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| ID | Type | Description | Link |
|---|---|---|---|
| 2012-003762-40 | EudraCT Number |
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| Name | Class |
|---|---|
| Cancer Research UK | OTHER |
| Novartis | INDUSTRY |
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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.
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| BKM120 plus radiotherapy | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| BKM120 | Drug | Buparlisib is a highly specific inhibitor of phosphatidylinositol 3-kinase (PI3K). Buparlisib is supplied as 10mg and 50mg hard gelatin capsules. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Dose Escalation Analysis: Number of DLTs Observed in Evaluable Patients | The maximum tolerated dose (MTD) was defined as the highest dose at which no more than 1 of 6 evaluable patients or 0 of 3 evaluable patients experience a dose limiting toxicity (DLT). The study was carried out using a 3+3 dose escalation design. DLTs were defined per NCI CTCAE v 4.0. The following were 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 baseline score of ≤ 1. | 8 weeks (10 weeks cohort 4 - this cohort was not opened) |
| Safety and Tolerability Analysis: Patients With Buparlisib Related Adverse Events | Adverse events (AEs) and Serious Adverse Events (SAEs) were also analysed for frequency. For further details, please consult the AEs/SAEs section. | 8 weeks (10 weeks cohort 4 - this cohort was not opened) |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in 18F-Misonidazole Uptake as Detected by PET-CT Scans: Response | 18F-Miso is a radiotracer that selectively accumulates in hypoxic tissues. 18F-Miso PET-CT scans are able to non-invasively image tumour hypoxia. A 18F-Miso PET-CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour hypoxia due to buparlisib treatment. For tumour hypoxia, a patient is classified as a 'responder' if there is evidence of a 10% or greater reduction in retained F-Misonidazole. Hypoxia was measured using TBRmean or TBRvolume (tumour-to-blood ratio). |
| Measure | Description | Time Frame |
|---|---|---|
| Determine Phosphorylation Status of Akt in Peripheral Blood Mononuclear Cells (PBMCs) | 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 during the trial. Reductions in phospho-Akt expression of PBMC's following BKM120 treatment were to be correlated with changes observed with the functional imaging investigations; however it was not possible to draw any meaningful conclusions due to huge inter- and intra- participant variability seen on staining (no scoring was performed). |
Inclusion Criteria:
Evidence of histologically confirmed NSCLC of any stage
Thoracic lesion requiring palliative radiotherapy and which has been identified on a scan within eight weeks of starting the trial.
Male or female, age ≥ 18 years at the day of consenting to the study.
Life expectancy of at least 16 weeks.
ECOG performance score of 0-2.
Patient is able to swallow and retain oral medication.
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.
Haematological and biochemical indices within the ranges shown below:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Geoff Higgins, MRCP, FRCR, D.Phil | University of Oxford | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Churchill Hospital | Oxford | OXON | OX3 7LE | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22108822 | Background | Fokas E, Im JH, Hill S, Yameen S, Stratford M, Beech J, Hackl W, Maira SM, Bernhard EJ, McKenna WG, Muschel RJ. Dual inhibition of the PI3K/mTOR pathway increases tumor radiosensitivity by normalizing tumor vasculature. Cancer Res. 2012 Jan 1;72(1):239-48. doi: 10.1158/0008-5472.CAN-11-2263. Epub 2011 Nov 22. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort 1: 50mg Buparlisib | These patients were treated with 50mg buparlisib OD for a total of fourteen days. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. BKM120: BKM120/buparlisib is a highly specific inhibitor of phosphatidylinositol 3-kinase (PI3K). BKM120 is supplied as 10mg and 50mg hard gelatin capsules. |
| FG001 | Cohort 2: 80mg Buparlisib | These patients were treated with 80mg buparlisib OD for a total of fourteen days. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. BKM120: BKM120/buparlisib is a highly specific inhibitor of phosphatidylinositol 3-kinase (PI3K). BKM120 is supplied as 10mg and 50mg hard gelatin capsules. |
| FG002 | Cohort 3: 100mg Buparlisib | These patients were treated with 100mg buparlisib OD for a total of fourteen days. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. BKM120: BKM120/buparlisib is a highly specific inhibitor of phosphatidylinositol 3-kinase (PI3K). BKM120 is supplied as 10mg and 50mg hard gelatin capsules. |
| FG003 | 100mg Buparlisib Expansion Cohort | These patients were treated with 100mg buparlisib OD for a total of fourteen days, after 100mg buparlisib OD was determined to be the MTD. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. BKM120: BKM120/buparlisib is a highly specific inhibitor of phosphatidylinositol 3-kinase (PI3K). BKM120 is supplied as 10mg and 50mg hard gelatin capsules. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Dose Escalation Phase: Cohort 1 | Patients treated at 50mg buparlisib once daily for a total of fourteen days for the dose escalation phase. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Dose Escalation Analysis: Number of DLTs Observed in Evaluable Patients | The maximum tolerated dose (MTD) was defined as the highest dose at which no more than 1 of 6 evaluable patients or 0 of 3 evaluable patients experience a dose limiting toxicity (DLT). The study was carried out using a 3+3 dose escalation design. DLTs were defined per NCI CTCAE v 4.0. The following were 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 baseline score of ≤ 1. | The Primary Dose Escalation analysis (the declaration of MTD) included all patients completing 14 days of buparlisib treatment and 56 days of evaluation or patients who withdrew early after experiencing DLT. | Posted | Count of Participants | Participants | 8 weeks (10 weeks cohort 4 - this cohort was not opened) |
The Investigator monitored each patient for clinical and laboratory evidence of adverse events on a routine basis throughout the study from the point of receiving any research procedures through study completion.
Participants were assessed for adverse events by site staff during their participation in the trial.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dose Escalation Phase: Cohort 1 | Patients treated at 50mg buparlisib once daily for a total of fourteen days for the dose escalation phase. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lower respiratory infection | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hiccups | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Stasya Ng | University of Oxford | +441865 617083 | octo-BKM120@oncology.ox.ac.uk |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 12, 2017 | Sep 25, 2018 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 18, 2017 | Sep 25, 2018 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D002289 | Carcinoma, Non-Small-Cell Lung |
| D008175 | Lung Neoplasms |
| D000860 | Hypoxia |
| ID | Term |
|---|---|
| D002283 | Carcinoma, Bronchogenic |
| D001984 | Bronchial Neoplasms |
| D012142 | Respiratory Tract Neoplasms |
| D013899 | Thoracic Neoplasms |
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| ID | Term |
|---|---|
| C571178 | NVP-BKM120 |
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|
| Days -1 and 8 |
| Blood Flow at Days -1 and 8 as Detected by Perfusion CT | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology due to buparlisib treatment. | Days -1 and 8 |
| Tumour-to-blood Volume Ratio in 18F-Misonidazole Uptake as Detected by Day -1 and Day 8 PET-CT Scans, to Investigate if Buparlisib Alters Hypoxia | 18F-Miso is a radiotracer that selectively accumulates in hypoxic tissues. 18F-Miso PET-CT scans are able to non-invasively image tumour hypoxia. A 18F-Miso PET-CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment. Tumour to blood volume ratio ("TBR volume") is measured by summing the number of tumour/node/metastases voxels with a value greater than or equal to 1.4. | Days -1 and 8 |
| Changes in Blood Flow as Detected by Perfusion CT: Response | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology due to buparlisib treatment. For tumour perfusion, a patient is classified as 'responder' if blood flow (BF) and/or blood volume (BV) is increased and/or mean transit time (MTT) is reduced from baseline measurements by more than 25%. | Days -1 and 8 |
| Percentage Change in Blood Flow as Detected by Perfusion CT at Days -1 and 8 | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology (blood flow) due to buparlisib treatment, and the percentage change between both scans calculated. | Days -1 and 8 |
| Tumour-to-blood Mean Ratio in 18F-Misonidazole Uptake as Detected by PET-CT Scans, to Investigate if Buparlisib Alters Hypoxia | 18F-Miso is a radiotracer that selectively accumulates in hypoxic tissues. 18F-Miso PET-CT scans are able to non-invasively image tumour hypoxia. A 18F-Miso PET-CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour hypoxia due to buparlisib treatment. Hypoxia was measured using TBRmean and TBRvolume (tumour-to-blood ratio mean, tumour-to-blood ratio volume). TBR mean is measured by dividing all tumour/node/metastases voxels by the mean value of the descending aorta activity concentration. | Days -1 and 8 |
| Tumour-to-blood Volume Ratio Percentage Changes Between Day -1 and Day 8 in 18F-Misonidazole Uptake as Detected by PET-CT Scans, to Investigate if Buparlisib Alters Hypoxia | 18F-Miso is a radiotracer that selectively accumulates in hypoxic tissues. 18F-Miso PET-CT scans are able to non-invasively image tumour hypoxia. A 18F-Miso PET-CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour hypoxia due to buparlisib treatment. The percentage change between the TBR volume for the 1st and 2nd scans was calculated. TBR volume is measured by summing the number of tumour/node/metastases voxels with a value greater than or equal to 1.4. Hypoxia was measured using TBRmean and TBRvolume (tumour-to-blood ratio mean, tumour-to-blood ratio volume). | Days -1 and 8 |
| Percentage Changes in Blood Volume Between Day -1 and Day 8 as Detected by Perfusion CT | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology due to buparlisib treatment, and the % change between the 2 scans calculated. | Days -1 and 8 |
| Blood Volume at Day -1 and Day 8 as Detected by Perfusion CT | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology due to buparlisib treatment | Days -1 and 8 |
| Mean Transit Time as Detected by Perfusion CT at Days -1 and 8 | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology (blood flow) due to buparlisib treatment. | Days -1 and 8 |
| Percentage Change in Mean Transit Time as Detected by Perfusion CT at Days -1 and 8 | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology (blood flow) due to buparlisib treatment, and the % change between the 2 scans was calculated. | Days -1 and 8 |
| Baseline, days 8, 14, 28 and 56 |
| Measure Tumour PTEN (Phosphatase and Tensin Homolog Gene) Levels | Exploratory studies aimed to correlate response to buparlisib with activation of specific molecular pathways present in the archived, diagnostic, tumour biopsy sample. | Archival sample taken before trial entry |
| Measure Tumour PRAS40 Levels | Exploratory studies will aim to correlate response to BKM120 with activation of specific molecular pathways present in the archived, diagnostic, tumour biopsy sample. | Archival sample taken before trial entry |
| Adverse Event |
|
| Physician Decision |
|
| Withdrawal by Subject |
|
| Dose Escalation Phase: Cohort 2 |
Patients treated at 80mg buparlisib once daily for a total of fourteen days for the dose escalation phase. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. |
| BG002 | Dose Escalation Phase: Cohort 3 | Patients treated at 100mg buparlisib once daily for a total of fourteen days for the dose escalation phase. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. |
| BG003 | Dose Expansion Phase | Patients treated at 100mg buparlisib once daily for a total of fourteen days after the MTD had been established at 100mg buparlisib. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Stage of Disease IV | Count of Participants | Participants |
|
| Gross tumour volume | Median | Full Range | mL |
|
| Histology: Adenocarcinoma | Count of Participants | Participants |
|
| Histology: Squamous cell | Count of Participants | Participants |
|
| Prior Chemotherapy Treatment | Count of Participants | Participants |
|
| Prior surgical treatment | Count of Participants | Participants |
|
| Prior Extra Thoracic Radiotherapy Treatment | Count of Participants | Participants |
|
| Eastern Cooperative Oncology Group Performance Status | Patients were clinically graded according to the ECOG performance scale based on their activity performance description (with 0 corresponding to the best outcome and 4 the worst). | Count of Participants | Participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Dose Escalation Phase: Cohort 1 | Patients treated at 50mg buparlisib once daily for a total of fourteen days for the dose escalation phase. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. |
| OG001 | Dose Escalation Phase: Cohort 2 | Patients treated at 80mg buparlisib once daily for a total of fourteen days for the dose escalation phase. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. |
| OG002 | Dose Escalation Phase: Cohort 3 | Patients treated at 100mg buparlisib once daily for a total of fourteen days for the dose escalation phase. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. |
|
|
| Primary | Safety and Tolerability Analysis: Patients With Buparlisib Related Adverse Events | Adverse events (AEs) and Serious Adverse Events (SAEs) were also analysed for frequency. For further details, please consult the AEs/SAEs section. | The safety and tolerability post-treatment analysis was based on all patients who received at least one MTD dose of buparlisib (n = 21). | Posted | Count of Participants | Participants | 8 weeks (10 weeks cohort 4 - this cohort was not opened) |
|
|
|
| Secondary | Changes in 18F-Misonidazole Uptake as Detected by PET-CT Scans: Response | 18F-Miso is a radiotracer that selectively accumulates in hypoxic tissues. 18F-Miso PET-CT scans are able to non-invasively image tumour hypoxia. A 18F-Miso PET-CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour hypoxia due to buparlisib treatment. For tumour hypoxia, a patient is classified as a 'responder' if there is evidence of a 10% or greater reduction in retained F-Misonidazole. Hypoxia was measured using TBRmean or TBRvolume (tumour-to-blood ratio). | The tumour hypoxia analysis involved all patients who had a pair of interpretable 18F-Miso PET scans. | Posted | Count of Participants | Participants | Days -1 and 8 |
|
|
|
| Secondary | Blood Flow at Days -1 and 8 as Detected by Perfusion CT | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology due to buparlisib treatment. | The tumour perfusion analysis involved all patients who had a pair of interpretable pCT scans. | Posted | Median | Inter-Quartile Range | mL/100g/min | Days -1 and 8 |
|
|
|
| Secondary | Tumour-to-blood Volume Ratio in 18F-Misonidazole Uptake as Detected by Day -1 and Day 8 PET-CT Scans, to Investigate if Buparlisib Alters Hypoxia | 18F-Miso is a radiotracer that selectively accumulates in hypoxic tissues. 18F-Miso PET-CT scans are able to non-invasively image tumour hypoxia. A 18F-Miso PET-CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment. Tumour to blood volume ratio ("TBR volume") is measured by summing the number of tumour/node/metastases voxels with a value greater than or equal to 1.4. | The tumour hypoxia analysis involved all patients who had a pair of interpretable PET scans. | Posted | Median | Inter-Quartile Range | Tumour to blood volume ratio | Days -1 and 8 |
|
|
|
| Secondary | Changes in Blood Flow as Detected by Perfusion CT: Response | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology due to buparlisib treatment. For tumour perfusion, a patient is classified as 'responder' if blood flow (BF) and/or blood volume (BV) is increased and/or mean transit time (MTT) is reduced from baseline measurements by more than 25%. | The tumour perfusion analysis involved all patients who had a pair of interpretable pCT scans. | Posted | Count of Participants | Participants | Days -1 and 8 |
|
|
|
| Secondary | Percentage Change in Blood Flow as Detected by Perfusion CT at Days -1 and 8 | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology (blood flow) due to buparlisib treatment, and the percentage change between both scans calculated. | The tumour perfusion analysis involved all patients who had a pair of interpretable pCT scans. | Posted | Median | Inter-Quartile Range | % change in mL/100g/min | Days -1 and 8 |
|
|
|
| Secondary | Tumour-to-blood Mean Ratio in 18F-Misonidazole Uptake as Detected by PET-CT Scans, to Investigate if Buparlisib Alters Hypoxia | 18F-Miso is a radiotracer that selectively accumulates in hypoxic tissues. 18F-Miso PET-CT scans are able to non-invasively image tumour hypoxia. A 18F-Miso PET-CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour hypoxia due to buparlisib treatment. Hypoxia was measured using TBRmean and TBRvolume (tumour-to-blood ratio mean, tumour-to-blood ratio volume). TBR mean is measured by dividing all tumour/node/metastases voxels by the mean value of the descending aorta activity concentration. | The tumour hypoxia analysis involved all patients who had a pair of interpretable PET scans. | Posted | Median | Inter-Quartile Range | Tumour to blood mean ratio | Days -1 and 8 |
|
|
|
| Secondary | Tumour-to-blood Volume Ratio Percentage Changes Between Day -1 and Day 8 in 18F-Misonidazole Uptake as Detected by PET-CT Scans, to Investigate if Buparlisib Alters Hypoxia | 18F-Miso is a radiotracer that selectively accumulates in hypoxic tissues. 18F-Miso PET-CT scans are able to non-invasively image tumour hypoxia. A 18F-Miso PET-CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour hypoxia due to buparlisib treatment. The percentage change between the TBR volume for the 1st and 2nd scans was calculated. TBR volume is measured by summing the number of tumour/node/metastases voxels with a value greater than or equal to 1.4. Hypoxia was measured using TBRmean and TBRvolume (tumour-to-blood ratio mean, tumour-to-blood ratio volume). | The tumour hypoxia analysis involved all patients who had a pair of interpretable PET scans. | Posted | Median | Inter-Quartile Range | % change in tumour to blood volume ratio | Days -1 and 8 |
|
|
|
| Secondary | Percentage Changes in Blood Volume Between Day -1 and Day 8 as Detected by Perfusion CT | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology due to buparlisib treatment, and the % change between the 2 scans calculated. | The tumour perfusion analysis involved all patients who had a pair of interpretable pCT scans. | Posted | Median | Inter-Quartile Range | % change in mL/100g | Days -1 and 8 |
|
|
|
| Secondary | Blood Volume at Day -1 and Day 8 as Detected by Perfusion CT | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology due to buparlisib treatment | The tumour perfusion analysis involved all patients who had a pair of interpretable pCT scans. | Posted | Median | Inter-Quartile Range | mL/100g | Days -1 and 8 |
|
|
|
| Secondary | Mean Transit Time as Detected by Perfusion CT at Days -1 and 8 | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology (blood flow) due to buparlisib treatment. | The tumour perfusion analysis involved all patients who had a pair of interpretable pCT scans. | Posted | Median | Inter-Quartile Range | seconds | Days -1 and 8 |
|
|
|
| Secondary | Percentage Change in Mean Transit Time as Detected by Perfusion CT at Days -1 and 8 | Perfusion CT is a technique used to study the vasculature within tumours and other tissues. It is non-invasive and readily incorporated into existing CT protocols using conventional contrast agents. A perfusion CT scan was conducted prior to commencing buparlisib and repeated prior to commencing radiotherapy treatment to identify changes in tumour physiology (blood flow) due to buparlisib treatment, and the % change between the 2 scans was calculated. | The tumour perfusion analysis involved all patients who had a pair of interpretable pCT scans. | Posted | Median | Inter-Quartile Range | % change in seconds | Days -1 and 8 |
|
|
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| Other Pre-specified | Determine Phosphorylation Status of Akt in Peripheral Blood Mononuclear Cells (PBMCs) | 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 during the trial. Reductions in phospho-Akt expression of PBMC's following BKM120 treatment were to be correlated with changes observed with the functional imaging investigations; however it was not possible to draw any meaningful conclusions due to huge inter- and intra- participant variability seen on staining (no scoring was performed). | No scoring was performed, as on staining it was determined that the inter- and intra- participant variability seen would prevent any meaningful conclusions from being drawn. | Posted | Baseline, days 8, 14, 28 and 56 |
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| Other Pre-specified | Measure Tumour PTEN (Phosphatase and Tensin Homolog Gene) Levels | Exploratory studies aimed to correlate response to buparlisib with activation of specific molecular pathways present in the archived, diagnostic, tumour biopsy sample. | Where possible, tissue was obtained from trial participants' diagnostic samples. | Posted | Count of Participants | Participants | Archival sample taken before trial entry |
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| Other Pre-specified | Measure Tumour PRAS40 Levels | Exploratory studies will aim to correlate response to BKM120 with activation of specific molecular pathways present in the archived, diagnostic, tumour biopsy sample. | Where possible, tissue was obtained from the trial participants' clinical diagnostic samples. | Posted | Count of Participants | Participants | Archival sample taken before trial entry |
|
|
|
| 1 |
| 4 |
| 1 |
| 4 |
| 4 |
| 4 |
| EG001 | Dose Escalation Phase: Cohort 2 | Patients treated at 80mg buparlisib once daily for a total of fourteen days for the dose escalation phase. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. | 1 | 4 | 2 | 4 | 4 | 4 |
| EG002 | Dose Escalation Phase: Cohort 3 and Dose Expansion Phase | Dose Escalation Phase: Cohort 3 consisted of patients treated at 100mg buparlisib once daily for a total of fourteen days for the dose escalation phase. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. The Dose Expansion Phase consisted of patients treated at 100mg buparlisib once daily for a total of fourteen days after the MTD had been established at 100mg buparlisib. One week after commencing buparlisib, patients started palliative radiotherapy treatment. Radiotherapy treatment was delivered as 20Gy in 5 fractions over a one week period. | 1 | 13 | 2 | 13 | 12 | 13 |
| Peripheral Ischaemia | Vascular disorders | MedDRA | Systematic Assessment |
|
| Lung infection | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Chest Pain | General disorders | MedDRA | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Sinus Tachycardia | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Radiotherapy Dermatitis | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Oral candidiasis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Lower Respiratory Tract Infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Weight decreased | Investigations | MedDRA | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Metastatic pain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Peripheral ischaemia | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Lung Infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Mood altered | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Peripheral swelling | General disorders | MedDRA | Systematic Assessment |
|
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Rash macular | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Conjunctivitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Flank pain | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Hyperhidrosis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Hypophosphataemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Personality Change | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Skin Mass | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Abdominal Pain | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA | Systematic Assessment |
|
| Dyspnoea exertional | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Depressed Mood | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Bronchial Obstruction | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Non-cardiac chest pain | General disorders | MedDRA | Systematic Assessment |
|
| Night sweats | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Skin Reaction | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Heterophoria | Eye disorders | MedDRA | Systematic Assessment |
|
| Fungating wound | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Diplopia | Eye disorders | MedDRA | Systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Neuralgia | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Ear pain | Ear and labyrinth disorders | MedDRA | Systematic Assessment |
|
| Hypercalcaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Radiation skin injury | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Nightmare | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Pain | General disorders | MedDRA | Systematic Assessment |
|
| Panic attack | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Rash pruritic | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
|
| Lethargy | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Maculopapular rash | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Male |
|
|
|
| Patients discontinued because of AEs |
|
| Patients discontinued because of SAEs |
|
| Title | Measurements |
|---|---|
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| Title | Measurements |
|---|---|
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| Insufficient tissue |
|