Philippe Moreau1*, Halyna V Pylypenko2*, Sebastian Grosicki3*, Evgeniy E Karamanesht4*, Xavier Leleu5, Maria E Grishunina6*, Grigoriy B Rekhtman7*, Zvenyslava Masliak8*, Tadeusz Robak9, Anna V Shubina10*, Jean-Paul Fermand11*, Martin Kropff12, James Cavet13*, Sudha Parasuraman14, Huaibao Feng15*, Donna M Skee15*, Helgi van de Velde16*, William M Deraedt16* and Jean-Luc Harousseau17
1University Hospital, Nantes, France
2Cherkassy Regional Oncology Dispensary, Cherkassy, Ukraine
3Oddzial Hematologiczny ZSM, Chorzów, Poland
4Kiev BMT Center, Kiev, Ukraine
5Hôpital Huriez, CHRU, Lille, France
6Nizhniy Novgorod Region Clinical Hospital, Nizhniy Novgorod, Russia
7Khmelnitskiy Regional Hospital, Khmelnitskiy, Ukraine
8SI Institute of Blood Pathology and Transfusion Medicine UAMS, Lviv, Ukraine
9Medical University of Lodz, Lodz, Poland
10S.P. Botkin Moscow City Clinical Hospital, Moscow, Russia
11Hopital Saint-Louis, Paris, France
12University of Münster, Münster, Germany
13The Christie NHS Foundation Trust, Manchester, United Kingdom
14Millennium Parmaceuticals, Inc., Cambridge, MA
15Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ
16Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium
17Centre René Gauducheau, Nantes/St Herblain, France
Background: Bortezomib (VELCADE®) is approved in the US and Europe for the treatment of patients with multiple myeloma (MM) in both the frontline and the relapse settings. The recommended dose of bortezomib is 1.3 mg/m2administered as a 3- to 5-second bolus intravenous (IV) injection. As an alternative to IV delivery, subcutaneous (SC) administration of bortezomib may be a good option for some patients, particularly those with poor venous access, since it would eliminate the need for repeated IV access or insertion of long-term central venous access devices, improving convenience for some patients and physicians. In a randomized phase 1 trial of SC versus IV bortezomib in 24 relapsed or refractory MM patients, both routes of administration demonstrated similar systemic drug exposure and proteasome inhibition, good local tolerability and, importantly, comparable response rates and safety profiles (Moreau et al. Haematologica 2008). A large, multicenter, international, randomized, phase 3 open-label trial was therefore undertaken to compare SC and IV administration in patients with previously treated MM to confirm these preliminary findings.
Methods: Eligible patients were aged >18 years with measurable secretory MM who had relapsed or progressed following prior systemic therapy and had a Karnofsky performance status of >70%. Patients who had received prior bortezomib or >3 previous lines of therapy, or who had peripheral neuropathy or neuropathic pain of NCI CTCAE grade >2 were excluded. Patients were randomized 2:1 to receive SC or IV bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 every 21 days for a total of eight cycles. SC injection sites were the thighs or abdomen, and the injection site was rotated for subsequent injections within a cycle. IV injections were administered at a concentration of 1 mg/ml as a 3- to 5-second IV push, and SC injections were administered at 2.5 mg/ml. For cycles 1–4, patients received bortezomib monotherapy. After 4 cycles, if a patient had no change or partial response (PR) as the best response and had not progressed, oral dexamethasone 20 mg could be added on the day of and day after bortezomib dosing (days 1, 2, 4, 5, 8, 9 and 11, 12) in the next 4 cycles. At the end of 8 cycles, patients who had an unconfirmed PR or who were evolving steadily to a delayed PR could receive two additional cycles of study medication. The primary endpoint was overall response rate (ORR; complete response [CR + PR]) after 4 cycles. Response was evaluated using EBMT response criteria, modified with the addition of the response categories of near CR (nCR) and very good partial response (VGPR). Secondary endpoints were CR, nCR and VGPR rates after 4 cycles, ORR after 8 cycles including the effect of adding dexamethasone, duration of response (DOR), time to progression (TTP), progression-free survival, 1-year survival, and time to response. Safety and tolerability of the two administration routes, including local tolerability of SC administration, were also assessed. Pharmacokinetics (PK) and pharmacodynamics (PD) (via whole blood 20S proteasome inhibition assay) were evaluated in a subset of patients.
Results: Between July 2008 and February 2010, 222 patients from 53 centers in 10 countries across Asia, Europe and South America were enrolled and randomized to SC or IV bortezomib (148 SC, 74 IV). 32 patients (18 SC, 14 IV) in 8 centers participated in the PK/PD substudy. The primary study analysis will occur in October 2010.
Conclusion:Final data for all primary and secondary endpoints will be presented during the meeting, including time-to-event data for DOR, TTP and 1-year survival rate, as well as PK/PD data.