ALBERT

Description: Abstract 3971 Background: Although outcomes have improved for patients (pts) with multiple myeloma (MM), relapsed/refractory MM remains associated with short survival and constitutes an unmet medical need. Glucocorticoids (GCs) are an important component of MM therapy; however, resistance is common. In preclinical models, interleukin-6 (IL-6) promotes the proliferation and survival of MM cells in the context of the bone marrow microenvironment and protects these cells from GC-induced apoptosis. Therefore, blocking IL-6 may disrupt resistance and restore sensitivity to GCs. Here, we report the final results from a Phase 2 open-label, non-randomized study that evaluated the safety and efficacy of siltuximab (S), a monoclonal antibody targeting soluble human IL-6, in combination with high-dose dexamethasone (D) in pts with relapsed and relapsed/refractory MM. Methods: Pts with measurable, secretory disease who had received at least 2 prior lines of therapy, one of which contained bortezomib, and progressed during or after their last line of treatment were eligible. Other key eligibility criteria included a creatinine clearance ≥20 mL/min, platelets ≥50,000/mm3, and neutrophils ≥1,000/mm3. S was administered 6 mg/kg IV on days 1 and 15 of a 28-day cycle and oral D 40mg once daily, on days 1–4, 9–12, and 17–20 for a max of 4 cycles; days 1–4 for subsequent cycles. The first 14 pts received S alone for the initial 1 to 2 cycles; 10 pts had D added for progressive disease post-Cycle 1 or suboptimal response post-Cycle 2. 39 subsequent pts received S+D concurrently as none of the first 14 pts achieved ≥PR while on S monotherapy. The primary endpoint was overall response rate (ORR, CR+PR) using EBMT criteria. Secondary endpoints were time to progression (TTP), progression-free survival (PFS), overall survival (OS), and incidence of AEs and SAEs. Results: Forty-nine pts received S+D. The median age was 65 yrs (range 43–89) and 43% of pts were female. The median disease duration was 4 yrs (range 0.7–13.2). Pts were heavily pretreated, having received prior bortezomib (100%), steroids (100%), IMIDs (90%), alkylating agents (91%) and ASCT (65%). The median number of prior lines of therapy was 4 (range 2–9); 86% had disease that was refractory to the last prior line. Of the 44 pts with prior D exposure, 32 (73%) were refractory to the last D-containing regimen. The median duration of therapy was 4 cycles (99 days). Of the 47 pts evaluable for response, the ORR by EBMT criteria was 17% (0 CRs, 8 PRs); the ORR + minimal response (MR) rate was 23.4% (N=11). Using IMWG criteria, the ORR + MR rate was 27.7% (9 PRs, 4 MRs). Of the 11 pts with at least MR by EBMT criteria, 5 pts were refractory to the last D-containing regimen and 7 experienced less than MR on a prior D-containing regimen. The median duration of response was 5.9 months (181 days, 95% CI: 147, 365). Three pts had a long-lasting response of 9 months or more. For all 49 pts, the median PFS was 3.7 months (114 days, 95% CI: 84, 148) and median OS was 20.4 months (621 days, 95% CI: 347,984). AEs occurring in ≥25% of pts were thrombocytopenia, fatigue, anemia, abnormal hepatic function, neutropenia, diarrhea, peripheral edema, dyspnea and dizziness. 74% of pts experienced a grade ≥3 AE; the most frequent non-hematologic grade ≥3 AEs were fatigue (8%), abnormal hepatic function (8%), and pneumonia (6%). Grade 4 hematologic toxicities were thrombocytopenia (12%), neutropenia (4%) and anemia (2%). 25% of pts discontinued treatment due to an AE. Twenty (41%) of the 49 pts experienced ≥1 SAE. The most frequently occurring SAEs were pneumonia (8%), thrombocytopenia (6%), septic shock, anemia, and hemolytic anemia (4% each). Five pts died during the study; 3 due to progressive disease, 2 due to infection (nosocomial infection, septic shock). Conclusions: The combination of siltuximab with dexamethasone was well tolerated. Although the ORR was modest in this relapsed/refractory patient population, responses were seen in pts with MM refractory to prior dexamethasone-containing therapy, suggesting that siltuximab may be able to at least partially overcome dexamethasone resistance in some cases. Overall, these results provide a rationale for further studies of siltuximab in combination with dexamethasone-based MM therapy. Disclosures: Voorhees: MedImmune: Consultancy; Pfizer: Research Funding; Centocor Ortho Biotech: Research Funding; Celgene: Research Funding; Merck: Research Funding. Off Label Use: Siltuximab for the treatment of multiple myeloma. Manges:Centocor Ortho Biotech: Research Funding. Sonneveld:Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Jagannath:Merck: Honoraria; Millennium Pharmaceuticals: Honoraria; Johnson and Johnson Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Research Funding. Somlo:Onyx: Consultancy; Millennium: Consultancy; Celgene: Consultancy, Speakers Bureau; Centocor Ortho Biotech: Research Funding. Krishnan:Celgene: Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau; Centocor Ortho Biotech: Research Funding. Lentzsch:Celgene: Consultancy, Research Funding; Onyx: Consultancy; Genzyme: Consultancy; Centocor Ortho Biotech: Research Funding. Frank:Centocor Ortho Biotech: Research Funding. Zweegman:Centocor Ortho Biotech: Research Funding. Wijermans:Centocor Ortho Biotech Research & Development: Research Funding. Rijnbeek:Ortho Biotech Oncology Research and Development: Employment. Qin:Johnson & Johnson Pharmaceutical Research & Development, LLC: Employment. Cornfeld:Ortho Biotech Oncology Research and Development: Employment. Xie:Ortho Biotech Oncology Research & Development: Employment. Thomas:Centocor Ortho Biotech: Research Funding; Millennium Pharmaceuticals: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding.

Description: Abstract 4045 Poster Board III-980 Introduction CNTO328 is a chimeric monoclonal antibody against the inflammatory cytokine, IL-6, which is currently being studied in hematologic and solid malignancies. IL-6 is reported to play a key role in the etiology and symptoms of Anemia of Cancer (AOC). Increased IL-6 during cancer associated inflammation up-regulates the hepatic production of hepcidin, which is the iron-regulatory hormone that may be responsible for most of the features of this disorder. CNTO328 treatment has previously been shown to be associated with Hb increases in Castleman's Disease (a disorder caused by deregulated IL-6 production) and Renal Cell Carcinoma (RCC). We retrospectively undertook this assessment in the RCC patients, to assess whether there was an associated decrease in hepcidin. Patients and Methods Serum Hb, IL-6 and CRP (a surrogate for IL-6 activity) levels were prospectively studied in RCC patients selected from two 6 mg/kg CNTO328 treatment cohorts (IV Q2W or Q3W) in a phase 1/2 study. Free and total IL-6 could not be measured due to interference of the drug with assay performance which prevents accurate measurement. Serum hepcidin levels were retrospectively measured using a hepcidin C-ELISA. The change from baseline in Hb, hepcidin and CRP levels was calculated at multiple time points. The association between Hb response (defined as max Hb increase of ≥1 g/dL) and change in hepcidin and CRP levels was evaluated by Pearson Correlation Coefficient (r). Results 38 RCC patients with a median baseline Hb of 13.2 g/dL (10.1-17.1) were studied. All patients had normal renal function throughout the study. Two patients were excluded from analysis because of blood transfusions at baseline. None of the patients studied received ESAs or blood transfusions during screening or treatment. Treatment with CNTO328 resulted in an Hb increase during study in 35 (92%) of the 38 patients starting on Day 8, with 25 (66%) achieving a max Hb increase of 31 g/dL (median 2.0; range 1.0-3.5). Hb responses were not due to tumor response, were independent of dosing schedule (Q2W vs Q3W) and were even seen in 6 (86%) out of 7 patients with a baseline Hb

Description: Abstract 3959 Introduction: Interleukin (IL)-6 serves as a growth factor for B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and Castleman's disease (CD). Siltuximab (CNTO 328) is a chimeric monoclonal antibody that neutralizes the biological activity of human IL-6. We have previously reported interim safety and efficacy of siltuximab, which is highly notable in CD (van Rhee et al, Blood 2008;112:1008; Kurzrock et al, Blood 2008;112:1009). We now report the long-term safety of siltuximab in the 29 patients who were treated for more than 1 yr. Methods: An open-label, dose-finding, phase 1 trial of siltuximab in patients with B-cell NHL, MM, or CD was conducted. Five dose-escalation cohorts with increasing total dose exposure [3 mg/kg q 2 weeks (n=6), 6 mg/kg q 2 weeks (n=7), 12 mg/kg q 3 weeks (n=10), 6 mg/kg q 1 week (n=6), 12 mg/kg q 2 weeks (n=6)] were studied initially. Two additional cohorts were subsequently added: 12 mg/kg q 3 weeks as a 1-hour infusion (n=12) and a CD extension cohort with exploratory biomarkers (9 mg/kg q 3 weeks, n=12; 12 mg/kg q 3 weeks, n=8). Between Jun 2005 and Sep 2009, 67 patients (37 CD, 13 MM, 17 NHL) with median age 54 (range 18–82) yrs were enrolled. Results: Twenty-nine patients (24 CD, 3 MM, 2 NHL) were treated for at least 1 yr, including 19 and 15 patients treated for 〉2 and 〉3 yrs, respectively, with maximum duration of therapy up to 5 yrs. The grade ≥3 AEs most commonly reported between yrs 1 and 2 (irrespective of attribution to siltuximab) were infections (n=7, 24%), including device-related infection and bacteraemia (n=1), staph bacteraemia (n=1), wound abscess and pneumonia (n=1), limb and vulval abscesses (n=1), rectal abscess (n=1), bronchitis (n=1), and herpes zoster (n=1). Other common grade ≥3 AEs were blood and lymphatic system disorders (14%, most were neutropenia [10%]), and gastrointestinal disorders (10%, most were nausea [7%]). Incidence of AEs in these system-organ classes did not increase with longer duration of treatment. AEs of all grades reported in 〉10% of patients between yrs 1 and 2 were: nausea (31%); diarrhea, upper respiratory tract infection (each 28%); leukopenia, hepatic function abnormal, hypertriglyceridemia (each 21%); anemia, neutropenia, thrombocytopenia, sinusitis, hypercholesterolemia (each 14%). However, the majority of these AEs were low grade and tended to decrease with time. SAEs did not increase over time (n=5 between yrs 1–2, n=2 between yrs 2–3, n=4 at 〉3 yrs), and no specific SAE was reported in more than 1 patient. No patient discontinued therapy due to an AE during the long-term follow-up period, and there were no treatment-related deaths. Although some patients experienced clinically significant laboratory-related AEs, the laboratory results showed that mean levels of creatinine and triglycerides remained stable over time. In the 15 patients treated for ≥3 yrs, the following laboratory parameters showed modest trends of increase in mean value at 36 mos: hemoglobin increased to 13.9 g/dL from 12.4 g/dL at baseline, cholesterol increased to 201.07 mg/dL from 160.73 mg/dL at baseline, and bilirubin increased to 0.76 mg/dL from 0.49 mg/dL at baseline. On the other hand, at 36 mos in these 15 patients, the mean neutrophil count decreased to 3.70 x103/μL from 6.65 x103/μL at baseline, and the mean platelet count decreased to 216.0 x103/μL from 381.8 x103/μL at baseline. No severe infusion-related reactions were reported. At the time of database lock, 20 patients (1 MM, 19 CD) were still receiving study treatment. All 24 CD patients treated for ≥1 yr had sustained clinical responses, and half (n=12) also had an objective radiologic response, including 1 CR and 11 PR based on central radiology review. Ten of the 12 responders were treated with the highest dose of siltuximab (12 mg/kg), including 1 patient who responded after switching to 12 mg/kg. In addition, 3 unconfirmed PR were seen in the CD patients. Five patients with MM or NHL treated for ≥1 yr also had clinical benefit, including 2 CR and 1 prolonged SD in 3 MM patients and durable PR (〉4 mos) in 2 NHL patients. Conclusion: Siltuximab appears to have a favorable safety profile suitable for chronic dosing and shows clinical activity as a single agent, especially in treating Castleman's disease. Phase 2 and 3 studies are ongoing to further evaluate the safety and efficacy of siltuximab in patients with multicentric Castleman's disease and in combination with other agents in patients with multiple myeloma. Disclosures: Kurzrock: Centocor Ortho Biotech Research & Development: Research Funding. Voorhees:Pfizer: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Centocor Ortho Biotech: Consultancy, Research Funding; Celgene: Research Funding; MedImmune: Consultancy, Research Funding. Casper:Johnson & Johnson: Research Funding. Fayad:Centocor Ortho Biotech Research & Development: Research Funding. Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers-Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy. Borghaei:Genetech: Honoraria; Amgen: Honoraria; Eli Lilly: Honoraria. Jagannath:Educational Concepts Group: Teaching/Lectures; Envision Communication: Membership on an entity's Board of Directors or advisory committees, Teaching/Lectures; Imedex, LLC: Teaching/Lectures; Japanese Society of Hematology: Teaching/Lectures; Medical Learning Institute: Teaching/Lectures; Becker Pharmaceutical: Questionnaire regarding drug usage; Clinical Care Options, LLC: Teaching/Lectures; American Society of Clinical Oncology (ASCO): Editorial Board – Cancer.net; Medicom Worldwide: Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Investigator's Meeting; Janssen Pharmaceuticals: Teaching/Lectures; Johnson & Johnson Pharmaceutical: Member, Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Teaching/Lectures; MMRF: Teaching/Lectures; PER Group: Teaching/Lectures; Prime Oncology: Teaching/Lectures; South Carolina Oncology Society: Teaching/Lectures; CIG Media Group: Editor for Clinical Lymphoma Myeloma Leukemia Journal; Research to Practice: Teaching/Lectures. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Qin:Ortho Biotech Oncology Research & Development: Employment. Qi:Ortho Biotech Oncology Research & Development: Employment. Cornfeld:Janssen Pharmaceuticals: Employment, Equity Ownership. van Rhee:Johnson & Johnson Pharmaceuticals: Consultancy, Research Funding.