ASH December 2010 Efficacy Analysis from Phase I Study of Lorvotuzumab Mertansine (IMGN901) Used as Monotherapy in Patients with Heavily Pre-Treated CD56-Positive Multiple Myeloma Abstract # 1962 Chanan-Khan, A.1, Wolf, J.2, Garcia, J.3, Gharibo, M.4, Jagannath, S. 5, Manfredi, D.1 , Sher, T. 1, Martin, C.6, Weitman, S.7*, O’Leary, J.8*, Zildjian, S.8*, Bulger, E.8*, and Vescio, R.6 Roswell Park Cancer Institute, Buffalo, NY1; Medical Center of University of California San Francisco, San Francisco, CA2; Hospital Privado de Cordoba, Cordoba, Argentina3; Cancer Institute of New Jersey, New Brunswick, NJ4; St. Vincent’s Comprehensive Cancer Center, New York, NY5; Cedars-Sinai Samuel Oschin Cancer Center, Los Angeles, CA6; The University of Texas Health Science Center at San Antonio, San Antonio, TX7; ImmunoGen, Inc., Waltham, MA8; Background Objectives Results Continued • Lorvotuzumab mertansine (IMGN901) is a novel antibody-drug Primary Table 3: Treatment-Related Adverse Events Experienced by >10% of Patientsa Figure 3 : Treatment Duration (n=37) conjugate (ADC) composed of a CD56-targeting antibody with the • To determine the dose-limiting toxicity (DLT) and maximum tolerated dose maytansinoid, DM1, attached via a disulfide linker. (MTD), and the recommended phase II dose of single agent lorvotuzumab Lorvotuzumab mertansine dose (mg/m2) • CD56 is a neural cell adhesion molecule (NCAM) with surface mertansine. 40 60 75 90 112 140 Total Treatment Duration in Cycles expression in approximately 70% of multiple myeloma cases. Other Secondary n=3 n=3 n=3 n=3 n=19 n=6 n=37 tumor types expressing CD56 include small cell lung cancer, Merkel cell • To determine the qualitative and quantitative toxicities of single agent MR PR All MR carcinoma, ovarian cancer and neuroendocrine tumors. lorvotuzumab mertansine. Preferred Term All Gr Gr 3 All Gr Gr 3 All Gr Gr 3 All Gr Gr 3 All Gr Gr 3 All Gr Gr 3 Grades Grade 3 PR • In preclinical xenograft models, lorvotuzumab mertansine has • To evaluate the pharmacokinetics of single agent lorvotuzumab mertansine. Headache 1 2 5 4 12 demonstrated potent anti-tumor activity as monotherapy and in • To evaluate overall objective response rate and duration of response (DOR). MR * Fatigue 6 5 2 11 2 combination in several models of human malignancy including multiple • To assess time to progression, progression free survival and overall survival. myeloma. Neuropathyb 1 1 6 2 2 10 2 MR • In clinical trials assessing alternative dosing schedules, lorvotuzumab Methods AST increased 1 3 2 1 7 mertansine has been found to have an acceptable safety profile and has Constipation 1 2 3 6 demonstrated activity signals in a variety of CD56+ tumor types. Trial Design Diarrhea 5 1 6 • Reported here is the safety and activity of lorvotuzumab mertansine 37 Patients • Phase I multi-center, dose escalation study with 3+3 design. Nausea 1 2 2 5 when administered as single agent therapy to patients with CD56- • The MTD defined as the highest dose at which no more than 1/6 patients Anorexia 1 2 2 5 postiive multiple myeloma. experienced a DLT in cycle 1. • Once MTD was declared, up to 40 patients are to be enrolled (expansion Paraesthesia 4 1 5 Figure 1: Lorvotuzumab Mertansine Structure and Routes of phase). Asthenia 1 2 1 1 4 1 Intracellular Activation • Responses are assessed using the European Blood and Bone Marrow ALT increased 1 1 2 4 Transplantation (EMBT) criteria. Blood Uric Acid 0 102030405055 85 linker DM1 Treatment Scheme Increased 1 1 2 4 O Lorvotuzumab Number of Weeks S S CH3 Humanized IgG1 antibody • Lorvotuzumab mertansine is administered as an intravenous (IV) infusion Myalgia 1 2 1 4 LorvotuzumabhuN901 HN NO • 40 60 75 90 112 140 O CH3 once weekly for two weeks every three weeks. 2 H3C O Conjugated to DM1 Dose Limiting Criteria a. Patients who experienced the same coded event more than once are counted only once under that coded event. (Dose Cohort mg/m ) CH3 O b. Neuropathy includes sensory neuropathy and peripheral neuropathy. Cl N O • Derivative of maytansine • Any of the following that are at least possibly related to lorvotuzumab CH3 • Antimitotic – inhibits tubulin Minimal Response (MR) H3CO mertansine: There were no treatment-related Grade 4 adverse events (AE). The grade 3 treatment-related AEs that are not included in CH3 O polymerization • Grade 4 neutropenia ≥ 5 days. this table (experienced by less than 10% of patients) are neutropenia (1 patient at 112 mg/m2), areflexia (1 patient at 140 Partial Response (PR) O Attached to antibody via a * Patient ongoing at time of data cut off. N • • Grade 3 or greater febrile neutropenia or Grade 4 thrombocytopenia. 2 2 H CO HO H mg/m ) and renal failure (1 patient at 140 mg/m ). Renal failure and fatigue were deemed the dose-limiting toxicities. CH 3 disulfide linker 3 • Grade 3 or 4 non-hematological toxicity (excluding alopecia or sub- n optimally treated nausea, vomiting or diarrhea). Figure 4: Case Descriptions n ~ 3.5 (DM1 is ~ 1.8% by weight of Mab) • Any other lorvotuzumab mertansine-related toxicity deemed dose limiting. Eligibility Case Description: Patient 0226 Monoclonal Protein (0232) Case Description: Patient 0244 Major Inclusion Criteria 5 450 • 62 year old female with stage III relapsed multiple myeloma with • 57 year old male with stage III relapsed/refractory multiple myeloma Bind to antigen • Diagnosed of multiple myeloma (CD56-positive) based on standard criteria. 400 multiple bone lesions. 4 on cell surface Internalization • Age ≥ 18 years and ECOG performance status of 0-2. 350 with multiple bone lesions. via endocytosis • One prior treatment with bortezomib, doxorubicin and 300 • Multiple radiation therapies and 6 prior lines of chemotherapy (most • Standard oncology phase I laboratory inclusion criteria. 3 Disulfide thalidomide (partial response). Progressed 3 months later. 250 recent treatment with cyclophosphamide). Progressive disease cleavage Major Exclusion Criteria 2 2 200 Tubulin • Treatment at 140 mg/m . The patient received 26 cycles of within 8 months of last therapy. DM1 • Significant residual neurological or cardiac toxicity from prior therapy. 150 Serum g/dL 2 Traffic to lorvotuzumab mertansine, and achieved partial response 1 100 Urine mg/24hr • Treatment at 112 mg/m . The patient has received 6 cycles of Lysosome • History of significant underlying cardiac disorders. Lysine-LINK-DM1 DM1 (duration of response 13 months) with a reduction of serum M 50 treatment and has achieved minimal response with a 42% reduction Disulfide • History of multiple sclerosis or other demyelinating disease or any CNS injury 0 0 Cleavage Tubulin component of 52%. in serum M component. Cancer Cell with residual neurological deficit. Jul-09 Oct-09 Jan-10 May-10 Aug-10 Degradation of • Patient decision to discontinue treatment. • Patient remains active on study. MAb in lysosome • Previous sensitivity to monoclonal antibody therapy. Bystander Serum Urine Cancer Cell • Prior malignancy within the last 3 years. Monoclonal Protein (0226) Monoclonal Protein (0244) Erickson et al, 2006 5 450 5 450 Results 400 Case Description: Patient 0232 400 4 350 • 51 year old male with stage III relapsed multiple myeloma with bone and 4 350 Lorvotuzumab mertansine binds with high affinity to CD56 expressed on the 300 soft tissue lesions. 300 surface of tumor cells. The conjugate is then internalized. Inside the cell, Table 1: Cohort Size (n=37) 3 250 3 250 • One prior treatment with bortezomib, doxorubicin and thalidomide DM1 is released by cleavage of the disulfide linker. The DM1 disrupts tubulin 2 200 2 200 Dose (mg/m2) 40 60 75 90 112 140 Total 150 (partial response). Progressed ~10 months later. 150 polymerization and microtubule assembly. Serum g/dL Serum g/dL 100 Urine mg/24hr 2 100 1 • Treatment at 112 mg/m . The patient received 10 cycles of lorvotuzumab 1 mg/24hr Urine Patients (n) 33 3 319637 50 50 Figure 2: Dose Response of Lorvotuzumab Mertansine in Myeloma mertansine, and achieved partial response with a 46% decrease in 0 0 0 0 Xenograft Models serum M component. Table 2: Patient Demographics and Disease Characteristics (n=37) Jun-08 Dec-08 Jul-09 Jan-10 Aug-10 May-10 Jul-10 Aug-10 Sep-10 Oct-10 • Investigator decision to discontinue treatment due to a slight decrease in response and increase in neuropathy (grade 2). NCI-H929 MOLP-8 Median Age, years (range) 61 (39-85) Serum Urine Serum Urine 2000 2000 ) 3 ) 3 Gender, n (%) 1500 1500 Table 4: Pharmacokinetics (n=37) Conclusions Male 21 (57) • The MTD has been identified as 112 mg/m2 and is being explored for activity in a less 1000 1000 Female 16 (43) Dose 40 60 75 90 112 140 heavily pretreated patient population (6 or fewer prior treatments) in the expansion phase. (mg/m2) ECOG Performance Status at Screening, n (%) • Preliminary pharmacokinetic data suggests that exposure and maximum plasma 500 500 Plasma Exposure (AUC) observed 0 23 (62) concentration of lorvotuzumab mertansine increase with increasing dose. Elimination half life MeanTumor Volume (mm Mean tumor volume (mm Number 4000 remains similar at all dose levels. 0 0 3 3 3 3 19 6 20 40 60 80 100 120 15 25 35 45 55 65 1 13 (35) patients (n) • Lorvotuzumab mertansine was generally well tolerated in this heavily pretreated population Days after Tumor Inoculation Days after Tumor Inoculation 2 1 (3) of patients. There was no clinically significant myelosuppression. Mild-to-moderate PBS PBS 3000 headache, fatigue and neuropathy were the most commonly reported treatment-related IMGN901, 7 mg/kg qw x2 IMGN901, 7 mg/kg qw x2 Race, n (%) Cmax 32.8 ± 53.3 ± 42.9 ± 49.3 ± 55.1 ± 81.5 ± IMGN901, 13 mg/kg qw x2 IMGN901, 13 mg/kg qw x2 adverse events.