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Abstract 3060 Background: CD138 represents one of the most reliable target antigens for identification of multiple myeloma (MM) cells and has been reported to be a highly sensitive and specific diagnostic marker of MM. BT062 (Biotest AG Dreieich, Germany) is an antibody-drug conjugate, comprised of the anti-CD138 chimerized MAb (nBT062) and the cytotoxic agent DM4. Once bound to CD138 on a target cell, the conjugate is internalized and releases DM4, leading to targeted cell death. Preclinical investigations demonstrated strong in vitro and in vivo anti-MM activity of BT062, providing the rationale for the conduct of clinical trials (Ikeda et al., 2009). Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), pharmacokinetics (PK) and anti-MM activity of increasing doses of BT062 on a repeated single dose schedule once every three weeks in patients with relapsed and/or refractory MM. Toxicities were assessed by CTCAE v3 and clinical response was assessed according to the international working group criteria. Methods: This is a prospective, open label, dose-escalation multicenter study. Patients aged ≥ 18 years with relapsed or relapsed/refractory MM who have failed previous treatments including an immunomodulatory agent and a proteasome inhibitor were eligible to participate. Patients with clinical response (or no evidence of progressive disease) and without unacceptable toxicities were eligible for further treatment cycles. Patients were enrolled in cohorts of 3 at each dose level, with DLT in the first cycle triggering cohort expansion. Results: A total of 32 patients have been treated with BT062, receiving one of 7 dose levels ranging from 10 mg/m2 to 200 mg/m2. Maximum administered dose has been defined at 200 mg/m2, with mucositis as the dose limiting toxicity (CTC grade III in 2 of the 3 patients in this cohort). Therefore, the MTD was defined at 160 mg/m2. Thirteen of 32 patients have been treated in an expanded MTD-cohort. No CTC grade 4 toxicity has been reported. The most frequently reported adverse events to date cover primarily events expected for the underlying disease and patient group. Most of the reported adverse events are CTC grade I to II. Nevertheless, a few adverse events have also been observed involving skin and/or mucosa (tissues of epithelial origin with CD138 expressing cells), as well as the eye. Severe events involving skin and/or mucosa (e.g. mucositis, hand/foot syndrome) have only been observed at the dose levels 160 mg/m2 or higher. Adverse events involving the eye (e.g. blurred vision, dry eye) have been reported in only 3 patients overall at the dose levels 160 mg/m2 or higher, all CTC grade I to II. At dose levels up to 120 mg/m2, preliminary PK results indicate an unusual rapid clearance from plasma in the early elimination phase, followed by a generally normal terminal elimination phase. A more typical clearance profile was observed for all patients at the 160 mg/m2 and 200 mg/m2 dose. To date, one patient showed a decrease in urine M-Protein by >50% after 8 repeated low doses of 20 mg/m2 each. At a high dose level of 160 mg/m2, another patient showed a >50% decrease of serum FLC after two doses of BT062. In total, stabilization of disease was noted in 13 patients. Patients with stable disease received a median of 5 cycles of therapy (range of 3–10). Most patients came off study due to disease progression. Conclusion: Preliminary data from this phase I study demonstrate an acceptable toxicity profile of BT062. Even in this phase I patient population, evidence of clinical activity was observed. Based on the favourable safety profile, the pharmacokinetic data and early signs of clinical activity, a Phase I/II study in MM is initiated to further evaluate the safety and anti-MM efficacy of BT062 in a more frequent dosing regimen. Updated results on safety, PK and efficacy of BT062 will be presented. Disclosures: Jagannath: Celgene: Honoraria; Millenium/Takeda Pharma: Honoraria; J&J Family: Honoraria; Onyx: Honoraria; Merck: Honoraria. Heffner:Millennium: Research Funding. Avigan:Genzyme: Consultancy, Research Funding; Celgene: Research Funding; Curetec: Research Funding. Lutz:ImmunoGen, Inc.: Employment. Uherek:Biotest AG: Employment. Osterroth:Biotest AG: Employment. Ruehle:Biotest AG: Employment. Haeder:Biotest AG: Employment. Niemann:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Munshi:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; Bristol Myers Squibb: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Abstract 1862 Poster Board I-887 Background: Biotest AG (Dreieich, Germany) is developing the immunoconjugate BT062, which comprises the anti-CD138 chimerized MAb (nBT062) and the cytotoxic agent maytansinoid (DM4). Once bound to CD138 on a target cell, the conjugate is internalized and releases DM4. At present, CD138 represents one of the most reliable target antigens for identification of multiple myeloma (MM) cells and has been reported to be a highly sensitive and specific diagnostic marker of MM. Preclinical investigations demonstrated significant in vitro and in vivo anti-MM activity of BT062, providing the rationale for the conduct of clinical trials (Ikeda et al., 2009). Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), pharmacokinetics (PK) and anti-MM activity of increasing doses of BT062 on a repeated single dose schedule once every three weeks in relapsed or relapsed/refractory MM. Clinical response was assessed as per the international working group criteria (Durie et al., 2006). Methods: This is a prospective, open label, dose-escalation multicenter study. Patients aged ≥ 18 years with relapsed or relapsed/refractory MM who have failed previous treatments including an immunomodulating agent and a proteasome inhibitor were eligible to participate. Patients with clinical response (or no evidence of progressive disease) and without unacceptable toxicities were eligible for further treatment cycles. Patients are enrolled in cohorts of 3 at each dose level, with DLT in the first cycle triggering cohort expansion. Results: To date 20 patients have been treated with BT062 at 7 dose levels ranging from 10 mg/m2 to 200 mg/m2. Maximum administered dose has not been defined to date with continued enrollment at 200 mg/m2 dose. None of the patients treated experienced serious hypersensitivity reactions or humoral responses (HAHA) against BT062. The most frequently reported adverse events to date cover primarily events expected for the underlying disease. Nevertheless, a few adverse events have also been observed involving skin and mucosa (tissues of epithelial origin with CD138 expressing cells). No grade 4 toxicity has been reported. Preliminary PK results indicate an unusual rapid clearance from plasma in the early elimination phase, followed by a generally normal terminal elimination phase at dose levels up to 120 mg/m2, whereas a more typical clearance profile was observed for all 3 patients at the 160 mg/m2 dose. Interestingly, even in phase I study decreased urine M-Protein or serum FLC levels have been observed in 2 patients. One of these patients showed a decrease in urine M-Protein by more than 50% after administration of 8 repeated low doses. At a high dose level another patient without detectable M-Protein levels, showed a decrease of serum FLC by more than 50% after having received the second dose of BT062. Furthermore, evidence of clinical benefit has been observed in at least 6 patients with early stabilization of M-protein levels (and light-chain burden) in serum and /or urine. Conclusion: Development of a monoclonal antibody in MM remains an important therapeutic option and BT062 is an exciting possibility. Preliminary data from this phase I study, demonstrate an acceptable toxicity profile of BT062 in the clinics. Even in phase I study, evidence of clinical activity is observed. These encouraging results and the unique PK observed support investigation of a more frequent dosing regimen for optimizing anti-MM responses. Updated data on safety, PK and efficacy of BT062 from this clinical trial will be presented at the meeting. Disclosures: Jagannath: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Avigan:Genzyme: Consultancy, Research Funding; Celgene: Research Funding. Lutz:Immunogen, Inc.: Employment. Haeder:Biotest AG: Employment. Ruehle:Biotest AG: Employment. Uherek:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Munshi:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Biotest AG: Consultancy, Research Funding.

Summary Introduction Severe community-acquired pneumonia is defined as community-acquired pneumonia that requires intensive medical care. Mortality in these patients is still high depending on time and admission. Since bad outcomes may occur despite antibiotic therapy to treat severe community-acquired pneumonia, the focus has shifted to targeting the host response. The CIGMA Study examines the safety and efficacy of the novel IgM-enriched immunoglobulin preparation BT086 when added to standard of care treatment. Methods/design The aim of this multicentre, randomised, placebo-controlled, double-blind, parallel-group, adaptive group-sequential phase II study is to determine the efficacy and safety of BT086, an IgM-enriched immunoglobulin preparation, as an adjunctive treatment in mechanically-ventilated patients with severe community-acquired pneumonia. The increase of ventilator-free days is the primary endpoint in this study. For this trial, ventilator-free days are defined as the number of days between successful extubation from endotracheal ventilation and day 28 after enrolment of the patient into the study. Two interim analyses were considered for this study. Discussion Several novel agents for treatment of sepsis have been evaluated in the last two decades; however, none has significantly reduced mortality rates. Failure was attributed to the heterogeneity of septic patients or sepsis. Severe community-acquired pneumonia was chosen as the indication for this study to increase homogeneity within this patient population. Trial registration EUDRACT 2010-022380-35.