ALBERT

Description: Abstract 312 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/m2 administered 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. Disclosures: Moreau: Jansen-Cilag: Honoraria; Millennium Pharmaceuticals, Inc.: Advisory board, Honoraria; Celgene: Honoraria. Off Label Use: Discussion of Velcade administered as an SC rather than an IV bolus is included. Leleu:Jansen-Cilag: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Co-Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Robak:Johnson & Johnson: Research Funding. Kropff:ORTHO BIOTECH: Honoraria; Celgene: Honoraria. Cavet:OrthoBiotech: Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Research Funding. Parasuraman:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Feng:Johnson & Johnson: Employment. Skee:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Deraedt:Johnson & Johnson: Employment, Equity Ownership. Harousseau:Jansen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Abstract 1863 Background: The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma (MM); the recommended dose and schedule is 1.3 mg/m2 administered by intravenous (IV) injection on days 1, 4, 8, and 11 of 21-day cycles. Findings from the phase 3 randomized, non-inferiority, MMY-3021 study (Moreau et al, Lancet Oncol 2011) demonstrated that subcutaneous (SC) administration of bortezomib, using the same dose and schedule, was feasible, and resulted in similar efficacy with an improved systemic safety profile (including significantly lower rates of peripheral neuropathy) versus IV bortezomib in patients with relapsed MM. These findings built upon an earlier randomized phase 1 study (CAN-1004; Moreau et al, Haematologica 2008). Here we present a comprehensive analysis of the PK and PD of SC versus IV bortezomib and evaluate the impact of SC administration site/concentration and patient characteristics, using all available data from MMY-3021 and CAN-1004, and pooled analyses. Methods: Patients with relapsed MM after 1–3 (MMY-3021) or ≥1 (CAN-1004) prior therapies were randomized to receive up to eight (or 10 for patients with late evolving response in MMY-3021) 21-day cycles of SC or IV bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11. The SC injection concentration was 1 mg/mL in CAN-1004, but 2.5 mg/mL in MMY-3021, to reduce the volume injected. SC injection sites were the thighs and abdomen, and were rotated for successive injections. In both studies, the IV injection concentration was 1 mg/mL. In MMY-3021, 17/18 SC and 14/14 IV patients enrolled to the PK/PD substudy at selected sites were assessable; in CAN-1004, 10/12 patients on each arm were included in the PK/PD analyses. Blood samples were collected pre-dosing and at multiple time points post-dose on day 11 of cycle 1 for PK/PD analyses. Results: PK analyses demonstrated that bortezomib systemic exposure was equivalent with SC versus IV administration in MMY-3021 (AUClast: 155 vs 151 ng.hr/mL, geometric mean ratio of 0.992 [90% CI: 80.18, 122.80]) and comparable in CAN-1004 (AUClast: 195 vs 241 ng.hr/mL), although as would be expected, Cmax was lower (MMY-3021, 20.4 vs 223 ng/mL, Figure; CAN-1004, 22.5 vs 162 ng/mL) and Tmax was longer (both studies, 30 vs 2 mins; Figure). PD parameters of proteasome inhibition were also similar with SC versus IV bortezomib (Emax: MMY-3021, 63.7 vs 69.3%; CAN-1004, 57.0 vs 68.8%; AUE72hr: MMY-3021, 1714 vs 1383 %.hr; CAN-1004, 1619 vs 1283 %.hr), although time to Emax was longer (MMY-3021, 120 vs 5 mins; CAN-1004, 120 vs 3 mins). Analyses of PK and PD parameters in MMY-3021 according to SC injection site showed no differences (Table). Comparison of SC bortezomib PK and PD parameters between MMY-3021 and CAN-1004 showed that SC injection concentration (2.5 vs 1 mg/mL) had no appreciable effect. Demographic covariates had no impact on bortezomib systemic exposure based on pooled bortezomib PK parameters following SC injection in the two studies. Full results from subgroup analyses will be presented. Conclusions: Data from these randomized studies of SC versus IV bortezomib in patients with relapsed MM demonstrate that SC administration results in equivalent bortezomib plasma exposure, albeit with a lower Cmax and longer Tmax, compared with IV administration, together with comparable PD effects. SC injection site and concentration of the injected solution did not affect bortezomib PK and PD parameters, and the demographic covariates did not appear to have an impact on the PK and PD of SC bortezomib. The non-inferior efficacy of SC versus IV bortezomib in relapsed or refractory MM demonstrated in MMY-3021, together with the equivalent total systemic exposures (AUC) via the SC and IV routes of administration, support the use of bortezomib via the SC route across the settings of clinical use in which the safety and efficacy of IV bortezomib has been established. Disclosures: Moreau: Janssen: Advisory board, Honoraria; Millennium Pharmaceuticals, Inc.: Advisory board, Honoraria. Off Label Use: Bortezomib administered via subcutaneous injection. Hulin:Celgene: Honoraria; Janssen-Cilag: Honoraria. Leleu:Janssen: Insitutional grants and lecture fees. Esseltine:Millennium Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Venkatakrishnan:Millennium Pharmaceuticals, Inc.: Employment. Skee:Janssen Research & Development: Employment. Feng:Janssen Research & Development: Employment. Girgis:Janssen Research & Development: Employment. Cakana:Janssen Research & Development: Employment. Deraedt:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Facon:Janssen: Advisory committee, Speakers Bureau.

Description: Abstract 3983 Background: Bortezomib is primarily metabolized by cytochrome P450 (CYP) 3A4 and 2C19 enzymes. Effects of co-administration of rifampicin (a potent CYP3A4 inducer) and dexamethasone (weak CYP3A4 inducer) on the pharmacokinetic (PK), pharmacodynamic (PD) and safety profiles of bortezomib were evaluated. Methods: Patients with relapsed or refractory multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) were enrolled in this open-label, 2-stage, parallel-group study. In stage 1, patients were randomized (1:1) to receive 3 cycles of bortezomib (1.3 mg/m2) on d 1, 4, 8, and 11 q3wk either alone or in combination with rifampicin 600 mg once-daily on d 4 to 10 of cycle 3 only. Stage 2 patients received bortezomib at same dose and schedule in combination with dexamethasone 40 mg once-daily on d 1 to 4 and d 9 to 12 of cycle 3 only. Patients could continue with bortezomib monotherapy for up to 10 cycles in case of clinical benefit. For PK/PD, blood samples were collected before and through 72 hours following bortezomib administration on d 11 of cycles 2 and 3. PK was the primary endpoint, secondary endpoints included PD (proteasome inhibition) and safety. Results: 61 patients were enrolled (39 MM, 22 NHL) in the study. 13 were treated with bortezomib + rifampicin, 18 with bortezomib + dexamethasone, and 30 with bortezomib only. Co-administration of rifampicin reduced the mean bortezomib maximum plasma concentration (Cmax) by approximately 23% (118 vs 93 ng/mL) and the mean area under plasma concentration-time curve from 0 to 72 hours (AUC72) by approximately 45% (223 vs 123 ng.h/mL). Co-administration of dexamethasone had no effect on mean AUC72 (179 vs 170 ng.h/mL). The mean bortezomib Cmax was 20% lower after co-administration of dexamethasone (140 vs 119 ng/mL); however this difference in Cmax was within the observed variability in Cmax during cycle 2 (CV=38%) and cycle 3 (CV=45%). Mean (SD) maximum percent proteasome inhibition (Emax) and area under percent proteasome inhibition-time curve from 0 to 72 hours (AUE72h) were comparable for bortezomib alone and in combination with rifampicin (Emax: 61.9 [4.56] vs. 62.3 [3.81] and AUE72h: 836 [323] vs. 777 [358]). Co-administration of dexamethasone did not affect the Emax (66.7 [4.27] vs. 61.8 [6.69]) or AUE72h (1329 [638] vs. 1157 [381]). Safety profiles were consistent with prior bortezomib experience in this population. Drug-related serious adverse events and treatment discontinuations were reported in 7/30 (23%) and 8/30 (27%) in bortezomib-only, in 3/13 (23%) and 3/13 (23%) in bortezomib + rifampicin, and 3/18 (17%) and 5/18 (28%) in bortezomib + dexamethasone subgroups. Investigator-assessed responses (CR+PR) were observed in 13/17 MM and 6/13 NHL patients in bortezomib-only, in 6/9 MM and 3/4 NHL patients in bortezomib + rifampicin, and in 10/13 MM and 2/5 NHL patients in bortezomib + dexamethasone subgroups. Conclusions: Co-administration of dexamethasone did not affect the PK or PD profiles of bortezomib. Co-administration of rifampicin reduced bortezomib exposure (AUC) by approximately 45%. Patients receiving bortezomib concomitantly with strong CYP3A4 inducers, such as rifampicin, should be monitored for reduction in clinical effect, while concomitant administration of weak CYP3A4 inducers, such as dexamethasone, is not expected to affect the bortezomib pharmacologic profile. Disclosures: Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Rule:Johnson & Johson: Consultancy, Speakers Bureau; Roche: Consultancy. Walewski:Johnson & Johnson: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Investigators fee. Shpilberg:Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feng:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Patel:Johnson & Johnson: Employment, Equity Ownership. Skee:Johnson & Johnson: Employment. Girgis:Johnson & Johnson: Employment. Louw:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Key Oncologics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.