Condition category
Cancer
Date applied
14/02/2012
Date assigned
14/02/2012
Last edited
17/08/2015
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Contact information

Type

Scientific

Primary contact

Mr Christopher Hayward

ORCID ID

Contact details

Peninsula College of Medicine & Dentistry
Universities of Exeter & Plymouth
ITTC Building
1 Tamar Science Park
Davy Road
Plymouth
PL6 8BX
United Kingdom
-
christopher.hayward@pms.ac.uk

Additional identifiers

EudraCT number

2011-001789-16

ClinicalTrials.gov number

Protocol/serial number

10563

Study information

Scientific title

Investigation of the intratumoural concentration and activity of sorafenib in cutaneous schwannomas

Acronym

Study hypothesis

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

London Bloomsbury NRES Committee, 26/08/2011, ref: 11/LO/0771

Study design

Non-randomised interventional trial

Primary study design

Interventional

Secondary study design

Non randomised study

Trial setting

GP practices

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

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

Phase

Phase IV

Drug names

Sorafenib

Primary outcome measures

Target inhibition by sorafenib in CS biopsies measured at Day 11.

Secondary outcome measures

No secondary outcome measures

Overall trial start date

06/02/2012

Overall trial end date

31/12/2015

Reason abandoned

Eligibility

Participant 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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 14; UK Sample Size: 14

Participant 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 John’s 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 John’s 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/PI’s discretion, should preclude participation
16. History of significant congenital or acquired bleeding disorder
17. Patients taking warfarin or cytotoxic drugs

Recruitment start date

06/02/2012

Recruitment end date

31/12/2015

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Peninsula College of Medicine & Dentistry
Plymouth
PL6 8BX
United Kingdom

Sponsor information

Organisation

Plymouth Hospitals NHS Trust (UK)

Sponsor details

Derriford Hospital
Derriford Road
Crownhill
Plymouth
PL6 8DH
United Kingdom
+44 (0)1752 202082
abc@email.com

Sponsor type

Hospital/treatment centre

Website

http://www.plymouthhospitals.nhs.uk

Funders

Funder type

Charity

Funder name

Samantha Dickson Brain Tumour Trust (UK)

Alternative name(s)

SDBTT

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes