Download A proof-of-principle phase 1b / randomised phase 2 study of afatinib

A proof-of-principle phase 1b / randomised phase 2 study of afatinib penetration into brain metastases (mets)
for patients undergoing neurosurgical resection, both with and without prior low-dose, targeted radiotherapy
San Antonio Breast Cancer Symposium 2016
1,2Richard
D. Baird, 3Nicola Ramenatte, 4Colin Watts, 1Alex Jonson, 2Linda Jones, 2Heather Biggs, 2Emma Harrison, 4Ingela Oberg, 4Gemma Bullen, 5Michael Williams, 3Wendi Qian, 6Fiona Gilbert, 1,3Duncan
Jodrell, 2,7Carlos Caldas, 8Konstantina Karabatsou, 9Laurence Dunn, 8Gillian Whitfield, 9Anthony Chalmers, 10Sarah Jefferies, 4Stephen Price
CamBMT1 chief investigator email:
[email protected]
Cambridge Cancer Centre, UK: 1Early Phase Clinical Trials Team; 2Breast Cancer Research Unit; 3Cambridge Clinical Trials Unit – Cancer Theme; 4Divison of Neurosurgery, Dept Clinical Neurosciences, University of Cambridge; 5Cancer Research UK Cambridge Institute
Pharmacokinetics/Bioanalytics Core Facility; 6Department of Radiology; 7CRUK Cambridge Institute; 8The Christie NHS Foundation Trust Manchester; 9University of Glasgow; 10Neuro-oncology multidisciplinary team, Cambridge University Hospitals NHS Foundation Trust
BACKGROUND
WINDOW STUDY DESIGN
STUDY OBJECTIVES / ENDPOINTS
PATIENT ELIGIBILITY CRITERIA
Brain metastases are a major problem
Timeline of study events
Primary objectives
Inclusion criteria
Safety run-in (phase 1b)
• Operable brain metastases from likely breast or lung origin as
determined by local MDT. Both of the following groups of
patients may be considered eligible:
1. Patients with a past history of histologically/cytologically
confirmed breast or lung cancer, now presenting with a
new likely brain metastasis from that primary.
2. Patients presenting with new, primary (breast/lung)
tumours, plus synchronous, operable brain metastases,
without pre-op tissue diagnosis.
• ECOG performance score 0, 1 or 2.
• Aged 18 years or older.
• Written informed consent.
• Patients receiving oral corticosteroids should receive a stable
dose for at least 3 days before start of afatinib, and are
anticipated to remain on this dose until after neurosurgical
resection.
• Brain metastases occur in 20% to 40% of all patients with cancer,
with an incidence 10 times higher than that of primary
malignant brain tumours.
• 30-50% of locally advanced NSCLC will relapse in CNS as the site
of first failure
• 30-50% of patients with HER2-positive or triple-negative,
metastatic breast cancer will eventually relapse in the CNS
• Brain mets in >30% of patients with advanced melanoma.
• To identify the recommended phase 2 dose of afatinib to be
combined with radiotherapy in phase 2
Randomised phase 2
• To investigate the effect of a single 2Gy or 4Gy fraction of lowdose targeted radiotherapy on the concentration of afatinib
delivered to brain mets
Primary endpoint
Patients with brain metastases have
limited treatment and trial options
• Steriods +/- whole brain radiotherapy the main treatment for
most patients
• Few clinical trials have been carried out for this population
• Patients with brain mets often excluded from clinical trials of
emerging investigational drugs
• Generally poor prognosis (weeks to short months)
Rationale for CamBMT1 study
• 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 preclinical and clinical data suggest that low-dose
radiotherapy may disrupt the BBB, and could facilitate
increased drug delivery into brain tumours.
• Primary endpoint: steady-state afatinib concentration in
resected brain metastases compared with plasma levels
• Afatinib concentration determined using a validated PK assay
(CRUK Cambridge institute)
Phase 1b safety run-in: 2 arms
• Arm A: afatinib + 2 Gy targeted radiotherapy
• Arm B: afatinib + 4 Gy targeted radiotherapy
• 3 planned afatinib dose levels in each arm: 20, 30 or 40mg QOD
• min 5 patients in each arm, cohorts can be expanded for toxicity
Secondary objectives
Safety run-in (phase 1b)
• To identify the recommended phase 2 dose of afatinib to be
combined with radiotherapy in phase 2
Exploratory objectives
Safety run-in (phase 1b)
Randomised Phase 2 – 3 arms:
(20 pts in each arm):
• Arm 1: afatinib only at Recommended Phase 2 Dose (RP2D)
• Arm 2: afatinib RP2D + 2 Gy targeted radiotherapy
• Arm 3: afatinib RP2D + 4 Gy targeted radiotherapy
• Characterisation of serial circulating tumour DNA (ctDNA)
profiles from the plasma of patients on study
• To undertake molecular profiling of resected cerebral
metastases (and primary tumours where available)
• To establish patient-derived xenografts from resected cerebral
metastases: to grow tumours in vitro / in vivo for molecular
profiling and functional characterisation (when feasible and
where sufficient tumour available)
Exclusion criteria
• History or presence of existing interstitial lung disease.
• Current clinically significant impairment of cardiac function
(greater than Class II according to New York Heart Association
[NYHA] classification).
• Unstable ischemic heart disease within the last 6 months,
including myocardial infarction.
• Presence of QTc interval prolongation >480 ms.
• Clinically significant eye (corneal & conjunctiva) diseases.
• Clinically significant skin diseases (eg.psoriasis, atopic
dermatitis)
• Clinically significant impairment of GI function or GI disease
including total gastrectomy that may alter the absorption of
afatinib.
• Clinically significant, active peptic ulcer disease.
• Known positive test for human immunodeficiency virus (HIV),
hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV)
antibody or patients with any untreated serious infections.
OT1-04-01
CamBMT1
•
CamBMT1 phase 1b has
completed recruitment
•
Phase 2 opening in q4 2016
in selected experimental
cancer medicine centres
initially drawn from the UK
Experimental Cancer
Medicine Centre network
(ecmcnetwork.org.uk)
ACKNOWLEDGEMENTS
CamBMT1 is an investigator-initiated trial, funded by grants from
Cancer Research UK / The Brain Tumour Charity and BoehringerIngelheim.
The investigators would like to thank the patients taking part in
the study, and their families. Support is also acknowledged from
the Cancer Research UK Cambridge Cancer Centre, the Cambridge
Experimental Cancer Medicine Centre (ECMC), and NIHR
Biomedical Research Centre (BRC). The CamBMT1 team is also
grateful for the support from the National Cancer Research
Institute Clinical Studies Groups for lung cancer, breast cancer,
brain cancer and CTRad, and patient advocates.
REFERENCES
• Afatinib - FDA approval 12 July 2013. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm360574.htm
• Cecchelli R, Berezowski V, Lundquist S, et al. Modelling of the blood-brain barrier in drug discovery and development. Nat Rev Drug
Discov 2007;6:650–61.
• Price SJ, Jena R, Green H a L, et al. Early radiotherapy dose response and lack of hypersensitivity effect in normal brain tissue: a
sequential dynamic susceptibility imaging study of cerebral perfusion. Clin Oncol (R Coll Radiol) 2007;19:577–87.
• Steeg PS, Camphausen KA, Smith QR. Brain metastases as preventive and therapeutic targets. Nat Rev Cancer 2011;11:352–63.