Palliative Thoracic Radiotherapy Plus BKM120

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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A CR-UK Phase I Study of BKM120 in Patients With Non-small Cell Lung Cancer (NSCLC) Receiving Thoracic Radiotherapy

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: BKM120


Participation Criteria
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Eligibility Criteria
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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: 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 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: Previous chemotherapy or biological therapy within four weeks of starting study treatment. Treatment with any other investigational agent, or participation in another interventional clinical trial within 28 days prior to enrolment. Patient has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy. 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. 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). Patient has poorly controlled diabetes mellitus (HbA1c > 8 %) Previous exposure to PI3K, mTOR, or AKT inhibitor Patient has a known hypersensitivity to any of the excipients of BKM120 Previous thoracic radiotherapy treatment Any previous extra-thoracic radiotherapy within 28 days prior to enrolment 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 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) Patient has ≥CTCAE grade 3 anxiety 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. 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) Patient has had major surgery within 14 days of starting the study drug. 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). 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. Patient has active cardiac disease or a history of myocardial infarction within 6 months of entering the trial, congestive heart failure ( New York Heart Association functional classification III-IV) or documented cardiomyopathy 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. Women of child-bearing potential must have a negative serum pregnancy test less than 72 hours prior to initiating treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BKM120 plus radiotherapy<br>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. | Drug: BKM120<br>* Buparlisib is a highly specific inhibitor of phosphatidylinositol 3-kinase (PI3K). Buparlisib is supplied as 10mg and 50mg hard gelatin capsules.<br>* Other names: buparlisib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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) | 

Secondary Outcome Measures

| Outcome Measure | 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). | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung cancer, BKM120, Hypoxia, Misonidazole, Radiotherapy, Buparlisib