Palliative Thoracic Radiotherapy Plus BKM120

NCT02128724 | Completed Phase 1 Results DMC

• 2 other identifiers: OCTO_0312012-003762-40
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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.

Conditions

Carcinoma, Non-Small-Cell Lung

Keywords

Lung cancer; BKM120; Hypoxia; Misonidazole; Radiotherapy; Buparlisib

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (11)

• Changes in 18F-Misonidazole Uptake as Detected by PET-CT Scans: Response

  Days -1 and 8

• Blood Flow at Days -1 and 8 as Detected by Perfusion CT

  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

  Days -1 and 8

• Changes in Blood Flow as Detected by Perfusion CT: Response

  Days -1 and 8

• Percentage Change in Blood Flow as Detected by Perfusion CT at Days -1 and 8

  Days -1 and 8

Other Outcomes (3)

• Determine Phosphorylation Status of Akt in Peripheral Blood Mononuclear Cells (PBMCs)

  Baseline, days 8, 14, 28 and 56

• Measure Tumour PTEN (Phosphatase and Tensin Homolog Gene) Levels

  Archival sample taken before trial entry

• Measure Tumour PRAS40 Levels

  Archival sample taken before trial entry

Study Arms (1)

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.

Drug: BKM120

Interventions

BKM120 DRUG

Buparlisib is a highly specific inhibitor of phosphatidylinositol 3-kinase (PI3K). Buparlisib is supplied as 10mg and 50mg hard gelatin capsules.

Also known as: buparlisib

BKM120 plus radiotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Oxford: lead
• Cancer Research UK: collaborator
• Novartis: collaborator

Study Sites (1)

Churchill Hospital

Oxford, OXON, OX3 7LE, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 22108822 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Hypoxia

Interventions

NVP-BKM120

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Stasya Ng
• Organization: University of Oxford

octo-BKM120@oncology.ox.ac.uk

+441865 617083

Study Officials

• Geoff Higgins, MRCP, FRCR, D.Phil

  University of Oxford

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 16, 2014
• First Posted: May 1, 2014
• Study Start: April 1, 2013
• Primary Completion: October 17, 2017
• Study Completion: October 17, 2017
• Last Updated: August 1, 2019
• Results First Posted: August 1, 2019

Record last verified: 2017-11

Locations

GB (1)