Activity of sorafenib in schwannomas

ISRCTN	ISRCTN49989464
DOI	https://doi.org/10.1186/ISRCTN49989464
EudraCT/CTIS number	2011-001789-16
Secondary identifying numbers	10563

Submission date: 14/02/2012
Registration date: 14/02/2012
Last edited: 19/05/2022

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

http://cancerhelp.cancerresearchuk.org/trials/a-trial-looking-sorafenib-in-skin-schwannomas

Contact information

Mr Christopher Hayward
Scientific

Peninsula College of Medicine & Dentistry
Universities of Exeter & Plymouth
ITTC Building
1 Tamar Science Park
Davy Road
Plymouth
PL6 8BX
United Kingdom

Email	christopher.hayward@pms.ac.uk

Study information

Study design	Non-randomised interventional trial
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	GP practice
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	Investigation of the intratumoural concentration and activity of sorafenib in cutaneous schwannomas
Study objectives	In this study we will assess the delivery and biological activity of sorafenib in cutaneous schwannomas. As cutaneous schwannomas are the hallmark in the patient group of interest- patients with multiple merlin deficient tumours- we have focused our research initially on schwannomas in NF2 patients. Tumours caused by NF2 gene mutation, especially in NF2 patients, present considerable management problems, with current treatment options limited to surgery and radiosurgery. Currently there is no proven drug treatment for merlin deficient tumours. However consensus recommendations to accelerate clinical trials in NF2 have recently been published and include the recommendation of phase 0 trials. We have been investigating potential therapeutic targets in merlin deficient tumours for many years. After detailed target identification, our own studies have shown that PDGFR is massively over expressed and activated in schwannomas. We showed that sorafenib substantially decreases cell proliferation in human primary schwannoma cells by inhibiting PDGFR. Sorafenib is an approved tyrosine kinase inhibitor. There is extensive literature on the pharmacokinetics, pharmacodynamics and safety of sorafenib and considerable experience with its use, mainly in the treatment of renal cell carcinoma and hepatocellular carcinoma. Pharmacokinetic studies show that sorafenib is rapidly absorbed and shows steady state levels after 7-10 days. This phase 0 study of 14 patients with cutaneous schwannomas amenable to biopsy is designed to investigate the intra-tumoural penetration and molecular activity of sorafenib in cutaneous schwannoma tissue after 11 days of daily sorafenib dosing compared to pre-treatment levels. It will provide evidence for a drug candidate to be used in Phase II/III multi-centre randomised clinical trials (RCTs) with NF2 patients and patients with merlin deficient tumours, for example inoperable meningiomas, and inoperable schwannomas.
Ethics approval(s)	London Bloomsbury NRES Committee, 26/08/2011, ref: 11/LO/0771
Health condition(s) or problem(s) studied	Brain and Nervous System Tumour
Intervention	One arm only. Treatment is Sorafenib (Nexavar - made by Bayer HealthCare, BayerSchering Pharma) administered as 2 x 200mg tablets (400mg) twice daily for 10 days (i.e. 800mg per day), plus 2 x 200mg (morning only) on the 11th day. Depending on an interim analysis of drug concentration and activity at the recruitment halfway stage, the second 7 participants may receive a lower dose of 400mg per day instead of 800mg. Note that this is an experimental study to determine the action of Sorafenib in the blood and skin tumours of patients with NF2; there are no intended or anticipated clinical benefits of taking part.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase IV
Drug / device / biological / vaccine name(s)	Sorafenib
Primary outcome measure	Target inhibition by sorafenib in CS biopsies measured at Day 11.
Secondary outcome measures	No secondary outcome measures
Overall study start date	06/02/2012
Completion date	31/12/2015

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	Planned Sample Size: 14; UK Sample Size: 14
Key inclusion criteria	1. Written informed consent 2. Diagnosis of NF2 3. Over 18 years in age 4. Presence of more at least two cutaneous schwannomas >1cm3 in area and accessible for biopsy 5. WHO/ECOG Performance Status 0 or 1 6. Adequate bone marrow function within 28 days prior to the baseline visit and: 6.1. WBC > 3.4x109/l 6.2. Platelets > 99x109/l 7. Adequate renal function within 28 days prior to the baseline visit 7.1. creatinine < 2.5 x upper limit of normal 8. Adequate hepatic function within 28 days prior to the baseline visit 8.1. LFT < 1.5 x upper limit of normal 8.2. Serum amylase < 1.5 x upper limit of normal 8.3. Prothrombin (PT) or INR (International Normalized Ratio) and Prothrombin Time (PTT) < 1.5 x upper limit of normal 8.3.1. Able to swallow tablets 9.3.2. Ppatients with the potential for pregnancy or impregnating their partner must agree to use acceptable methods of birth control to avoid conception 8.4. Female patients who are not using hormonal contraception must agree to employ two barrier methods of contraception (e.g. condom, diaphragm with spermicidal jelly) during the study and for 3 months following the end of their study participation 8.5. Female patients who are using hormonal contraception must agree to use an additional barrier method (e.g. condom or diaphragm with spermicidal jelly) during the study and for 3 months following the end of study participation 8.6. Post menopausal women must be amenorrheic for at least 12 months to be considered of nonchildbearing potential. 9. Women of childbearing potential with a negative serum pregnancy test at screening and a negative urine pregnancy test at the baseline visit 10. Male and female 11. Lower Age Limit 18 years
Key exclusion criteria	1. Hypersensitivity to sorafenib or any of its excipients 2. Cardiac arrhythmias requiring antiarrhythmics (betablockers and digoxin are allowed) 3. Symptomatic coronary artery disease or ischemia 4. Myocardial infarction (MI) within the last six months; congestive cardiac failure > NYHA Class II 5. Active clinically serious bacterial or fungal infections 6. Known history of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C 7. Pregnant or breastfeeding 8. Patients with uncontrolled hypertension 9. Serious uncontrolled concomitant medical or psychiatric illness 9.1. Concomitant medications which have adverse interactions with sorafenib: rifampicin, ritonavir, ketoconazole, itraconazole and St Johns Wort 10. Treatment with strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) which has not been discontinued or switched to a different medication at least 2 weeks prior to starting the study drug. 11. Treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, St Johns Wort), which has not been discontinued or switched to a different medication at least 2 weeks prior to starting the study drug. 12. Grade 3 or higher impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome) 13. History of acute pancreatitis within one year of study entry or medical history of chronic pancreatitis 14. History of another primary malignancy that is currently clinically significant or currently requires active intervention. 15. Any other clinically significant medical or surgical condition which, according to the CI/PIs discretion, should preclude participation 16. History of significant congenital or acquired bleeding disorder 17. Patients taking warfarin or cytotoxic drugs
Date of first enrolment	06/02/2012
Date of final enrolment	31/12/2015

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

Peninsula College of Medicine & Dentistry

Plymouth
PL6 8BX
United Kingdom

Sponsor information

Plymouth Hospitals NHS Trust (UK)
Hospital/treatment centre

Derriford Hospital
Derriford Road
Crownhill
Plymouth
PL6 8DH
England
United Kingdom

Phone	+44 (0)1752 202082
Email	abc@email.com
Website	http://www.plymouthhospitals.nhs.uk
"ROR"	https://ror.org/05x3jck08

Funders

Funder type

Charity

Samantha Dickson Brain Tumour Trust (UK)
Private sector organisation / Other non-profit organizations

Alternative name(s): SDBTT
Location: United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan	Not provided at time of registration

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Basic results		03/05/2021	19/05/2022	No	No
HRA research summary			28/06/2023	No	No

Editorial Notes

19/05/2022: EU Clinical Trials Register results added.
24/01/2018: No publications found, verifying study status with principal investigator.