Abstract OT1-04-01: Cambridge brain mets trial 1 (CamBMT1): A proof-of-principle phase 1b / randomised phase 2 study of afatinib penetration into brain metastases for patients undergoing neurosurgical resection, both with and without prior low-dose, targeted radiotherapy
Authors: Baird RD , Ramenatte N , Watts C , Jonson A , Jones L , Biggs H , Harrison E , Oberg I , Bullen G , Williams M , Qian W , Gilbert F , Jodrell D , Caldas C , Karabatsou K , Dunn L , Jena R , Whitfield G , Chalmers A , Jefferies S , Price S 
Published: March 2017

Abstract
Background
Failure of drugs to cross the blood brain barrier (BBB) can be a major reason for treatment failure for patients with brain tumors. For most patients who don't respond to treatment, it is not known whether this is due to inadequate drug concentrations in the tumor, or due to drug resistance. Preliminary data suggest that low-dose radiotherapy may disrupt the BBB, and could facilitate increased drug delivery into brain tumors. Afatinib is a potent, irreversible inhibitor of EGFR / HER2 / HER4 and takes approximately 8 days to achieve steady-state concentrations in cancer patients.
Aims
CamBMT1 has been designed to investigate the delivery of afatinib into brain metastases and whether this might be enhanced by low dose-radiotherapy.
Patient Population
Key eligibility criteria
Patients with operable brain metastases from breast or lung primaries for whom neurosurgical resection would be standard of care, as determined by the local multi-disciplinary team. ECOG PS 0, 1 or 2.
Trial design
After a phase 1b safety run- in, the phase 2 part of the trial randomises patients (n=60) into 3 pre-operative arms:
Arm 1afatinib alone for 11 days, then neurosurgery on day 12Arm 2afatinib for 11 days plus a single 2 Gy fraction on day 10, then neurosurgery on day 12Arm 3afatinib for 11 days plus a single 4 Gy fraction on day 10, then neurosurgery on day 12
Primary endpoint: to compare steady-state afatinib concentration in resected brain metastases, following afatinib administered alone, or in combination with radiotherapy (2 Gy or 4 Gy). Afatinib concentrations are measured in the resected brain metastases 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 metastases, for comparison with paired primary lung and breast cancers; the establishment and study of patient-derived xenografts.
Statistical methods
With 20 patients randomised in each of 3 arms in the phase 2 part of CamBMT1, the trial has a power of 84% at a significance level of 20% (one-sided) to detect an increase in afatinib concentrations with targeted radiotherapy, measured as a Cohen's D (standardised mean difference) ≥0.5.
Accrual
By the end of q2 2016, phase 1b had nearly completed enrolment. The randomised phase 2 part of CamBMT1 is due to open by q4 2016 at additional Experimental Cancer Medicine Centres.
Acknowledgments
CamBMT1 is funded by Cancer Research UK, the Brain Tumour Charity and Boehringer-Ingelheim.
Citation Format: Baird RD, Ramenatte N, Watts C, Jonson A, Jones L, Biggs H, Harrison E, Oberg I, Bullen G, Williams M, Qian W, Gilbert F, Jodrell D, Caldas C, Karabatsou K, Dunn L, Jena R, Whitfield G, Chalmers A, Jefferies S, Price S. Cambridge brain mets trial 1 (CamBMT1): A proof-of-principle phase 1b / randomised phase 2 study of afatinib penetration into brain metastases for patients undergoing neurosurgical resection, both with and without prior low-dose, targeted radiotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-01.