UCL/08/0254

University College London

Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT

REVEAL Trial Coordinator, CR UK & UCL Cancer Trials Centre , ctc.sponsor@ucl.ac.uk

REVEAL Trial Coordinator, CR UK & UCL Cancer Trials Centre , ctc.sponsor@ucl.ac.uk

No

No

No

Final

21 Jan 2014

No

Yes

18 Dec 2014

Yes

To assess the efficacy, safety and tolerability of two bortezomib-based combination chemotherapy regimens: VD (bortezomib [Velcade], and dexamethasone) and CVD (cyclophosphamide, bortezomib [Velcade] and dexamethasone) in a randomized parallel phase II design in patients with AL amyloidosis who have Mayo stage II or III disease.

Due to the potential effect of the trial treatment on pregnancy and lactation, and effect of doxorubicin on exposed sperm, the trial subjects had consented to use a reliable and acceptable form of contraception during the trial and for at least 6 months after the last trial treatment. All women of childbearing potential at risk of becoming pregnant had to undergo pregnancy tests during baseline investigations and prior to start of each cycle. Since the trial population were patients with cardiac amyloidosis, a 24 hour Holter monitor was used to monitor heart rate and rhythm. Trial subjects who experienced related non-haematological toxicity had their next dose of the drug withheld or delayed start of next cycle, those who experienced grade 4 neutropenia or febrile neutropenia were considered for G-CSF. The trial treatment were to be discontinued if already withheld and the AE did not resolve as expected. For adverse events attributable to Bortezomib, other than peripheral neuropathy, re-start of the treatment was to be at a reduced dose after resolution. The trial also incorporated several dose adjustments for renal and hepatic insufficiency. Since fluid retention is a common side effect of Dexamethasone in patients with amyloidosis, optimisation and close monitoring of fluid balance or dose adjustment of the drug was advised. Trial subjects who experienced generalised oedema, greater than grade 3 local reactions or painful local reactions were allowed intravenous administration of bortezomib until resolution of the reaction. Trial subjects had regular clinic visits during and after treatment where they were assessed for toxicity and monitored for adverse events. If these occurred out of clinic hours, all trial subjects were given patient cards with contact details of the local haematology team that they could access at any time for advice. All trial subjects received prophylaxis during treatment and until a specified time after as applicable.

12 Jul 2007

No

Yes

United Kingdom: 7

7

7

0

0

0

0

0

0

5

2

0

Overall Trial (overall period)

Not applicable

Yes

Bortezomib

L01XX32

Velcade

Solution for injection

Subcutaneous use

Initially, bortezomib was given twice weekly in combination with Doxorubicin and Dexamethasone (PAD) at a dose of 1mg/m^2 intravenously on days 1, 4, 8 and 11 of each 21-day cycle for a minimum of 3 cycles to a maximum of 6 cycles. This was given with doxorubicin at 18mg/m^2 i.v. on days 1 & 8 and dexamethasone at 20mg PO on days 1, 4, 8 and 11. Following a protocol amendment, route of administration for bortezomib was changed to subcutaneous and day 8 of doxorubicin removed from the schedule.

Bortezomib

L01XX32

Velcade

Solution for injection

Subcutaneous use

After a review of the safety data by the IDMC, the trial protocol was amended to remove doxorubicin from the combination regimen. Patients from this point onward were treated on bortezomib and dexamethasone. Dosage and administration of bortezomib was changed to from twice weekly to weekly in combination with Dexamethasone only (VD) at a dose of 1.3mg/m^2 s.c. on days 1, 8, 15 and 22 of each 35-day cycle for a minimum of 3 cycles to a maximum of 6 cycles. Dexamethasone was given 20mg PO on days 1, 8, 15 and 22

Bortezomib

L01XX32

Velcade

Solution for injection

Subcutaneous use

Initially, bortezomib was given twice weekly with the combination of cyclophosphamide and dexamethasone (CVD) at a dose of 1mg/m^2 on days 1, 4, 8, 11 and 15 of each 21-day cycle for a minimum of 3 cycles to a maximum of 6 cycles. After a protocol amendment, dosage and administration was changed to weekly in at a dose of 1.3mg/m^2 on days 1, 8, 15 and 22 of each 35-day cycle for a minimum of 3 cycles to a maximum of 6 cycles. Cyclophosphamide was given 350mg/m^2 (max 500mg) PO on days 1 and 15 Dexamethasone 20mg PO on days 1 - 4

PAD Regimen

VD Regimen

CVD Regimen

PAD Regimen

VD Regimen

CVD Regimen

No statistical analyses was done due to small number of Trial subjects

Primary

Response was assessed at the end of 3 cycles of chemotherapy

Note: No statistical analyses have been specified for the endpoint. Due to premature closure of trial, only a few trial subjects were recruited, therefore formal statistical analyses could not be carried out

Secondary

From date of first randomisation to 12 months post first randomisation

All adverse events (including serious) that occurred between informed consent and 30 days post last trial treatment administration (or after this date if thought to be related to the trial treatment)

Trial subjects were assessed for adverse events prior the start of each treatment cycle. All adverse events were recorded in the patient notes and the trial CRFs. Those meeting the definition of a Serious Adverse Event were also reported using the trial specific SAE Reporting template.

4.03

PAD Regimen

VD Regimen

CVD Regimen