A CR-UK phase I study of BKM120 in patients with non-small cell lung cancer (NSCLC) receiving thoracic radiotherapy

ISRCTN	ISRCTN04813360
DOI	https://doi.org/10.1186/ISRCTN04813360
EudraCT/CTIS number	2012-003762-40
ClinicalTrials.gov number	NCT02128724
Secondary identifying numbers	13615

Submission date: 25/01/2013
Registration date: 29/01/2013
Last edited: 24/06/2019

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

http://www.cancerresearchuk.org/cancer-help/trials/a-study-looking-adding-biological-therapy-to-radiotherapy-non-small-cell-lung-cancer-bkm120

Contact information

Ms Stasya Ng
Scientific

Old Road Campus
Roosevelt Drive
Headington
Oxford
OX3 7DQ
United Kingdom

Email	octo-BKM120@oncology.ox.ac.uk

Study information

Study design	Non-randomised open-label 3+3 cohort dose-escalation phase I study
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details to request a patient information sheet
Scientific title	A CR-UK phase I dose escalation study of BKM120 in patients with non-small cell lung cancer (NSCLC) receiving thoracic radiotherapy
Study acronym	BKM120
Study objectives	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.
Ethics approval(s)	NRES Committee South Central - Oxford B, 07/01/2013, ref: 12/SC/0674
Health condition(s) or problem(s) studied	Topic: National Cancer Research Network; Subtopic: Lung Cancer; Disease: Lung (non-small cell)
Intervention	BKM120 Cohort 1, 50 mg OD (days 1-14). 20 Gy in 5 fractions (days 8-14) BKM120 Cohort 2, 80 mg OD (days 1-14). 20 Gy in 5 fractions (days 8-14) BKM120 Cohort 3, 100 mg OD (days 1-14). 20 Gy in 5 fractions (days 8-14) BKM120 Cohort 4, At maximum tolerated dose (MTD) (days 1 to 28). 20 Gy in 5 fractions (days 22 - 28)
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase I
Drug / device / biological / vaccine name(s)	BKM120
Primary outcome measure	The safety, dose-limiting toxicity (DLT) and MTD of BKM120 with radiotherapy
Secondary outcome measures	Current secondary outcome measures as of 19/07/2016: 1. To evaluate Akt phosphorylation as a predictive marker of response to BKM120; Timepoint(s): Determine phosphorylation status of Akt in peripheral blood mononuclear cells (PBMC) at baseline, during BKM120 treatment and following BKM120 + RT treatment 2. To investigate potential biomarkers that correlate with response to BKM120; Timepoint(s): Measure tumour pAkt and Phosphatase and tensin homolog (PTEN) levels and then identify mutation status of RAS, PI3K and EGFR by PCR 3. To investigate whether BKM120 alters tumour hypoxia and perfusion; Timepoint(s): Changes in 18F-Misonidazole uptake as detected by PET-CT scans. Changes in blood flow as detected by perfusion CT Previous secondary outcome measures: 1. To evaluate Akt phosphorylation as a predictive marker of response to BKM120; Timepoint(s): Determine phosphorylation status of Akt in peripheral blood mononuclear cells (PBMC) at baseline, during BKM120 treatment and following BKM120 + RT treatment 2. To investigate potential biomarkers that correlate with response to BKM120; Timepoint(s): Measure tumour pAkt and Phosphatase and tensin homolog (PTEN) levels and then identify mutation status of RAS, PI3K and EGFR by PCR 3. To investigate whether BKM120 alters tumour hypoxia and perfusion; Timepoint(s): Changes in 18F-Misonidazole uptake as detected by PET-CT scans
Overall study start date	31/03/2013
Completion date	17/10/2017

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	UK Sample Size: 2-30
Total final enrolment	21
Key inclusion criteria	Current inclusion criteria as of 02/03/2017: 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. Eastern Cooperative Oncology Group (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: 8.1. Haemoglobin (Hb) >= 9.0 g/dL 8.2. Absolute neutrophil count >= 1.5 x 109/L 8.3. Platelet count >=100 x 109/L 8.4. International Normalised Ratio (INR) <= 1.5 8.5. Potassium, calcium and Magnesium Within normal range 8.6. Alanine aminotranferease (ALT) and aspartate aminotransferase (AST) not above normal range or< =3.0 times ULN if liver metastases are present 8.7. 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 8.8. Creatinine <= 1.5 x ULN 8.9. Fasting plasma glucose (FPG) <= 120mg/dL [6.7 mmol/L] Previous inclusion criteria from 19/07/2016 to 02/03/2017: 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. Eastern Cooperative Oncology Group (ECOG) performance score of 0-1 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: 8.1. Haemoglobin (Hb) >= 9.0 g/dL 8.2. Absolute neutrophil count >= 1.5 x 109/L 8.3. Platelet count >=100 x 109/L 8.4. International Normalised Ratio (INR) <= 1.5 8.5. Potassium, calcium and Magnesium Within normal range 8.6. Alanine aminotranferease (ALT) and aspartate aminotransferase (AST) not above normal range or< =3.0 times ULN if liver metastases are present 8.7. 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 8.8. Creatinine <= 1.5 x ULN 8.9. Fasting plasma glucose (FPG) <= 120mg/dL [6.7 mmol/L] Original inclusion criteria: 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. Eastern Cooperative Oncology Group (ECOG) performance score of 0-1 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: 8.1. Haemoglobin (Hb) >= 9.0 g/dL 8.2. Absolute neutrophil count >= 1.5 x 109/L 8.3. Platelet count >=100 x 109/L 8.4. International Normalised Ratio (INR) <= 1.5 8.5. Potassium, calcium and Magnesium Within normal range 8.6. Alanine aminotranferease (ALT) and aspartate aminotransferase (AST) within normal range or< =3.0 times ULN if liver metastases are present 8.7. Total serum bilirubin within 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 Gilberts disease and absence of other contributing disease process at the time of diagnosis 8.8. Creatinine <= 1.5 x ULN 8.9. Fasting plasma glucose (FPG) <= 120mg/dL [6.7 mmol/L]
Key exclusion criteria	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 PHQ9 or a cut-off of >= 15 in the GAD7 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 PHQ9 (independent of the total score of the PHQ9) 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 Hep B, Hep C or HIV. 20. Patient has active cardiac disease including any of the following: 20.1. LVEF < 50% as determined by MUGA scan or ECHO 20.2. QTc > 480 msec on screening ECG (using the QTcF formula) 20.3. 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. 20.4. Angina pectoris that requires the use of antianginal medication 20.5. Ventricular arrhythmias except for benign premature ventricular contractions 20.6. Any other cardiac arrhythmia not controlled with medication 20.7. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication 20.8. Conduction abnormality requiring a pacemaker 20.9. Valvular disease with documented compromise in cardiac function 20.10. Symptomatic pericarditis 20.11. History of myocardial infarction within 6 months of entering the trial 20.12. History of congestive heart failure( New York Heart Association functional classification III-IV) 20.13. Documented cardiomyopathy 21. Pregnant or breastfeeding women, or women of childbearing potential unless effective methods of contraception are used. Women of childbearing potential 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: 21.1. True abstinence 21.2. Surgical sterilization 21.3. Male partner sterilization Or use of a combination of any two of the following (a+b): a) Placement of an IUD or IUS b) Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidalfoam/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 use contraception for at least 16 weeks after completing BKM120. Women of childbearing potential must have a negative serum pregnancy test <= 72 hours prior to initiating treatment
Date of first enrolment	31/03/2013
Date of final enrolment	31/08/2017

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

Churchill Hospital

Oxford
OX3 7LE
United Kingdom

Sponsor information

University of Oxford (UK)
University/education

Clinical Trials and Research Governance (CTRG)
Joint Research Office
Block 60 Churchill Hospital
Headington
OX3 7LJ
England
United Kingdom

Website	http://www.admin.ox.ac.uk/researchsupport/ctrg/
"ROR"	https://ror.org/052gg0110

Funders

Funder type

Charity

Cancer Research UK (UK)
Private sector organisation / Other non-profit organizations

Alternative name(s): CR_UK, Cancer Research UK - London, CRUK
Location: United Kingdom

Oxford Cancer Imaging Centre (UK)

No information available

Results and Publications

Intention to publish date	31/03/2019
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	The current plan is that the research will be published in a specialist peer-reviewed scientific journal.
IPD sharing plan	The datasets generated during and/or analysed during the current study are/will be available upon request from Sarah Pearson (octo-enquiries@oncology.ox.ac.uk). Type of data: PET imaging data When the data will become available and for how long: Currently available, no specific limit on duration at present. By what access criteria will be shared: Internal/external researchers will have to complete a data sharing form (available on request) specifying amongst other details the motivation of their request, background, rationale, details of funding and approvals and also agree to specific conditions of data sharing. There is no specific restriction on the types of analyses at present and upon approval data will be transferred using a secure method. Consent: Consent not specifically obtained but the data is completely anonymised including scan dates. This is in compliance with the MRC’s Good Practice Principles for Sharing Individual Participant Data From Publicly Funded Clinical Trials V1.0 4.2.2. Ethical/legal restrictions: The researchers would expect the research to be ethically approved where required and for legal compliance as appropriate.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Basic results		18/10/2018	18/10/2018	No	No
Results article	results	01/05/2019	19/06/2019	Yes	No
HRA research summary			28/06/2023	No	No

Additional files

ISRCTN04813360_BasicResults_18Oct2018.pdf: Uploaded 18/10/2018

Editorial Notes

24/06/2019: IPD sharing statement added.
19/06/2019: Publication reference and total final enrolment number added.
18/10/2018: The basic results of this trial have been uploaded as an additional file.
30/05/2018: Internal review.
19/01/2018: The overall trial end date was changed from 31/03/2018 to 17/10/2017.
06/03/2017: Publication and dissemination plan and IPD sharing plan added.
02/03/2017: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/12/2016 to 31/08/2017.
2. The overall trial end date was changed from 30/04/2017 to 31/03/2018.
28/05/2015: The overall trial end date was changed from 30/08/2016 to 30/04/2017.
15/05/2015: The overall trial end date was changed from 30/06/2014 to 30/08/2016.