Based on Protocol version 7.0, 12 Jan 2017 
Centre for Statistics in Medicine 
 
 
Name 
Title/Role 
Signature 
Date 
Author 
Vicky Strauss 
Senior Trial 
Statistician 
 
18Oct2017 
Reviewer 
Seid Mohammed 
Trial Statistician  
 
18Oct2017 
Reviewer 
Daniel McGowan 
Clinical Lecturer 
 
26 Oct 2017 
Reviewer 
Stasya Ng 
Trial Manager 
 
26 Oct 2017 
Approver 
Geoffrey Higgins 
 Chief Investigator 
 
20 Oct 2017 
 
Sponsored by the University of Oxford 
Ms Heather House, Clinical Trials & Research Governance (CTRG), University of Oxford, Joint Research 
Office, Block 60, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, Tel: +44 (0)1865 572245, Fax: 
+44 (0)1865 572242, E-mail: heather.house@admin.ox.ac.uk 
 
 
 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 2 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
Table of Contents 
1. 
Introduction ................................................................................................................. 4 
1.1 
Key Personnel ...................................................................................................................... 4 
2. 
Background Information ........................................................................................... 6 
2.1 
Objectives ............................................................................................................................. 6 
2.1.1 
Primary Objective ...................................................................................................................... 6 
2.1.2 
Secondary Objective ................................................................................................................. 6 
2.1.3 
Tertiary/Exploratory Objective................................................................................................. 6 
2.2 
Study Design ........................................................................................................................ 6 
2.2.1 
Dose Escalation Phase .............................................................................................................. 7 
2.2.2 
Dose Expansion Phase .............................................................................................................. 8 
2.2.3 
Cohort 4 ...................................................................................................................................... 8 
2.2.4 
Duration of the Study ............................................................................................................... 8 
2.2.5 
Participating Centres of the Study .......................................................................................... 8 
2.3 
Treatment Interventions ................................................................................................... 8 
2.4 
Eligibility ............................................................................................................................... 9 
2.4.1 
Inclusion Criteria ........................................................................................................................ 9 
2.4.2 
Exclusion Criteria ..................................................................................................................... 10 
2.5 
Trial Closure ....................................................................................................................... 11 
2.6 
Sample Size ........................................................................................................................ 12 
2.7 
Randomisation ................................................................................................................... 12 
2.8 
Definition of Outcomes .................................................................................................... 12 
2.8.1 
Primary Outcome ..................................................................................................................... 12 
2.8.2 
Secondary Outcomes .............................................................................................................. 12 
2.9 
Outcomes Assessment Schedule ................................................................................... 13 
2.9.1 
Escalation and Expansion Phase ........................................................................................... 13 
3. 
Quality Control and Data Validation ..................................................................... 14 
3.1 
Data Cleaning..................................................................................................................... 14 
3.2 
Data Derivation and Manipulation ................................................................................ 14 
3.3 
Validation of Results ........................................................................................................ 14 
4. 
Data Monitoring Committee and Interim Analyses .......................................... 15 
5. 
Descriptive Analyses ................................................................................................ 16 
5.1 
Representativeness of Study Sample and Patient Throughput .............................. 16 
5.2 
Baseline Comparability of Escalation and Expansion Phases ................................. 17 
5.3 
Comparison of Losses to Follow-up .............................................................................. 17 
5.3.1 
Dose escalation phase ............................................................................................................ 17 
5.3.2 
Expansion phase ...................................................................................................................... 18 
5.4 
Description of Available Data ......................................................................................... 18 
5.5 
Description of Compliance with Therapy ..................................................................... 18 
5.6 
Unblinding of Randomised Treatments........................................................................ 18 
5.7 
Reliability ............................................................................................................................ 18 
6. 
Definition of Populations for Analysis .................................................................. 18 
7. 
Analyses to Address Primary Aims ........................................................................ 20 
7.1 
Statistical Methods Used for Analysis of Primary Outcomes .................................. 20 
7.2 
Adjustment of P Values for Multiple Testing .............................................................. 20 
7.3 
Missing Data ....................................................................................................................... 20 
7.4 
Pre-specified Subgroup Analysis ................................................................................... 20 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
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7.5 
Treatment by Centre Interaction .................................................................................. 20 
7.6 
Sensitivity Analysis ........................................................................................................... 20 
8. 
Analysis to Address Secondary Aims .................................................................... 21 
8.1 
Evaluation/Definition of Secondary Outcomes (where applicable) ...................... 21 
8.2 
Statistical Methods Used for Analysis of Secondary Outcomes .............................. 21 
9. 
Analysis of Exploratory Aims .................................................................................. 22 
9.1 
Evaluation/Definition of Exploratory Outcomes (where applicable) .................... 22 
9.2 
Statistical Methods Used for Analysis of Exploratory Outcomes ............................ 22 
9.3 
Additional Exploratory Analysis Not Specified Prior to Receiving Data ................ 22 
10. Serious Adverse Events ........................................................................................... 23 
11. Document History ..................................................................................................... 24 
 
 
 
 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 4 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
1. 
INTRODUCTION 
 
This document details the proposed presentation and analysis for the main paper(s) reporting results from 
the phase I dose escalation study of the PI3K inhibitor BKM120, given concomitantly with 
palliative radiotherapy for the treatment of Non-Small Cell Lung Cancer (NSCLC). The results 
reported in these papers should follow the strategy set out here. Subsequent analyses of a more exploratory 
nature will not be bound by this strategy, though they are expected to follow the broad principles laid down 
here. The principles are not intended to curtail exploratory analysis (for example, to decide cut-points for 
categorisation of continuous variables), nor to prohibit accepted practices (for example, data transformation 
prior to analysis), but they are intended to establish the rules that will be followed, as closely as possible, 
when analysing and reporting the trial.  
 
The analysis strategy will be available on request when the principal papers are submitted for publication in 
a journal. Suggestions for subsequent analyses by journal editors or referees, will be considered carefully, 
and carried out as far as possible in line with the principles of this analysis strategy; if reported, the source 
of the suggestion will be acknowledged. 
 
Any deviations from the statistical analysis plan will be described and justified in the final report of the trial. 
The analysis should be carried out by an identified, appropriately qualified and experienced statistician, who 
should ensure the integrity of the data during their processing. Examples of such procedures include quality 
control and evaluation procedures. 
 
 
1.1 
Key Personnel 
 
 
Trial statistician(s):  
Victoria Strauss 
 
 
 
 
 
Centre for Statistics in Medicine (CSM) 
 
 
 
 
 
University of Oxford 
 
 
 
 
 
Windmill Road 
 
 
 
 
 
Oxford OX3 7LD 
 
 
 
 
 
Tel: 01865 737911 
 
 
 
 
 
Email: victoria.strauss@csm.ox.ac.uk 
 
Seid Mohammed 
 
 
 
 
 
Centre for Statistics in Medicine (CSM) 
 
 
 
 
 
University of Oxford 
 
 
 
 
 
Windmill Road 
 
 
 
 
 
Oxford OX3 7LD 
 
 
 
 
 
Tel: 01865 225667 
 
 
 
 
 
Email: seid.mohammed@csm.ox.ac.uk 
 
Chief Investigator: 
 
Geoffrey Higgins  
 
 
 
 
 
 
 
 
 
Gray Institute for Radiation Oncology and Biology  
University of Oxford  
Old Road Campus Research Building 
Oxford OX3 7DQ 
Tel: 01865 617062 
Email: geoffrey.higgins@oncology.ox.ac.uk 
 
Trial Manager:  
            Stasya Ng  
 
 
 
 
         Oncology Clinical Trials Office (OCTO)  
Department of Oncology 
University of Oxford  
Old Road Campus Research Building 
Roosevelt Drive 
Oxford OX3 7DQ 
Tel: 01865 617083 
Fax: 01865 617010 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 5 of 24 
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Email: stasya.ng@oncology.ox.ac.uk 
 
Clinical Lecturer:                    Daniel McGowan 
                                              Department of Oncology 
                                                             University of Oxford 
  
 
 
 
          Old Road Campus Research Building 
                                                         Email: Daniel.mcgowan@oncology.ox.ac.uk 
 
Phospho AKT Expression:  
Marcus Green 
Oxford ECMC GCP laboratories 
 
 
 
 
          Department of Oncology 
 
 
 
 
          University of Oxford 
  
 
 
 
          Old Road Campus Research Building 
 
 
 
 
          Roosevelt Drive 
 
 
 
 
          Headington 
 
 
 
 
          Oxford OX3 7DQ  
 
 
 
 
          Tel: +44 (0)1865 617 050 
 
 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 6 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
2. 
BACKGROUND INFORMATION 
 
Lung cancer is the most common malignancy in industrialised countries. In 2008 approximately 41000 
people in the UK were diagnosed with lung cancer, of which approximately 80% were due to non-small cell 
lung cancer (NSCLC). In the same year there were over 35000 deaths due to lung cancer, reflecting the poor 
prognosis associated with the disease. Radiotherapy (RT) plays an important role in the management of 
patients with NSCLC. Patients with non-metastatic disease may be treated with radical RT alone (Stage I-II), 
or with combination radical chemo-RT treatment (Stage III). Patients with metastatic disease (Stage IV) or 
with disease not amenable to radical RT treatment, often receive palliative thoracic RT in order to alleviate 
their symptoms. 
 
The overall prognosis associated with NSCLC remains very poor despite improvements associated with 
combined modality treatment and with technical advances enabling the delivery of more accurate RT 
treatment. 
 
Pre-clinical data suggests that BKM120 renders tumour cells more sensitive to ionising radiation and reduces 
tumour hypoxia and perfusion. All of these effects may enhance the efficacy of RT treatment.  
 
This trial will therefore assess whether BKM120 can be safely combined with thoracic RT treatment and 
whether it alters the tumour microenvironment in a way that is likely to improve RT. 
 
 
2.1 
Objectives 
 
2.1.1 
Primary Objective 
 
The primary aim in the dose escalation phase of the trial is to determine the safety, dose-limiting toxicity 
(DLT) and MTD of BKM120 when administered concomitantly with thoracic radiotherapy in patients with 
incurable NSCLC. 
 
 
2.1.2 
Secondary Objective 
 
The secondary aim is to investigate whether BKM120 alters tumour hypoxia and perfusion. 
 
 
2.1.3 
Tertiary/Exploratory Objective 
 
The tertiary aims are: 
 
- 
To evaluate Akt phosphorylation as a predictive marker of response to BKM120 
 
- 
To investigate potential biomarkers that correlate with response to BKM120 
 
 
2.2 
Study Design 
 
This study is a single-centre, open-label, 3+3 design dose escalation phase studying the use of BKM120 in 
combination with thoracic RT. A dose expansion phase and a further cohort of patients, referred to as 
Cohort 4 are also incorporated. Patients with incurable NSCLC requiring palliative thoracic RT are eligible for 
entry (refer to Section 2.3 for full details of eligibility criteria).  
 
The dose escalation phase of the study ended upon the declaration of the MTD of BKM120 in August 2015 
(details will be reported in the statistical report). The study is currently recruiting to the expansion phase. 
 
The trial will recruit 2-30 evaluable patients presenting with any stage of NSCLC, requiring palliative RT 
treatment. 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 7 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
2.2.1 
Dose Escalation Phase 
 
The escalation phase consisted of three cohorts of patients, each treated at different dose levels of BKM120: 
the starting dose of 50mg, the escalated dose of 80mg and the highest dose level of 100mg. This phase of 
the study used a standard 3+3 dose escalation design to determine the MTD of BKM120, illustrated in Figure 
1. 
 
 
Figure 2.1: Dose escalation phase trial design of dose escalation 
 
 
 
 
2.2.1.1 Dose Limiting Toxicity 
 
The following was considered a DLT if it occurred at any point whilst the patient was on study and was 
based on clinical and laboratory toxicity assessments (NCI-CTCAE version 4.0): 
 
1) Any ≥ grade 3 non-haematological toxicity (excluding nausea, vomiting or diarrhoea) that requires 
hospital admission or which does not resolve to ≤ grade 2 within 7 consecutive days of optimal 
treatment.  
2) Any ≥ grade 3 nausea, vomiting or diarrhoea will be considered DLT only if any of them persist for >48 
hours despite maximum supportive care.  
3) ≥ Grade 3 pneumonitis  
4) Any ≥ grade 4 haematological toxicity.  
5) Mood deterioration from baseline DLT will be any grade ≥3 mood change if BL score of 2. DLT will be any 
grade ≥2 mood change if BL score of ≤ 1.  
 
 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 8 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
2.2.1.2 Evaluability 
 
A patient was deemed evaluable for the dose escalation analysis if they completed their time on study or 
experienced a DLT beforehand. 
 
 
 
2.2.1.3 Maximum Tolerated Doses 
 
The MTD was defined as the highest dose of BKM120 in combination with radiotherapy at which no more 
than 1 of 6 evaluable patients or 0 of 3 evaluable patients experienced a DLT. 
 
 
2.2.2 
Dose Expansion Phase 
 
Upon completion of the dose escalation phase, an expansion phase will consist of a further 6 evaluable 
patients, i.e. 6 patients with a pair of analysable scans for imaging parameter derivation (refer to the 
Imaging Analysis Plan V1.0 16Jun2016). The patients in the expansion phase are treated at the MTD level of 
BKM120 with palliative RT to investigate whether BKM120 alters tumour hypoxia and perfusion.  
 
 
2.2.3 
Cohort 4 
 
As stated in the Protocol V7.0, this cohort will only be opened if there is no evidence of BKM120 induced 
changes in the tumour hypoxia and perfusion in cohorts 1-3 (including the expansion phase), i.e. if more 
than 50% of the patients treated with the MTD of BKM120 (n = 9 to 12) are defined as non-responders 
(refer to Section 2.8.2). A total of six patients will be entered into Cohort 4 to reinvestigate whether BKM120 
alters tumour hypoxia and perfusion by increasing the intake of BKM120 at the MTD level, treated in 
combination of palliative RT. 
 
As stated in the TMG Minutes 09Jun2017, the recruitment will be completed by 31Aug2017, regardless of 
whether there is a need to open cohort 4 or not.  
 
An interim imaging data review was also taken place on 08Jun2017 by Dr Daniel McGowan to confirm there 
are more than 50% non-responders among 9 patients treated with the MTD of BKM120.  
 
 
2.2.4 
Duration of the Study 
 
Date start of recruitment: 
          
 
 
January 2013 
Number recruited in the escalation phase:   
 
 
11 patients 
Number to be recruited for expansion cohort:  
 
 
6 patients 
Number to be included for Cohort 4 (if opened):           
6 patients 
Date of expected end of recruitment: 
          
 
August 2017 
Date of expected end of follow-up: 
          
 
October 2017 
Date of expected final analysis:           
 
 
January 2018 
 
 
2.2.5 
Participating Centres of the Study 
 
The study is conducted in a single centre (Oxford, UK). 
 
 
2.3 
Treatment Interventions 
 
The Investigational Medicinal Product (IMP) in this trial is BKM120 (Buparlisib) in patients with NSCLC 
receiving thoracic RT. BKM120 has previously been used in a single-agent phase I study and is currently 
being used in clinical trials in combination with both chemotherapies (e.g. paclitaxel and carboplatin) and 
biological therapies (trastuzumab) but there are currently no trials combining BKM120 with RT treatment. 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 9 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
 
In the dose escalation phase, patients were assigned to the appropriate BKM120 dose level according to the 
3+3 dose escalation design. BKM120 was not escalated above 100mg, as this dose has previously been 
established as the recommended phase two dose for future single agent studies. In the expansion phase, 
treatment will be as per the dose escalation phase, but with all patients treated at the MTD level of BKM120. 
Patients in Cohort 4 will have 3 weeks of BKM120 at the MTD level. Dosage details of BKM120 and RT are 
given in Table 2.1.  
 
 
Table 2.1: Treatment doses planned per BKM120 dose cohort 
Dose Level 
RT 
BKM120 
BKM120 dose escalation plan 
1 
20Gy in 5 
fractions 
(days 8 - 14) 
50 mg od 
(days 1 to 14) 
Three patients will be entered 
If 0/3 have DLT proceed to DL2  
If 1/3 have DLT expand dose level to a total of 6 patients. 
If none of the additional 3 patients develop DLT, proceed to DL2. 
If any further patient(s) develop DLT (≥ 2/6) the MTD is exceeded and 
the trial will be terminated. 
2 
20Gy in 5 
fractions 
(days 8 - 14) 
80 mg od 
(days 1 to 14) 
Three patients will be entered  
If 0/3 have DLT proceed to DL3. 
If 1/3 have DLT expand dose level to a total of 6 patients. 
If none of the additional 3 patients develop DLT, proceed to DL3. 
If any further patient(s) develop DLT (≥ 2/6) the MTD will be defined as 
50mg od. 
3 
20Gy in 5 
fractions 
(days 8 - 14) 
100 mg od 
(days 1 to 14) 
Three patients will be entered 
If 0/3 have DLT then the MTD is 100 mg od. 
If 1/3 have DLT expand dose level to a total of 6 patients. 
If none of the additional 3 patients develop DLT, the RPTD is 100 mg bd. 
If any further patient(s) develop DLT (≥ 2/6) the MTD will be defined as 
80mg od. 
Expanded 
cohort at 
MTD 
20Gy in 5 
fractions 
(days 8 - 14) 
MTD dose 
(days 1 to 14) 
Once the MTD has been reached a further 6 patients will be treated at 
the MTD of BKM120 with palliative RT. 
 
4 
20Gy in 5 
fractions 
(days 22 – 28) 
At MTD 
(days 1 to 28) 
This cohort will only be used if there is no evidence of BKM120 induced 
changes in the tumour microenvironment on functional imaging in 
cohorts 1-3. A total of six patients will be entered into this cohort. 
 
BKM120 is supplied as 10mg and 50mg hard gelatin capsules and administered on a continuous daily dosing 
from the morning of day 1, until the morning of the day of the final RT treatment.  
 
All patients will receive palliative RT in 20Gy in 5 fractions in the last week of BKM120 treatment. 
 
 
2.4 
Eligibility 
 
All patients will be screened for inclusion and exclusion criteria within 4 weeks prior to the first dose of 
BKM120. Written informed consent must be obtained before any study specific procedures are performed. 
The Investigator will determine patient eligibility based on the following criteria. 
 
 
2.4.1 
Inclusion Criteria 
 
A patient is eligible for inclusion in this study if all of the following criteria apply: 
  
1. Evidence of histologically confirmed NSCLC of any stage  


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 10 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
2. Thoracic lesion requiring palliative radiotherapy and which has been identified on a scan within eight 
weeks of starting the trial 
3. Male or female, age  18 years at the day of consenting to the study 
4. Life expectancy of at least 16 weeks 
5. ECOG performance score of 0-2 
6. Patient is able to swallow and retain oral medication  
7. The patient is willing to provide written informed consent and is likely to comply with the protocol 
for the duration of the study, and scheduled follow-up visits and examinations 
8. Haematological and biochemical indices within the ranges shown below: 
Lab Test 
Value required 
Haemoglobin (Hb) 
≥ 9.0 g/dL 
Absolute neutrophil count 
≥ 1.5 x 109/L 
Platelet count 
≥100 x 109/L 
International Normalised Ratio (INR) 
≤ 1.5 
Potassium, calcium and Magnesium 
Within normal range 
ALT and AST 
Not above normal range or ≤3.0 times ULN 
if liver metastases are present 
Total Serum Bilirubin 
Not above normal range, or ≤1.5 times ULN 
if liver metastases are present or total 
bilirubin ≤3.0 times ULN if the chief 
investigator is satisfied that the patient has 
well documented Gilbert’s disease and 
absence of other contributing disease 
process at the time of diagnosis 
Creatinine  
≤ 1.5 x ULN 
Fasting plasma glucose (FPG)  
≤ 120mg/dL [6.7 mmol/L] 
 
 
2.4.2 
Exclusion Criteria 
 
A patient is not eligible for the trial if any of the following criteria apply: 
 
1. Previous chemotherapy or biological therapy within four weeks of starting study treatment. 
2. Treatment with any other investigational agent, or participation in another interventional clinical trial 
within 28 days prior to enrolment. 
3. Patient has not recovered to grade 1 or better (except alopecia) from related side effects of any 
prior antineoplastic therapy. 
4. Treatment at the start of study treatment with any drugs known to be moderate or strong inhibitors 
or inducers of isoenzyme CYP3A4, and the treatment cannot be discontinued or switched to a 
different medication prior to starting study drug. 
5. Presence of active uncontrolled or symptomatic CNS metastases. Patients with asymptomatic CNS 
metastases may participate in this trial. Any prior local treatment for CNS metastases must have been completed treatment  28 days prior to enrolment in the trial (including surgery and 
radiotherapy). 
6. Patient has poorly controlled diabetes mellitus (HbA1c > 8 %) 
7. Previous exposure to PI3K, mTOR, or AKT inhibitor 
8. Patient has a known hypersensitivity to any of the excipients of BKM120 
9. Previous thoracic radiotherapy treatment 
10. Any previous extra-thoracic radiotherapy within 28 days prior to enrolment 
11. Medically documented history of or active major depressive episode, bipolar disorder, obsessive-
compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or risk of doing harm to 
others 
12. Patient meets the cut-off score of ≥ 12 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 ideation in the PHQ-9 (independent of the total score of the PHQ-9) 
13. Patient has ≥CTCAE grade 3 anxiety 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 11 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
14. Other psychological, social or medical condition, physical examination finding or a laboratory 
abnormality that the Investigator considers would make the patient a poor trial candidate or could 
interfere with protocol compliance or the interpretation of trial results. 
15. Patient has a concurrent malignancy or has had any malignancy (other than NSCLC) in the last 3 
years prior to start of study treatment (with the exception of adequately treated basal or squamous 
cell carcinoma or cervical carcinoma in situ) 
16. Patient has had major surgery within 14 days of starting the study drug. 
17. Patient has any other concurrent severe, and/or uncontrolled medical condition that would, in the 
investigator’s judgement contraindicate patient participation in the clinical study (e.g. chronic 
pancreatitis, chronic active hepatitis). 
18. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of BKM120. Patients who are known to be serologically positive for Hepatitis B, Hepatitis 
C or HIV. 
19. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV.  
20. 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)  
 
Patient is taking a medication that has a known risk of causing QT interval prolongation or 
inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to an 
alternative medication.  
 
Angina pectoris that requires the use of anti-anginal medication  
 
Ventricular arrhythmias except for benign premature ventricular contractions  
 
Any other cardiac arrhythmia not controlled with medication  
 
Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication  
 
Conduction abnormality requiring a pacemaker  
 
Valvular disease with documented compromise in cardiac function  
 
Symptomatic pericarditis  
 
History of myocardial infarction within 6 months of entering the trial  
 
History of congestive heart failure( New York Heart Association functional classification III-IV)  
 
Documented cardiomyopathy  
21. Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of 
contraception are used. Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, must use highly effective methods of contraception. Oral 
contraception, injected or implanted hormonal methods are not allowed as BKM120 potentially 
decreases the effectiveness of hormonal contraceptives. Acceptable methods of contraception are 
either:  
 
True abstinence: When this is in line with the preferred and usual lifestyle of the patient. 
[Periodic abstinence (eg calendar, ovulation, sympotothermal, post ovulation methods) and 
withdrawal are not acceptable methods of contraception].  
 
Surgical sterilization: Have had bilateral oophorectomy (with or without hysterectomy) or tubal 
ligation at least six weeks before taking BKM120. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level assessment.  
 
Male partner sterilization (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate). [For female study patients, the vasectomised male partner should be 
the sole partner for that patient]  
 
Or 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 Female patients must use 
acceptable methods of contraception must continue to use contraception for at least 4 
weeks after completing BKM120. Male patients (and their female partners) will need to 
continue to use contraception for at least 16 weeks after completing BKM120. Women of 
child-bearing potential must have a negative serum pregnancy test ≤ 72 hours prior to 
initiating treatment 
 
2.5 
Trial Closure 
 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 12 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
The end of the trial is defined as the last visit of the last patient enrolled in the trial i.e. approximately 6 
weeks post completion of BKM120 plus radiotherapy. The sponsor and the Chief Investigator reserve the 
right to terminate the study earlier at any time. In terminating the study, they must ensure that adequate 
consideration is given to the protection of the participants’ best interests. 
2.6 
Sample Size  
 
Between 2 and 18 patients were to be recruited to the dose escalation phase. A 3+3 cohort design was used 
to establish the MTD of 50mg, 80mg and 100mg for BKM120 with palliative RT. In August 2015, the 
escalation phase closed recruitment with a total of 11 patients recruited. The expansion phase intends to 
recruit an additional 6 evaluable patients treated at the MTD of BKM120 with palliative RT.  
 
Recruitment ended on 31Aug2017. A total of 10 patients have been recruited in the expansion phase. 
Among 10 recruited, 6 had evaluable FMIO-PET scans.  
 
2.7 
Randomisation 
 
BKM120 is not a randomised study; no randomisation is performed. 
 
2.8 
Definition of Outcomes 
 
2.8.1 
Primary Outcome 
 
The MTD of BKM120 was defined as the highest dose of BKM120 in combination with thoracic RT at which 
no more than 1 of 6 evaluable patients or 0 of 3 evaluable patients experienced a DLT. The definition of a 
DLT and evaluability can be found in Section 2.2.1.1 and Section 2.2.1.2, respectively. 
 
The trial management group (TMG) declared the MTD in August 2015 (refer to the statistical report). 
 
 
2.8.2 
Secondary Outcomes 
 
As stated in the Protocol V7.0,  
 
Changes in 18F-Misonidazole retention and in blood flow between pre and post BKM120 treatment are 
defined as response to BKM120 treatment based upon changes in tumour hypoxia and perfusion as detected 
by 18F-Miso PET-CT scans and perfusion CT scans respectively. Each patient will be classified as a ‘responder’ 
or ‘non-responder’ on the basis or their pre- and post- BKM120 imaging. Those patients whose imaging 
demonstrates the presence of a physiological response on either perfusion CT and/or 18F-Misonidazole PET-
CT will be classified as a ‘responder’ whilst those that do not show a response on either imaging modality 
will be classed as a ‘non-responder’. 
 
As stated in the IAP V1.0_01Jun2016,  
Hypoxia will be measured using TBRmean or TBRvolume (tumour-to-blood ratio) from each PET-CT scan. 
From perfusion-CT, blood flow (BF), blood volume (BV) and mean transit time (MTT) will be derived.  
 
In the file of secondary Analysis Template For IEPTOC V2.0_07Apr2016,  
 
For each parameter, patients will be classified as ‘responders’ if their differences are ≥ 10% for at least one 
of the hypoxia parameters. The cut-off of 25% for perfusion will be used to define perfusion responders. 
Patients will be classified as ‘responders’ to Buparlisib if they are deemed as a responder to hypoxia or 
perfusion. 
  


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 13 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
2.9 
Outcomes Assessment Schedule 
 
2.9.1 
Escalation and Expansion Phase 
 
 
Day-28 to 
day -2 
Day -1 
Day 1 
Day 8 
Day 14 
Day 28 
Day 56 
Written Informed Consent Screening 
X 
 
 
 
 
 
 
Written Informed Consent Main Study 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Relevant medical history/current medical conditions 
X 
 
 
 
 
 
 
Diagnosis and extent of cancer 
X 
 
 
 
 
 
 
Prior antineoplastic therapy 
X 
 
 
 
 
 
 
18F-Miso PET-CT and Perfusion CT scans 
 
X 
 
X 
 
 
 
Blood samples from 18F-Miso PET-CT 
 
X 
 
X 
 
 
 
Vital signs 
 
X 
 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
Weight 
 
X 
 
X 
X 
X 
X 
Physical examination 
 
X 
 
X 
X 
X 
X 
ECOG performance status 
X 
X 
 
X 
X 
X 
X 
Patient self-rating mood scales for depression (PHQ-9) and anxiety (GAD-7) 
X 
X 
 
X 
X 
X 
X 
ECG 
X 
 
 
 
X 
 
X 
Prior/concomitant medications 
X 
 
 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Haematology 
X 
 
 
X 
X 
X 
X 
Clinical chemistry 
X 
 
 
X 
X 
X 
X 
Lipase 
X 
 
 
 
X 
 
X 
Fasting plasma glucose (FPG)  
X 
 
 
X 
X 
X 
X 
HbA1C 
X 
 
 
 
 
 
 
Liver Function Tests 
X 
 
 
X 
X 
X 
X 
Blood test for pAkt measurement 
X 
 
 
X 
X 
X 
X 
Coagulation (INR) 
X 
 
 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
X 
 
X 
Dispensing of BKM120 
 
X 
 
 
 
 
 
BKM120a 
 
 
Once daily 
 
 
Radiotherapy 
 
 
 
20 Gy in 5 fractions 
 
 
Pregnancy test (if applicable) 
 
X 
If clinically indicated 
a BKM120 taken at 50mg,  80mg, 100mg (cohorts 1-3 of the escalation phase respectively) or MTD (expansion phase) once daily continuously on days 1-14


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 14 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
3. 
QUALITY CONTROL AND DATA VALIDATION 
 
3.1 
Data Cleaning 
 
Day-to-day monitoring of data entered into the trial database is carried out by the Oncology Clinical Trials 
Office (OCTO) staff.  
 
The trial statisticians, based in the Centre for Statistics in Medicine (CSM), will perform routine data 
cleaning to ensure the integrity of the data.  
 
 
3.2 
Data Derivation and Manipulation 
 
Data derivation/manipulation will be checked to ensure validity of the derived data, where appropriate. 
Calculations performed by the computer can be checked by hand for the smallest of 5% or 20 observations 
within the dataset, where appropriate. 
 
 
3.3 
Validation of Results 
 
It is not intended that the analyses will be repeated by a statistician independent of the trial. 
 
 
 
 
 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 15 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
4. 
DATA MONITORING COMMITTEE AND INTERIM 
ANALYSES 
 
An Independent Early Phase Trial Oversight Committee (IEPTOC) will be in place to monitor the safety and 
progress of the trial. This committee meets approximately twice a year to monitor recruitment to the trial 
and protocol compliance as well as adverse events.   
 
The primary research question of the dose escalation phase has been answered, with the MTD of BKM120 
determined (refer to the statistical report). Formal interim analyses took place to decide and agree on 
whether or not to dose-escalate in the dose escalation phase of the trial. 
 
There are no planned statistical interim analyses for this trial. Statistical interim analyses will only be 
performed if requested by IEPTOC.  
 
However, imaging data will be monitored throughout the trial by the Trial Management Group (TMG) to 
ratify Dr Daniel McGowan’s decision on the imaging evaluability. 
   
 
 
 
 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 16 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
 
5. 
DESCRIPTIVE ANALYSES  
 
5.1 
Representativeness of Study Sample and Patient Throughput 
 
Patient throughput for dose escalation phase will be illustrated using CONSORT flow diagram, as suggested 
in  Figure 5.1. 
 
 
 Figure 5.1: CONSORT flow diagram 
 
 
Additionally, reasons for non-participation will be reported. 
Protocol deviations will be reported. 
 
 
 
Excluded N =  
 
 Not meeting inclusion criteria (n = ) 
 Refused to participate (n = ) 
 FMISO failure (n = ) 
Assessed for eligibility and consent  
N =  
Eligible and recruited N =  
Allocated to Cohort 1 (50 mg) 
N =  
Allocated to Cohort 2 (80 mg)  
N =  
 
Allocated to Cohort 3 (100 mg)  
N =  
 
Escalate 
Escalate 
Evaluable for dose escalation analysis 
N = [1] 
Evaluable for dose escalation analysis 
N = [1] 
 
 
Escalation phase 
N =  
Expansion phase 
N =  
Evaluable for 
dose escalation 
analysis N =  
 
Evaluable for imaging endpoint 
analysis[2]  
PET N =  
pCT  N =  
 
Evaluable for imaging endpoint 
analysis[2] 
PET N =  
pCT N =  
  
Evaluable for 
imaging 
endpoint 
analysis[2] 
PET N =   
pCT  N=  
Evaluable for 
imaging 
endpoint 
analysis[2] 
PET N =  
pCT  N=  


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 17 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
5.2 
Baseline Comparability of Escalation and Expansion Phases 
 
A table showing characteristics of dose escalation phase patients and dose expansion phase at baseline will 
be presented to show comparability of the groups. Numbers (with percentages) for binary and categorical 
variables and means (with standard deviations), or medians (with ranges) for continuous variables will be 
presented; there will be no tests of statistical significance nor confidence intervals for differences between 
groups on any baseline variable.  
 
Characteristics to be described in tabular form include: 
 
Table 5 Baseline characteristics 
 
Characteristics 
Dose escalation phase 
Expansion 
cohort 
Cohort 1 
Cohort 2 
Cohort 3 
Demographic 
 
 
 
 
Age 
 
 
 
 
Gender 
 
 
 
 
Height 
 
 
 
 
Weight 
 
 
 
 
IMC 
 
 
 
 
Physical exam 
 
 
 
 
ECOG performance status 
 
 
 
 
Height 
 
 
 
 
Weight 
 
 
 
 
BMI 
 
 
 
 
SBP 
 
 
 
 
DBP 
 
 
 
 
Temperature 
 
 
 
 
Pulse rate 
 
 
 
 
Haematology 
 
 
 
 
Haemoglobin 
 
 
 
 
WBC 
 
 
 
 
Platelets 
 
 
 
 
Neutrophils 
 
 
 
 
Lymphocytes 
 
 
 
 
INR 
 
 
 
 
Biochemistry 
 
 
 
 
Sodium 
 
 
 
 
Potassium 
 
 
 
 
Calcium 
 
 
 
 
Magnesium 
 
 
 
 
Phosphate 
 
 
 
 
Urea 
 
 
 
 
Creatinine 
 
 
 
 
Albumin 
 
 
 
 
Bilirubin 
 
 
 
 
Alkaline phosphatase 
 
 
 
 
AST 
 
 
 
 
ALT 
 
 
 
 
LDH 
 
 
 
 
                                    
5.3 
Comparison of Losses to Follow-up 
 
5.3.1 
Dose escalation phase 
 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 18 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
The numbers and pattern of losses to follow-up over the duration of the study will be reported for duration 
of BKM120 treatment (14 days) and for the duration of dose escalation decision (56 days) for each cohort 
and all cohorts together.  
 
5.3.2 
Expansion phase 
 
The numbers and pattern of losses to follow-up over the duration of the study will be reported for duration 
of BKM120 treatment (14 days) and for the duration of the study evaluations (56 days) for all patients 
treated at the MTD of BKM120 with palliative RT. 
 
5.4 
Description of Available Data  
 
The patterns of availability of toxicity, primary and secondary outcomes data, from baseline to end of 
follow-up, will be summarised for the each phase of the trial (escalation and expansion). 
 
Evaluability of imaging data will be documented in the non-CRF imaging data. It has been decided to 
exclude patients with very small volume of baseline hypoxia as using the scan for the responder analysis 
would be inappropriate. No formal clarification of small volume is provided, but, potential excluded cases 
will be discussed with TMG.  
 
As of TMG09Jun2017, it was decided to exclude BKC3114 because this patient had baseline hypoxia of 
0.5ml in a 110ml tumour (BKM120_TMGMinutes_V1.0_09Jun2017).  
 
The completeness of the data will be described but no missing data will be imputed. 
 
5.5 
 Description of Compliance with Therapy  
 
A summary of the treatment received in dose escalation phase 1 will be provided. This will include 
information in terms of treatment with BKM120 from day 1 to 14 and RT from day 8 to 14 and doses for all 
patients of each cohort. 
 
A summary of the treatment received in expansion phase will be provided. This will include information in 
terms of treatment with BKM120 from day 1 to 14 and RT from day 8 to 14 and doses for all patients. 
Deviations from protocol including loss to follow-up, withdrawal by clinician and withdrawal of consent will 
be included. 
 
5.6 
Unblinding of Randomised Treatments 
 
This is not a placebo controlled trial and therefore it is not blinded. 
 
5.7 
Reliability 
Data validation checks for the analysis specified in this SAP will be performed as per OCTRU SOPs.  
Reliability-Quality control plans are as documented in the IAP_V1.0_01Jun2016.  
 
6. 
DEFINITION OF POPULATIONS FOR ANALYSIS 
 
Dose escalation phase: 
The primary dose escalation analysis will include all patients completing 14 days of BKM120 treatment and 
56 days of evaluation or patients who withdraw early after experiencing DLT. 
 
Dose escalation phase: 
The primary safety and tolerability analysis will be based on all patients receiving a study dose level of 
50mg, 80mg and 100mg BKM120. 
 
Dose expansion phase: 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 19 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
The primary safety and tolerability post-treatment analysis will be based on all patients who receive at 
least one MTD dose of BKM120.  
 
Secondary endpoints: 
The secondary tumour hypoxia and perfusion analysis will include all patients who have data available from 
both scans (pre-BKM120 and post-BKM120). 
 
 
 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 20 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
7. 
ANALYSES TO ADDRESS PRIMARY AIMS 
 
It is expected that STATA and R will be used for the analysis. 
 
7.1 
Statistical Methods Used for Analysis of Primary Outcomes  
 
The primary dose escalation phase I analysis will be to find the MTD that is defined as the dose of BKM120 
in combination with RT which no more than 1 of 6 patients or 0 of 3 patients experience a DLT. MTD 
analysis will be a frequency of patients with DLT according to dose escalation of BKM120 (50mg, 80mg, 
100mg). DLT will be based on any observed toxicity attributed either to BKM120 or its interaction with RT, 
and MTD analysis will be a frequency of patients with DLT within study treatment: 
 
1) Any ≥ grade 3 non-haematological toxicity (excluding nausea, vomiting or diarrhoea) that requires 
hospital admission or which does not resolve to ≤ grade 2 within 7 consecutive days of optimal 
treatment.  
2) Any ≥ grade 3 nausea, vomiting or diarrhoea will be considered DLT only if any of them persist for >48 
hours despite maximum supportive care.  
3) ≥ Grade 3 pneumonitis  
4) Any ≥ grade 4 haematological toxicity.  
5) Mood deterioration from baseline DLT will be any grade ≥3 mood change if BL score of 2. DLT will be 
any grade ≥2 mood change if BL score of ≤ 1.  
 
Note that mood alteration is a difference of at least one grade from baseline measurements on the mood 
questionnaires and this could also be judged on psychiatric interview. 
 
The primary safety analysis will be a summarisation of descriptive statistics with patients grouped 
according to dose cohort. Toxicity grading using NCI CTCAE V4.03, physical examination, biochemistry and 
haematology data will be summarised across time. 
 
7.2 
Adjustment of P Values for Multiple Testing 
 
No formal adjustment for multiple significance testing is intended.  
 
7.3 
Missing Data 
 
No missing data will be imputed 
 
7.4 
Pre-specified Subgroup Analysis  
 
No subgroup analysis is planned. 
 
7.5 
Treatment by Centre Interaction 
 
This is a single centre trial. Consequently, no treatment by centre interaction analysis is planned. 
 
7.6 
Sensitivity Analysis 
 
None specified. 
 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 21 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
8. 
ANALYSIS TO ADDRESS SECONDARY AIMS 
 
These investigate other aspects to determine the effect of BKM120 on secondary aims.  
 
 
8.1 
Evaluation/Definition of Secondary Outcomes (where 
applicable) 
 
Secondary outcomes 
 
Changes in 18F-Misonidazole uptake as detected by PET-CT scans. 
 
Changes in blood flow as detected by perfusion CT. 
 
 
8.2 
Statistical Methods Used for Analysis of Secondary Outcomes 
 
For each of the parameters, mean (SD) and/or median (IQR) per cohort will be used to summarise the 
data, split by cohort (1,2,3+expansion). % change between parameters from each scan for each patient 
will also be presented in Table 8.1. Mean/median % change per cohort will be provided.  Table 8.1 can 
also be repeated to report the results for TBRmean (hypoxia) and BF, BV and MTT (perfusion) parameters.  
Table 8.1: TBRvolume derived from PET-CT scans for hypoxia evaluation 
Patient 
TBRvolume 
First Scan 
Second Scan 
% Change 
1 
 
 
 
2 
 
 
 
… 
 
 
 
9 
 
 
 
Cohort-specific 
mean/median 
 
 
 
 
Patients will be defined as “responders” or non-responders as described in Section 2.8.2. Number of 
responders and non-responders per cohort will be reported. 
 
Box-and-whisker plots will be used to display each of the parameters in the pre and post treatment and 
also Waterfall plots be used to show the percentage change in each of the parameters for each patient. 
 
An appropriate statistical test (either paired t-test or Mann-Whitney U test) will be used to test the change 
of the pre and post scan results (if % change is zero or not) regardless of the dose they have received. But 
no formal statistical test will be used to test whether changes from the first to second scan are different 
between the three dose levels of Buparlisib because of the small sample size.  
 
 
 
 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 22 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
9. 
ANALYSIS OF EXPLORATORY AIMS 
 
These investigate other aspects to determine the effect of BKM120 on exploratory aims.  
 
9.1 
Evaluation/Definition of Exploratory Outcomes (where 
applicable) 
 
Exploratory outcomes 
 
To evaluate Akt phosphorylation as a predictive marker of response to BKM120 
 
To investigate potential biomarkers that correlate with response to BKM120 
 
9.2 
Statistical Methods Used for Analysis of Exploratory 
Outcomes 
Details of this analysis will be defined in the statistical report if a statistical support is required. If the 
statistical support is not required, it would be defined in a separate lab report. 
 
The proportion of cells staining with a pAKT antibody will be presented for patients classed as ‘responders’ 
and ‘non-responders’ using means (with standard deviations) and/or medians (with ranges) and will be 
compared using Mann-Whitney U test. 
 
 
Number (with percentages) of patients with mutation status of potential biomarkers (eg p53, RAS, PI3K, 
EGFR) will be presented and compared between ‘responders’ and ‘non-responders’ using chi-square test or 
Fisher’s Exact test (as appropriate). 
 
9.3 
Additional Exploratory Analysis Not Specified Prior to 
Receiving Data 
 
Any analyses not specified in the analysis protocol will be exploratory in nature. The exploratory nature of 
the analysis and the indication for carrying out the analysis will be described in any publication or 
presentation. 
 
 
 
 
 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 23 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
10. 
SERIOUS ADVERSE EVENTS 
 
The period for adverse event collection and recording will be from when the first patient has the first dose 
of BKM120 to the end follow-up of last recruited patient.  
 
For each patient, adverse events will be collected from the time of their first dose of BKM120 to the end of 
follow-up. 
 
Serious adverse events are defined as those that are fatal, life threatening, disabling or require in-patient 
hospitalisation or prolongation of hospitalisation, results in persistent or significant incapacity/disability, is a 
congenital anomaly or birth defect or is any other medically important event. For further details see Section 
13 of the Protocol. 
 
 
Serious adverse events for each cohort 1-3 will be summarized by descriptive statistics. An overall category 
for any serious adverse event will also be summarized as will the number of patients with at least one SAE. 
Results will be shown overall and separately for the dose escalation and expansion phase. The analysis will 
be conducted in evaluable patients (patients who have at least one study dose of BKM120) in each phase. 
A summary of adverse events will be made as part of the safety and tolerability primary aim (see section 
7.1). 
 
 
 


BKM120 
 
Funded by OCIC, CR_UK, ECMC network and Novartis 
OCTO protocol No: OCTO_031 
 
EudraCT Number: 2012-003762-40 
 
 
Page 24 of 24 
BKM120_Statistical_Analysis_Plan_V3.0_18Oct2017_VS_SM_GH_SN_DM 
 
 
11. 
DOCUMENT HISTORY  
 
 
 
 
Version 
No. 
Version 
Date 
Author 
Significant changes from previous version together with reasons 
1.0 
19Oct2012 
CC 
First version based on Protocol version 0.12, 01Oct2012 
2.0 
13Nov2012 
CC 
Updated based on Protocol version 1.0, 07Nov2012. Minor changes 
including some grammatical corrections and improvements to the content 
2.1 
31Jul2015 
PV 
Updated based on Protocol version 5.0, 07Jul2014. Updates based on SBL 
comments from previous version. Changes on duration of study, consort 
diagrams, patients groups for analysis, sensitivity analysis and minor 
grammatical corrections. Added list of abbreviations/definitions 
2.3 
13Oct2017 
VS 
Updated based on protocol version 7.0, 12 Jan 2017.  
2.4 
16Oct2017 
VS 
Updated based on comments from SN and SM. 
3.0 
18Oct2017 
VS 
Updated based on comments from SN, SM and DM