Palliative Thoracic Radiotherapy Plus BKM120

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

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