Failure of drugs to cross the blood brain barrier (BBB) can be a major reason for treatment failure for patients with brain tumours. For most patients who don't respond to treatment, it is not known whether this is due to inadequate drug concentrations in the tumour, or due to drug resistance. Preliminary data suggest that low-dose radiotherapy may disrupt the BBB, and could facilitate increased drug delivery into brain tumours. Afatinib is a potent, irreversible inhibitor of EGFR / HER2 / HER4 and takes approximately 8 days to achieve steady-state concentrations in cancer patients. CamBMT1 has been designed to investigate the delivery of afatinib into brain mets and whether this might be enhanced by low dose-radiotherapy.
Study population: patients with operable brain mets from breast or lung primaries for whom neurosurgical resection would be standard of care. After a phase 1b safety run-in, the phase 2 part of the trial randomises patients (n = 60) into 3 pre-operative arms:
|Arm 1: afatinib alone for 11 days, then neurosurgery on day 12|
|Arm 2: afatinib for 11 days plus a single 2 Gy fraction on day 10, then neurosurgery on day 12|
|Arm 3: afatinib for 11 days plus a single 4 Gy fraction on day 10, then neurosurgery on day 12|
The primary endpoint is to compare steady-state afatinib concentration in resected brain mets, following afatinib administered alone, or in combination with radiotherapy (2 Gy or 4 Gy). Afatinib concentrations are measured in the resected brain mets and in plasma. Secondary endpoints: safety of afatinib administration in combination with radiotherapy; and multi-sequence MRI (optional) to detect changes in perfusion, vascular density, blood-brain-barrier permeability and interstitial pressure. Exploratory endpoints: molecular profiling of resected brain mets, for comparison with paired primary lung and breast cancers; the study of patient-derived xenografts. CamBMT1 is a multi-centre trial now opening at additional Experimental Cancer Medicine Centres, and is funded by Cancer Research UK, the Brain Tumour Charity and Boehringer-Ingelheim.
Clinical trial identification
EudraCT Number: 2013-002398-23
Legal entity responsible for the study
Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge
Cancer Research UK The Brain Tumour Charity Boehringer-Ingelheim
All authors have declared no conflicts of interest.