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Background: While CD37 is widely expressed on malignant B cells in NHL and chronic lymphocytic leukemia (CLL), few therapies are in development exploiting this target. In normal tissues, high CD37 expression is restricted to blood cells and lymphoid tissues, making CD37 well suited to an ADC approach. IMGN529 is a CD37-targeting ADC consisting of a CD37-binding antibody with intrinsic pro-apoptotic and immune effector activities conjugated to the maytansinoid anti-mitotic, DM1. Its unique profile enables IMGN529 to potentially kill CD37-positive B cells via multiple mechanisms of action. In preclinical studies, IMGN529 exhibits targeted, potent activity against NHL cells via direct inhibition of cell survival and effector function by its antibody and tubulin-disruption by DM1. Methods: A Phase I study is being conducted to evaluate safety, pharmacokinetics, pharmacodynamics, exploratory biomarkers and preliminary evidence of activity of IMGN529 and to determine the maximum tolerated dose/recommended phase 2 dose of IMGN529 in adult patients (pts) with relapsed or refractory NHL. IMGN529 is given intravenously on Day (d) 1 of each 21d cycle (C). Efficacy is evaluated based on Cheson response criteria. CD37 is being evaluated by IHC in available tumor samples to assess expression of CD37 among different NHL subtypes. Results: To date, 31 pts have been enrolled (66% male), median age of 65 years: Diffuse large B-cell (DLBCL, n = 14), Follicular lymphoma (FL, n = 10), MCL (n = 5), MZL (n = 2). Dose escalation began at 0.1 mg/kg. Early onset, transient grade 3-4 neutropenia was reported in 6 patients receiving doses at or below 0.8 mg/kg, potentially attributed to cytokine release. Peri-infusional steroid administration was added to the study protocol, and the incidence and severity of this neutropenia was significantly reduced. Additional patients have been enrolled and increasingly higher dose levels evaluated. To date the highest dose evaluated is 1.0 mg/kg. Cytokine levels are currently being evaluated in trial patients to gain a better understanding of the mechanisms underlying the early onset neutropenia. At the 1.0 mg/kg dose cohort grade 3-4 neutropenia was reported (1 DLT of febrile neutropenia among 6 patients) around d10 of the cycle and granulocyte colony stimulating factor (G-CSF) was added as primary prophylaxis. The most common treatment-emergent adverse events (AEs) occurring in ≥ 20% of the 31 pts enrolled were neutropenia (30%), fever (27%), asthenia (20%) and fatigue (20%). A reduction in lymphocyte count seen early after dosing (d2) in the majority of pts suggests a CD37-mediated reduction in lymphocytes, consistent with the mechanism of action of a CD37-targeted therapy. Four objective responses have been reported in patients who had received multiple lines of prior therapy. At the 1.0 mg/kg dose level, two patients with DLBCL who were heavily pretreated and who relapsed following autologous transplant have achieved an objective response that is ongoing. One pt has achieved a PR and one patient has achieved a CR. As previously reported, at doses of 0.2 mg/kg and 0.4 mg/kg one pt with transformed FL, who progressed following an autologous transplant, and one pt with DLBCL achieved a PR. The maximum tolerated dose has not yet been achieved and dose escalation is ongoing with additional data expected. Conclusions: IMGN529, a CD37-targeting ADC, demonstrates clinical activity in patients with NHL and has the potential to be a novel therapeutic for B-cell lymphoproliferative malignancies. Disclosures Stathis: ImmunoGen, Inc: Travel assistance Other; Pfizer: Research Funding; Oncoethix SA: Research Funding. Flinn:ImmunoGen, Inc: Research Funding. Maddocks:Pharmacyclics, Seattle Genetics, MorphoSys: Advisory Board Other, Research Funding. Zucca:Roche, Mundipharma, Novartis, Jannsen, Celgene: Consultancy, Honoraria, Research Funding, travel assistance Other. Romanelli:ImmunoGen, Inc.: Employment, Equity Ownership; sanofi: Employment. Zildjian:ImmunoGen, Inc: Employment. Ruiz-Soto:ImmunoGen, Inc: Employment; Sanofi: Past employment within 1 year, Past employment within 1 year Other.

Abstract 1962 Background: Lorvotuzumab mertansine, also known as IMGN901 (huN901-DM1/BB-10901) is a novel anticancer agent consisting of a potent cytotoxic maytansinoid, DM1, attached to a CD56-binding monoclonal antibody, lorvotuzumab, using an engineered linker. Once bound to CD56 on a cancer cell and internalized, the DM1 is released to kill the cancer cell. Greater than 70% of multiple myeloma (MM) cases have surface expression of CD56. Safety information from the dose-escalation phase of this study was reported (ASH 114:2883, 2009) as the study was entering its expansion phase. Objectives: This study is designed to determine the MTD, pharmacokinetics (PK), and activity of IMGN901 used as monotherapy in patients with CD56+ MM, with additional information on its safety and efficacy to be obtained from its expansion phase. Methods: Patients with CD56+ relapsed or relapsed/refractory MM receive a single IV infusion of IMGN901 weekly for 2 consecutive weeks every 3 weeks. During the dose-escalation phase, patients were enrolled into each dose level in cohorts of 3, with dose-limiting toxicity (DLT) triggering cohort expansion. Once the MTD was determined, an expansion cohort was opened to further characterize the safety and efficacy of IMGN901 administered at its MTD. Results: Thirty-seven CD56+ MM patients have received IMGN901 at doses ranging from 40 to 140 mg/m2/week with 19 patients treated at the MTD of 112 mg/m2. Most of these 37 patients had been treated with 6 or more chemotherapy regimens prior to study entry. Among the 28 evaluable patients, 13 received IMGN901 treatment for more than three months, with 2 remaining on treatment for more than a year. Five of these patients achieved an objective response (OR) according to the European Bone Marrow Transplant Criteria – 2 partial responses and 3 minimal responses. The clinical benefit rate approximates 46%. Three patients have experienced four grade 3 drug-related toxicities that are considered at least possibly related to IMGN901: fatigue, renal failure, weakness, and absence of deep tendon reflexes. No grade 4 drug-related toxicities have been reported. No patients have demonstrated a humoral response against either the antibody or DM1 component of IMGN901. Conclusion: In this population of patients with heavily pretreated MM, IMGN901 demonstrates an ability to provide sustained clinical benefit and tolerability. This warrants its continued investigation as monotherapy and supports its investigation as part of a combination regimen. Disclosures: Jagannath: Millennium: Honoraria; Orthobiotec (Canada): Honoraria; Celgene: Honoraria; Merck: Honoraria; Onyx Pharma: Honoraria; Proteolix: Honoraria; Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom World Wide: Membership on an entity's Board of Directors or advisory committees; Optum Health Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees. Zildjian:ImmunoGen, Inc.: Employment. O'Leary:ImmunoGen, Inc.: Employment.

Abstract 1934 Background: Lorvotuzumab mertansine, also known as IMGN901 (huN901-DM1/BB-10901) is a novel anticancer agent consisting of a potent cytotoxic maytansinoid, DM1, attached to a CD56-binding monoclonal antibody, lorvotuzumab, using an engineered disulfide linker. Once bound to CD56 on a cancer cell and internalized, the conjugate releases DM1. About 78% of multiple myeloma (MM) cases have strong surface expression of CD56. In preclinical settings, IMGN901 showed significant in vitro and in vivo anti-myeloma activity as a single agent and in combination with approved drugs such as lenalidomide. IMGN901 has also been shown to be active and well tolerated as a single agent in a separate phase I study in patients with relapsed or relapsed/refractory MM. Objectives: To determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), pharmacokinetics (PK), and activity of IMGN901 in combination with lenalidomide and dexamethasone in patients with MM. Methods: Patients with CD56+ relapsed or relapsed/refractory MM receive IMGN901once weekly for 3 consecutive weeks every 4 weeks (Days 1, 8, 15 every 28 days). Lenalidomide (25mg) is taken orally once daily on Days 1 to 21 every 28 days and dexamethasone (40mg) is taken orally once weekly for 4 weeks (Days 1, 8, 15, and 22 every 28 days). The doses of lenalidomide and dexamethasone will remain fixed while escalating dose levels of IMGN901 are assessed. Patients are enrolled into each dose level in cohorts of 3, with DLTs triggering cohort expansion. Pharmacokinetics of IMGN901 and lenalidomide at the MTD will be collected, with exploratory pharmacodynamic studies planned. Results: The first dose cohort (75mg/m2 IMGN901) has been fully enrolled and accrual to the second dose cohort (90mg/m2) has commenced. There has been no DLT, no serious adverse events, and no drug-related grade 3 or 4 toxicities. Among the three patients enrolled in the 75mg/m2 dose cohort, by the end of cycle 2, one withdrew secondary to progressive disease (PD) and the other two had achieved a partial response (PR) based on the International Uniform Response Criteria for MM; the two patients with PRs remain on study. One of these patients had received 3 prior lines of therapy plus a transplant. This patient's PR has since improved to a very good partial response (as of end of Cycle 3). The other responding patient had received 4 prior treatment regimens plus 2 transplants. Conclusions: In this assessment of IMGN901 used in combination with lenalidomide and dexamethasone in patients with CD56+ relapsed or relapsed/refractory MM, objective evidence of clinical activity has been observed in two of the three patients who received the first dose level of IMGN901 evaluated. The combination has been well tolerated to date, MTD has not been defined and dose escalation continues. This very early experience is encouraging and supports the continued assessment of IMGN901 used in combination with lenalidomide and dexamethasone for patients with CD56+ relapsed or relapsed/refractory MM. Disclosures: Ailawadhi: Celgene: Speakers Bureau. Zildjian:ImmunoGen, Inc.: Employment. O'Leary:ImmunoGen, Inc.: Employment.

Abstract 2883 Poster Board II-859 Background: IMGN901 (huN901-DM1/BB-10901) is a novel anticancer agent consisting of a potent cytotoxic maytansinoid, DM1, attached to a CD56-binding monoclonal antibody, huN901, using an engineered linker. Once bound to CD56 on a cancer cell, the conjugate is internalized and releases DM1. About 70% of multiple myeloma (MM) cases have surface expression of CD56. In preclinical settings, IMGN901 showed significant in vitro and in vivo anti-myeloma activity as a single agent and in combination with approved drugs such as lenalidomide. Objectives: To determine the maximum tolerated dose (MTD), pharmacokinetics (PK), and activity of IMGN901, used as monotherapy, in patients with MM. Methods: Patients with CD56+ relapsed or relapsed/refractory MM receive a single IV infusion of IMGN901 on 2 consecutive weeks every 3 weeks. Patients are enrolled into each dose level in cohorts of 3, with dose-limiting toxicity (DLT) triggering cohort expansion. The European Bone Marrow Transplant (EBMT) criteria were used for response assessment. Results: Twenty-three CD56+ MM patients have received IMGN901 at doses ranging from 40 to 140 mg/m2/week. Most of these 23 patients had been treated with 6 or more chemotherapy regimens prior to study entry. Two of 6 patients treated at the 140 mg/m2/week dose experienced DLT (grade 3 fatigue and grade 3 acute renal failure) and a lower dose has been defined as the MTD. Commonly reported adverse events that were at least possibly related to IMGN901 were fatigue, increased aspartate aminotransferase, increased uric acid, sensory neuropathy and headache. None of the patients experienced serious hypersensitivity reactions or demonstrated a humoral response against either the antibody or DM1 component of IMGN901. Sustained partial response (PR) was documented in 1 patient treated at 140 mg/m2/week and 3 minor responses (MR) were reported in 1 patient each at doses of 60, 90, and 112 mg/m2/week. Of the 23 patients receiving any dose level of IMGN901, 8 remained on IMGN901 treatment for at least 15 weeks. Five of these 8 patients continued treatment on IMGN901 for at least 24 weeks, and two of these 5 patients remained on IMGN901 for at least 50 weeks. Preliminary PK results indicate an approximately linear relationship between dose and observed maximal serum concentration. Conclusion: This is the first study of IMGN901 in patients with MM. The MTD of this agent in MM patients is now defined. Our experience with IMGN901 in this clinical trial demonstrates an overall favorable safety profile. Although the primary objective of this clinical trial was to determine the MTD of single agent IMGN901, exciting single agent activity was observed in heavily pretreated MM patients. This is particularly encouraging as the duration of treatment with IMGN901 in some patients was longer than duration of treatment with prior regimens of approved agents. Clinical observations noted here (including single agent efficacy and the favorable toxicity profile) as well as findings from preclinical combination studies warrant continued investigation of this novel agent in patients with MM especially in combination with approved anti-myeloma agents/regimens such as lenalidomide and dexamethasone. Disclosures: Chanan-Khan: 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; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Merck: Honoraria. Miller:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Guild:ImmunoGen, Inc: Employment. Zildjian:ImmunoGen, Inc: Employment. Qin:ImmunoGen, Inc.: Employment. O'Leary:ImmunoGen, Inc.: Employment.

Background: IMGN901 (huN901-DM1) is a novel conjugate of the cytotoxic maytansinoid, DM1, with the humanized CD56-binding monoclonal antibody, N901. Once bound to CD56 on a cancer cell, the conjugate is internalized and releases DM1. About 70% of multiple myeloma (MM) cases have surface expression of CD56. Preclinical investigations demonstrated significant in vitro and in vivo anti-myeloma activity of IMGN901. Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of increasing doses of IMGN901 given for MM on a weekly schedule. Methods: Patients with relapsed or relapsed/refractory MM who have failed at least one prior therapy and have CD56-expressing MM received a single IV infusion of IMGN901 on 2 consecutive weeks every 3 weeks. Patients are enrolled in cohorts of 3 at each dose level, with DLT triggering cohort expansion. Results: Eighteen patients have received IMGN901 to date in this study - 3 patients each at 40, 60, 75, 90, 112, and 140 mg/m2/week. One patient experienced a DLT (grade 3 fatigue) on 140 mg/m2/week, and this cohort is being expanded to enroll up to 6 patients. No patients have experienced serious hypersensitivity reactions or evidence of presence of humoral responses against the huN901 antibody component (HAHA) or against the DM1 component (HADA). Preliminary PK results indicate an approximately linear relationship between dosing and observed maximal serum concentration. A confirmed minor response (MR) was documented in 3 heavily pretreated patients (1 patient each at 60, 90, and 112 mg/m2/week) using the European Bone Marrow Transplant criteria. Durable stable disease was reported at doses of 60, 90, 112, and 140 mg/m2/week. Of the 18 patients treated in the study, eight patients remained on treatment with IMGN901 for at least 15 weeks, five of these 8 patients remained on treatment for at least 24 weeks, and two of these 5 patients remained on treatment for at least 42 weeks. This phase I study provides preliminary evidence of safety as well as clinical activity of IMGN901 in patients with CD56-positive MM who have failed established MM treatments. Updated results of this ongoing study will be presented.