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Background Subcutaneous injections of anti-CD20 antibodies may offer benefits to both patients and the healthcare system for treatment of B-cell malignancies. Design and Methods A pilot study was undertaken to evaluate the potential for subcutaneous dosing with 2nd generation anti-CD20 antibody veltuzumab in patients with CD20+ indolent non-Hodgkin’s lymphoma. Patients with previously untreated or relapsed disease received 4 doses of 80, 160, or 320 mg veltuzumab injected subcutaneously every two weeks. Responses were assessed by computed tomography scans, with other evaluations including adverse events, safety laboratories, B-cell blood levels, serum veltuzumab levels, and human anti-veltuzumab antibody (HAHA) titers. Results Seventeen patients (14 follicular lymphoma; 13 stage III or IV disease; 5 treatment-naive) completed treatment with only occasional, mild-moderate, transient injection reactions and no other safety issues. Subcutaneous veltuzumab demonstrated a slow release pattern over several days, achieving a mean Cmax of 19, 25 and 63 μg/mL at 80, 160, and 320 mg doses for a total of 4 administrations, respectively. Depletion of circulating B cells occurred after the first injection. The objective response rate (partial responses plus complete responses plus complete responses unconfirmed) was 47% (8/17) with a complete response/complete response unconfirmed rate of 24% (4/17); 4 of 8 objective responses continued for 60 weeks or more. All serum samples evaluated for human anti-veltuzumab antibody were negative. Conclusions Subcutaneous injections of low-dose veltuzumab are convenient, well tolerated, and capable of achieving sustained serum levels, B-cell depletion, and durable objective responses in indolent non-Hodgkin’s lymphoma. ([Clinicaltrials.gov][1] identifier: [NCT00546793][2]) [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00546793&atom=%2Fhaematol%2F96%2F4%2F567.atom

Purpose Fractionated radioimmunotherapy targeting CD22 may substantially improve responses and outcome in non-Hodgkin's lymphoma (NHL). Patients and Methods A multicenter trial evaluated two or three weekly infusions of yttrium-90 (90Y) epratuzumab tetraxetan (humanized anti-CD22 antibody) in 64 patients with relapsed/refractory NHL, including 17 patients who underwent prior autologous stem-cell transplantation (ASCT). Objective (OR) and complete responses (CR/complete response unconfirmed [CRu]), as well as progression-free survival (PFS), were determined. Results At the maximum total 90Y dose of 45 mCi/m2 (1,665 MBq/m2), grade 3 to 4 hematologic toxicities were reversible to grade 1 in patients with less than 25% bone marrow involvement. The overall OR rate and median PFS for all 61 evaluable patients was 62% (CR/CRu, 48%) and 9.5 months, respectively. Patients without prior ASCT obtained high OR rates of 71% (CR/CRu, 55%) across all NHL subtypes and 90Y doses, even in poor-risk categories (refractory to last anti-CD20–containing regimen, 73% [CR/CRu, 60%]; bulky disease: 71% [CR/CRu, 43%]). Patients with prior ASCT received lower doses, but achieved an OR rate of 41% (CR/CRu, 29%). For patients with follicular lymphoma (FL), OR rates and median PFS increased with total 90Y-dose, reaching 100% (CR/CRu, 92%) and 24.6 months, respectively, at the highest dose levels (> 30 mCi/m2 total 90Y-dose [1,110 MBq/m2]). Further, patients with FL refractory to prior anti-CD20–containing regimens achieved 90% (nine of 10 patients) OR and CR/CRu rates and a median PFS of 21.5 months. Conclusion Fractionated anti-CD22 radioimmunotherapy provides high total doses of 90Y, yielding high rates of durable CR/CRus in relapsed/refractory NHL, resulting in 20 mCi/m2 × 2 weeks as the recommended dose for future studies.

Purpose This is a multicenter phase I/II dose-finding study in relapsed/refractory B-cell non-Hodgkin's lymphoma (NHL) evaluating veltuzumab, a humanized anti-CD20 antibody with structure-function differences from chimeric rituximab. Patients and Methods Eighty-two patients (median age, 64 years; 79% stage III/IV, one to nine prior treatments) received four once-weekly doses of 80 to 750 mg/m2 of veltuzumab and were assessed for safety, efficacy, pharmacodynamics, pharmacokinetics, and immunogenicity. Results Veltuzumab was well tolerated, with no grade 3 to 4 drug-related adverse events despite short infusion times (typically 2 hours initially, 1 hour subsequently at doses < 375 mg/m2). In follicular lymphoma, 24 (44%) of 55 patients had objective responses (OR), with 15 (27%) complete responses (CRs) or CRs unconfirmed (CRus) by International Working Group criteria, and with some responses occurring despite two to five prior rituximab-containing regimens, less favorable prognosis (elevated lactate dehydrogenase, tumors > 5 cm, and Follicular Lymphoma International Prognostic Index ≥ 2), and at all dose levels. The CRs/CRus were durable (median duration, 19.7 months), with five patients still ongoing (15.9 to 37.6 months duration). In marginal zone lymphoma, five (83%) of six patients had ORs, with two CRs/CRus (33%), and in diffuse large B-cell lymphoma, three (43%) of seven patients achieved partial responses. At all dose levels studied, B cells were depleted after the first infusion, veltuzumab serum half-lives were similar after the fourth infusion, and mean antibody serum levels exceeded values considered important for anti-CD20 therapy (ie, 25 μg/mL). Conclusion Veltuzumab appeared safe and active at all tested doses, encouraging further study, including dose levels less than those typically used with rituximab.

Purpose: Humanized antibody hPAM4 specifically binds a mucin glycoprotein expressed in pancreatic adenocarcinomas. This phase I study evaluated a single dose of 90Y-clivatuzumab tetraxetan (90Y-labeled hPAM4) in patients with advanced pancreatic cancer. Experimental Design: Twenty-one patients (4 stage III; 17 stage IV) received 111In-hPAM4 for imaging and serum sampling before 90Y-hPAM4. Study procedures evaluated adverse events, safety laboratories, computed tomography (CT) scans, biomarkers, pharmacokinetics, radiation dosimetry, and immunogenicity (HAHA). Results: 111In-hPAM4 showed normal biodistribution with radiation dose estimates to red marrow and solid organs acceptable for radioimmunotherapy and with tumor targeting in 12 patients. One patient withdrew before 90Y-hPAM4; otherwise, 20 patients received 90Y doses of 15 (n = 7), 20 (n = 9), and 25 mCi/m2 (n = 4). Treatment was well tolerated; the only significant drug-related toxicities were (NCI CTC v.3) grade 3 to 4 neutropenia and thrombocytopenia increasing with 90Y dose. There were no bleeding events or serious infections, and most cytopenias recovered to grade 1 within 12 weeks. Three patients at 25 mCi/m2 encountered dose-limiting toxicity with grade 4 cytopenias more than 7 days, establishing 20 mCi/m2 as the maximal tolerated 90Y dose. Two patients developed HAHA of uncertain clinical significance. Most patients progressed rapidly and with CA19-9 levels increasing within 1 month of therapy, but 7 remained progression-free by CT for 1.5 to 5.6 months, including 3 achieving transient partial responses (32%–52% tumor diameter shrinkage). Conclusion: 90Y-Clivatuzumab tetraxetan was well tolerated with manageable hematologic toxicity at the maximal tolerated 90Y dose, and is a potential new therapeutic for advanced pancreatic cancer. Clin Cancer Res; 17(12); 4091–100. ©2011 AACR.

BACKGROUND. In this international, multicenter trial, the authors evaluated rituximab (anti-CD20) plus epratuzumab (anti-CD22) in patients with postchemotherapy relapsed/refractory, indolent non-Hodgkin lymphoma (NHL), including long-term efficacy. METHODS. Forty-nine patients with follicular NHL (FL) (N = 41) or small lymphocytic lymphoma (SLL) (N = 7) received intravenous epratuzumab 360 mg/m2 and then intravenous rituximab 375 mg/m2 weekly ×4. The regimen was tolerated well. RESULTS. Twenty-two of 41 patients with FL (54%) had an objective response (OR), including 10 (24%) complete responses (CR) (CR/unconfirmed CR [CRu]), whereas 4 of 7 patients with SLL (57%) had ORs, including 3 (43%) with CR/CRu. Rituximab-naive patients (N = 34) had an OR rate of 50% (26% CR/CRu rate), whereas patients who previously responded to rituximab (N = 14) had an OR rate of 64% (29% CR/CRu rate). An OR rate of 85% was observed in patients with FL who had Follicular Lymphoma International Prognostic Index (FLIPI) risk scores of 0 or 1 (N = 13), whereas 28 patients with intermediate or high-risk FLIPI scores (≥2) had an OR rate of 39% (18% CR/CRu rate). In patients with FL, the median response duration was 13.4 months, and that duration increased to 29.1 months for 10 patients who had a CR/CRu, including 4 patients who had durable responses with remissions that continued for >4 years. In patients with SLL, the median response duration was 20 months, including 1 patient who had a response that continued for >3 years. CONCLUSIONS. The combination of epratuzumab and rituximab induced durable responses in patients with recurrent, indolent NHL. Cancer 2008. © 2008 American Cancer Society.

PurposeA multicenter, single-arm study examining efficacy and toxicity of epratuzumab combined with rituximab was conducted in patients with recurrent or refractory non-Hodgkin's lymphoma.Patients and MethodsSixty-five patients were enrolled; 34 patients with follicular lymphoma (FL), 15 patients with diffuse large B-cell lymphoma (DLBCL), and 16 patients with other lymphomas. The patients had received a median of two prior therapies (range, 1 to 4); 23% had received rituximab. Epratuzumab was given at 360 mg/m2intravenously over 60 minutes followed by infusion of 375 mg/m2rituximab, weekly for 4 consecutive weeks.ResultsCombination therapy was well tolerated without greater toxicity than rituximab alone. The objective response (OR) rate was 47% (30 of 64) in assessable patients (46%; 30 of 65 in all patients), being highest in FL (64%; 21 of 33) and DLBCL (47%; seven of 15), and with 24% (eight of 33) and 33% (five of 15) achieving complete response (CR) or complete response unconfirmed (CRu) in these two groups, respectively. Two of six patients with marginal zone lymphoma responded to treatment (one CR). There was a trend for the response rates to be higher in patients with low prognostic index scores (statistically significant with respect to the Follicular Lymphoma International Prognostic Index score in FL patients), with 12 FL patients and three DLBCL patients in groups 0 to 1 having OR (CR/CRu) rates of 83% (33%) and 100% (100%), respectively. The median duration of response was 16 months for FL, with five patients currently progression free for 18 months to 30 months, and 6 months for DLBCL, with two patients currently progression free for 12 months and 18 months.ConclusionEpratuzumab combined with rituximab was well tolerated, demonstrating promising antilymphoma activity that warrants additional study.

240 Background: The90Y-labeled anti-mucin humanized mAb, clivatuzumab tetraxetan (90Y-hPAM4), is in clinical development in APC. A phase I/II trial of 90Y-hPAM4 with low-dose radiosensitizing Gem has now concluded 90Y-dose escalation. Methods: Pts with untreated, inoperable, stage 3-4 APC received 200 mg/m2 Gem once-weekly x 4 with 90Y-hPAM4 on wks 2-4, and with 90Y escalated in cohorts by 3+3 design. Tumor responses were assessed by CT, FDG/PET and serum CA19.9, with cycles repeated until progression or unacceptable toxicity. Results: Of 42 pts (40-87 yrs, ECOG PS 0-1, 36 stage 4), 4 withdrew early while 38 received weekly x 3 90Y doses of 6.5 (N=4), 9 (N=12), 12 (N=17) and 15 (N=5) mCi/m2. Treatment was well-tolerated with few non-hematologic side-effects, including 13 pts retreated with 1-3 additional cycles. CTCv3 grade 3-4 plts or ANC developed in 21/38 (55%) pts after cycle 1 and all (100%) retreated pts after last cycle. Escalation reached limits on radiation doses to the marrow, but hematologic suppression was reversible without major infections or bleeding events, except for 3 pts after repeated cycles, one with extensive marrow tumor infiltration. By CT, the overall disease control rate was 55%, including 6 pts (16%) with partial responses (PRs) by RECIST criteria and 15 pts (39%) with stabilization as best response. After cycle 1, 43% (10/23) improved by PET studies (negative or >25% reduced uptake), and 36% (9/25) with elevated CA19.9 levels had >50 decreases. With 26% (10/38) of pts still in follow-up, 55% (21/38) have now achieved survival of ≥ 6 months [18% (7/38) ≥ 1 yr]. Treatment outcome may increase with 90Y dose, since pts treated at 3 x ≥12 mCi/m2 vs ≤9 mCi/m2 had 19% vs 6% PRs by CT, 47% vs 22% CA19.9 decreases, 63% vs 25% PET improvement, and 64% vs. 44% survival ≥ 6 months. Anecdotally, PS and pain level improved, which needs validation. Updated survival will be presented at the meeting. Conclusions: Fractionated 90Y-hPAM4 plus low-dose Gem showed encouraging therapeutic activity with manageable hematological toxicity. The 12-mCi/m2 dose level was selected for continued dose exploration now underway, involving standard Gem doses and adding maintenance Gem. [Table: see text]

Abstract 3757 Poster Board III-693 Background Low IV doses of veltuzumab, a 2nd generation humanized anti-CD20 monoclonal antibody with structure-function differences from chimeric rituximab, have shown clinical activity in non-Hodgkin's lymphoma (Morschhauser et al., J Clin Oncol, 2009; 27:3346-53). By avoiding lengthy IV administration and the need for dedicated infusion suites, subcutaneous (SC) injections of low-dose veluzumab may offer benefits to both patients and the healthcare system for treatment of B-cell malignancies, and this may be particularly useful in the setting of indolent disease. Methods A multicenter, phase I/II study was undertaken to evaluate the safety, tolerability, and preliminary efficacy of SC veltuzumab in previously untreated or relapsed CD20+ indolent non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). All patients (pts) received 4 SC injections of veltuzumab 2 weeks apart at dose levels of 80, 160, or 320 mg. Efficacy was assessed by CT-based IWG (NHL) or hematology-based NCI/IWCLL (CLL) criteria 4 and 12 weeks later, with responding pts continuing follow-up. Other evaluations included AEs, safety laboratories, B-cell blood levels (CD19), serum veltuzumab levels, and human anti-veltuzumab antibody (HAHA) titers. Results Twenty-six pts (10M/16F, median age 64), including 15 NHL pts (12 follicular, 3 other indolent NHL; 5 treatment naïve) most with stage III or IV disease (12/15), and 11 CLL pts (4 treatment naïve) most with Rai stage II or III disease, have now received SC veltuzumab at 80 mg (3 NHL, 3 CLL), 160 mg (9 NHL, 3 CLL) or 320 mg (3 NHL, 5 CLL) dose levels. Pre-treatment with antihistamines or steroids was not required. SC veltuzumab was well tolerated with only mild, transient injection-site reactions and tenderness, and no other safety issues. To date, all HAHA response results have been negative. In NHL pts, SC veltuzumab demonstrated good bio-availability, with a slow release pattern over several days, and a mean Cmax of 18.7, 19.5 and 64.0 μg/mL at 80, 160, and 320 mg dose levels, respectively. Depletion of circulating B cells was observed starting after 1st injection. In the 15 NHL pts, the objective response rate (CR+CRu+PR) was 53% (8/15) with a complete response (CR) rate of 20% (3/15) and with 7/8 ORs currently continuing in remission, up to 6 months after treatment. The 11 CLL pts presented with mean white blood cell levels of 55K/μL (maximum 122K/μL) and achieved much lower serum veltuzumab levels, with mean Cmax values of 4.0, 2.5 and 21.0 μg/mL at the 80, 160, and 320 mg dose levels, respectively. There were no ORs, but 5 of 7 (71%) CLL pts with response assessments currently available showed stable disease with >70% decreases in B-cell levels for up to 12 weeks. Conclusions SC administration of veltuzumab is well tolerated, achieves slow but efficient delivery into the blood, and is pharmacologically active when given every 2 weeks for a total of 4 doses. In CLL with high levels of circulating leukemic cells, more frequent and prolonged dosing is likely required. However, in NHL, these low SC doses achieved sustained serum levels with objective response rates comparable to those seen even with higher IV doses. Disclosures: Negrea: Immunomedics: Research Funding. Off Label Use: veltuzumab for investigational treatment of NHL/CLL. Allen:Immunomedics: Research Funding. Rai:Immunomedics: Research Funding. Elstrom:Immunomedics: Research Funding. Abassi:Immunomedics: Research Funding. Farber:Immunomedics: Research Funding. Teoh:Immunomedics: Employment. Horne:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.

Abstract 1322 Poster Board I-344 Background Veltuzumab, a 2nd-generation humanized anti-CD20 monoclonal antibody with structure-function differences from rituximab, has demonstrated clinical activity at low doses in non-Hodgkin's lymphoma (Morschhauser et al., J Clin Oncol, 2009; 27:3346-53). Since chimeric anti-CD20 rituximab is therapeutically active in ITP, we conducted a clinical trial of low-dose veltuzumab in ITP, initially administered by intravenous (IV) infusion, but following development of a high-concentration formulation, now administered by subcutaneous (SC) injection. Methods A multicenter, phase I/II study was undertaken to evaluate the safety and tolerability of low-dose veltuzumab in adults who had ITP for at least 6 months, had failed ≥1 standard therapy, and presented with platelets ≤30K/≤L, but without major bleeding. All patients received 2 doses of veltuzumab 2 weeks apart (without steroids) and were followed for up to 12 weeks, with responding patients continuing in long-term follow-up. Efficacy was assessed by an increase in platelet count with confirmation at least 1 week apart. Responses were classified as complete (CR, >150K/μL), partial (PR, 50-150K/μL), or minor (MR, 30-50K/μL). Adverse events and safety laboratories were evaluated using NCI CTC v3 toxicity grades. Other evaluations included circulating B-cell levels (CD19), veltuzumab serum levels, and human anti-veltuzumab antibody (HAHA) titers. Results The study has enrolled 25 patients (7M/18F, 21-92 years old, 5 post-splenectomy) with 7 receiving 2 IV veltuzumab doses at 80 (N=3), 120 (N=3), or 200 mg (N=1), and 10 receiving 2 SC doses at 80 (N=3), 160 (N=4), or 320 mg (N=3) during the completed Phase I portion of the study. The Phase II portion is now underway with 8 additional patients having received 2 SC veltuzumab doses at 320 mg. The 25 patients had a median duration of ITP of 1.8 years (range 0.2 - 20) with previous treatments including steroids (N=24), IVIG/anti-D (N=15), azathioprine/danazol (N=7), rituximab (N=5), TPO-R agonists (N=3) and vincristine/Doxil (N=2). One patient had a Grade 3 infusion reaction after receiving ∼100 mg veltuzumab at first IV dose. Otherwise veltuzumab was well tolerated with a limited number of Grade 1 infusion/injection reactions and no other safety issues. B cells were depleted rapidly with both IV and SC dosing with recovery times yet to be determined. At 80 and 120 mg x 2, IV veltuzumab achieved expected serum levels (mean Cmax 20.3 and 46.0 μg/mL, respectively) with a mean serum half-life of ∼1 week after last dose. SC veltuzumab had slower release over several days with lower serum levels, but comparable availability/exposure. Two patients developed low-level HAHA titers of uncertain clinical significance. Of 21 patients now with post-treatment response assessments, 13 (62%) achieved an objective response (CR+PR+MR), including 6 (29%) CRs. Responses, including CRs, occurred with both SC and IV administrations, and across all dose levels, with the highest OR (CR) rate of 100% (60%) seen in patients with more recently diagnosed ITP (≤1 year), albeit in small numbers of patients (N=5). Of 6 CRs, 5 are still continuing with a current median duration of response of 9 months (2.5 - 15 mo.) Conclusions Low-dose veltuzumab (2 doses, 2 weeks apart) demonstrates promising activity in relapsed ITP, including durable complete responses. Compared to IV infusions, subcutaneous injections offer practical benefits to both patients and the healthcare system, and the study is continuing to provide additional/confirmatory data for further clinical development of SC veltuzumab in ITP. Disclosures Saleh: Immunomedics: Research Funding. Off Label Use: veltuzumab, an investigational anti-CD20 antibody in clinical studies. Liebman:Immunomedics: Research Funding. Bernstein:Immunomedics: Research Funding. Negrea:Immunomedics: Research Funding. Bussel:Immunomedics: Research Funding. Onyegbula:Immunomedics: Research Funding. Farber:Immunomedics: Research Funding. Abassi:Immunomedics: Research Funding. Cosgriff:Immunomedics: Research Funding. Pennington:Immunomedics: Research Funding. Horne:Immunomedics: Employment. Teoh:Immunomedics: Employment. Gomaa:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.

8593 Background: CD74 (HLA-DR-associated invariant chain) is highly expressed in multiple myeloma (MM), rapidly internalized, and a promising target for immunotherapy. Methods: A multicenter dose-escalation study was initiated in patients (pts) with relapsed/refractory MM who had failed at least 2 standard therapies. Pts received milatuzumab IV twice-weekly for 4 wks, with doses escalated by a 3+3 cohort design. Pts were evaluated over 12 wks, with responding pts continuing follow-up. AEs and safety laboratories were evaluated by NCI CTC v3 grades, with any treatment-related Grade 3–4 events considered dose-limiting toxicity (DLT). Responses were classified by EBMT criteria, with PK and immunogenicity evaluated by serum milatuzumab levels and human anti-milatuzumab antibody (HAHA) titers, respectively. Results: Twenty-one pts (12M/9F, median age 63) have now received 1.5 (n=8), 4.0 (n=9) or 8.0 mg/kg (n=4) doses twice weekly. They had MM for 0.9–16.8 years (median 5.4), predominantly IgG subtype, were heavily pretreated (4 median prior treatments), and were Durie-Salmon stage II (n=13) or III (n=8). After increasing premedications and slowing administration, infusions were well tolerated (Grade 1–2). There was 1 DLT (infusion reaction) and 3 SAEs (bact. meningitis, confusion/hypercalcemia, fever post demerol) at 1.5 mg/kg, 1 DLT (unexplained anemia) and 2 SAEs (cord compression, epistaxis/thrombocytopenia), at 4.0 mg/kg, but no DLTs or SAEs at 8.0 mg/kg. There has been no pattern of other AEs nor effects on routine laboratories, including serum chemistries, CBC, serum immunoglobulins, B- or T-cells, and no cases of HAHA. At current doses, milatuzumab is rapidly cleared from serum, with little accumulation and low trough levels across infusions. There have been no objective responses so far, but 4 pts have had stable disease by EBMT criteria for at least 3 months post-treatment, occurring with a possible trend towards higher milatuzumab serum levels than pts with earlier disease progression. Conclusions: Milatuzumab doses up to 8.0 mg/kg may be given safely twice-weekly for 4 weeks. In spite of rapid clearance, several patients have had disease stabilization at 4.0 and 8.0 mg/kg doses, which is encouraging. Accrual of the next cohort receiving 16.0 mg/kg is ongoing. [Table: see text]

8530 Background: Low IV doses of veltuzumab, a second-generation anti-CD20 monoclonal antibody with structure-function differences from chimeric rituximab, have shown clinical activity, thus justifying subcutaneous (SC) injections. Methods: A phase I/II study was initiated in patients (pts) with previously untreated or relapsed CD20+ indolent NHL or CLL who received 4 SC injections of veltuzumab 2 weeks apart at dose levels of 80, 160, or 320 mg. Efficacy was assessed by CT-based IWG (NHL) or hematology-based NCI/IWCLL (CLL) criteria 4 and 12 weeks later, with responding pts continuing follow-up. Other evaluations included AEs, safety laboratories, B-cell blood levels (CD19), serum veltuzumab levels, and human anti-veltuzumab antibody (HAHA) titers. Results: Nineteen pts (8M/11F, median age 63), including 14 NHL pts (11 follicular, 3 other indolent NHL; 5 treatment naive) most with stage III or IV disease (11/14) and 5 CLL pts (4 treatment naïve) all with Rai stage II or III disease, have now received SC veltuzumab at 80 mg (3 NHL, 3 CLL), 160 mg (9 NHL, 2 CLL) or 320 mg (2 NHL) dose levels. Pre-treatment with antihistamines or steroids has not been required, and SC veltuzumab was well tolerated with only mild, transient injection site reactions and tenderness. To date, all HAHA results have been negative. In NHL pts, SC veltuzumab demonstrates good bio-availability, with a slow release pattern over several days and depletion of circulating B cells starting after 1st injection. Initial response information is currently available for 10 pts. For 7 NHL pts, 4 weeks after treatment with 80 or 160 mg doses, 2 pts had partial responses, 3 pts showed stable disease, and 2 pts had disease progression. For 3 CLL pts who received 80 mg doses, serum veltuzumab levels were lower, but all pts still achieved 65–75% decreases in circulating leukemic cells over the course of treatment. Conclusions: SC administration of veltuzumab is well tolerated, achieves slow but efficient delivery into the blood, and is pharmacologically active. The low doses currently evaluated in B-cell malignancies show evidence of therapeutic activity, achieving objective responses in NHL and notable reductions in circulating leukemic cells in CLL. [Table: see text]

BACKGROUND: Veltuzumab (hA20), a humanized MAb with significant structurefunction differences from rituximab, has shown clinical activity at low doses in non- Hodgkin’s lymphoma. Since anti-CD20 immunotherapy has demonstrated activity in ITP with standard doses of rituximab, we hypothesized that low-dose veltuzumab would be effective in this disorder, thus also justifying subcutaneous injections. The goal of this first study in ITP is to evaluate the safety and tolerability of veltuzumab administered at low doses either intravenously or by subcutaneous injection, to obtain information on efficacy, pharmacodynamics, pharmacokinetics, and immunogenicity, and to determine feasible doses for further studies. METHODS: A multicenter, phase I/II study was initiated in adult ITP patients with platelets 6 months, who had failed ≥1 standard therapy. Patients were administered 2 doses of veltuzumab 2 weeks apart and evaluated for efficacy over 12 weeks, with responding patients continuing evaluation in long-term follow-up. Efficacy was assessed by platelet level responses with increases confirmed at least 1 week apart classified as complete (CR, >150K/μL), partial (PR, 50–150K/μL), or minor (MR, 30–50K/μL) responses. Adverse events and safety laboratories were evaluated by NCI CTC v3 toxicity grades. Pharmacodynamics were evaluated by B-cell levels (CD19), while pharmacokinetics and immunogenicity were evaluated by serum veltuzumab levels and human anti-veltuzumab antibody (HAHA) titers, respectively, using an ELISA assay performed by the Sponsor. RESULTS: Seven patients (5F/2M, median age 41, 2 splenectomized) have now received intravenous veltuzumab at doses of 80 mg (N=3), 120 mg (N=3) or 200 mg (N=1). They had ITP for 0.5 – 12 years, had received prior steroids (N=7), IVIG and/or WinRho (N=6), or chemotherapy (N=3), and had 6–27 K platelets/μL and Grade 0–1 bleeding scores at study entry. One patient withdrew after receiving 100 mg and experiencing a Grade 3 infusion reaction, subsequently undergoing splenectomy. Otherwise, the treatment was well tolerated with all infusions completed within 60 – 90 minutes. Of the 6 evaluable patients, all 4 non-splenectomized patients responded to treatment with at least a doubling of their baseline platelet levels, achieving 2 CRs, 1 PR, and 1 MR. At present, both CRs are still continuing with >100 K platelets/μL at 16 and 24 weeks after treatment. The patient with a PR, who was treated at 80 mg, had platelets decreased 30 K/μL just prior to 1st infusion and has continued to maintain these levels now 12 weeks after treatment, while the other has since been treated with cyclosporine, also without response. Veltuzumab quickly depleted B cells after the first dose, with decreases sustained >12 weeks. Even at these low doses, veltuzumab achieved expected serum levels (mean Cmax, 20.3 and 46.0 μg/mL at 80 and 120 mg, respectively) and remained in circulation without evidence of rapid clearance or sequestration (mean post-treatment half-life ~1 week). Two patients developed low-level positive HAHA results of uncertain clinical significance after treatment. CONCLUSIONS: These initial results indicate that doses of 80 or 120 mg veltuzumab have acceptable safety and demonstrate promising activity for ITP, including durable complete responses. Based on these findings, the study is proceeding, with patients now being recruited for therapy with low-dose veltuzumab administered by subcutaneous injection.

BACKGROUND: CD74 (HLA-DR-associated invariant chain) is highly expressed in multiple myeloma and other B-cell lymphomas, rapidly internalized, and a promising target for therapeutic intervention in these diseases, including conjugated drug delivery. Milatuzumab (hLL1) is a humanized MAb which recognizes CD74 and has shown efficacy in various preclinical B-lymphoma models, particularly multiple myeloma, but with rapid blood clearance seen in cynomolgus monkeys. The goal of this first clinical study of milatuzumab is to evaluate the safety, tolerability, and feasibility of twice-weekly dosing in multiple myeloma; to determine a maximum tolerated dose (MTD); to obtain preliminary information on efficacy, pharmacodynamics, and immunogenicity; and to identify acceptable doses for subsequent studies. METHODS: A multicenter study was initiated in patients with relapsed/refractory multiple myeloma who had failed at least 2 standard therapies. All patients received milatuzumab intravenously twice weekly for 4 weeks, and then were evaluated for safety and efficacy over 12 weeks, with responding patients continuing long-term follow-up. To determine the MTD, patients were entered in cohorts treated at escalating doses according to a 3+3 design. Adverse events and safety laboratories were evaluated by NCI CTC v3 toxicity grades, with any Grade 3–4 toxicity considered dose-limiting toxicity (DLT). Efficacy assessments used serum and urine M-protein electrophoresis and other evaluations as required for classifying responses by EBMT criteria, while pharmacokinetics and immunogenicity were evaluated by serum milatuzumab levels and human anti-milatuzumab antibody (HAHA) titers, respectively, using an ELISA assay. RESULTS: Eighteen patients (9F/9M, median age 61) have now received milatuzumab at 1.5 mg/kg (n=8), 4.0 mg/kg (n=9) or 8.0 mg/kg (n=1). They had multiple myeloma for 0.9–16.8 years (median 5.6), predominantly IgG subtype, were heavily pretreated (4.5 median prior treatments), and were either Durie-Salmon stage II (n=10) or III (n=8). One DLT (Grade 3 infusion reaction) was observed at 1.5 mg/kg. Subsequently, increased premedication as well as slow drug infusions resulted in improved tolerability (transient mild-moderate (Grade 1–2) infusion reaction), including the single patient treated at 8.0 mg/kg. At 4.0 mg/kg, one patient had a DLT with an acute hemoglobin drop to Grade 3 levels without definitive explanation. Additionally, one other patient at the 1.5-mg/kg dose had a serious event of bacterial meningitis post-treatment, which resolved. No pattern of other adverse reactions has been seen, nor effects on routine laboratories, including serum chemistries, CBC, serum immunoglobulins, B- or T-lymphocytes. Milatuzumab is rapidly cleared from serum, with little accumulation at successive infusions for patients treated at 1.5 or 4.0 mg/kg (mean peak serum levels, respectively: 13.5 and 38.0 μg/mL at 1st infusion, 13.0 and 53.6 μg/mL at last infusion), and results pending at 8.0 mg/kg. In all post-treatment samples evaluated, HAHA results have been negative. At 1.5 mg/kg, there were no objective responses, and efficacy results are not yet available at 8.0 mg/kg, but at 4.0 mg/kg, 3 patients have had stable disease by EBMT criteria at 8+ to 12+ weeks after treatment. CONCLUSIONS: These initial results indicate that milatuzumab may be safely administered to patients with multiple myeloma. The occurrence of stable disease in several patients in encouraging, in spite of rapid clearance at twice-weekly doses of 1.5 mg/kg and 4.0 mg/kg. Accrual of the next cohort receiving doses of 8.0 mg/kg is ongoing.

BACKGROUND: Epratuzumab, an anti-CD22 humanized monoclonal antibody, has shown clinical activity as a single-agent (Leonard et al, J Clin Oncol.2003; 21:3051–3059) and in combination with rituximab in relapsed/refractory B-cell NHL (Leonard et al, J Clin Oncol.2005; 23:5044–5051). To evaluate this combination regimen in a larger cohort of patients and to evaluate long-term efficacy, we conducted an international multicenter, open-label, single-arm study in patients with recurrent indolent NHL. METHODS: Forty-nine patients (23F/26M, median age: 61, elevated LDH: 25%, bone marrow involvement: 49%) with chemotherapy-relapsed or refractory follicular NHL (n=41) or small lymphocytic lymphoma (n=7) (as well as one enrolled patient with histological evidence of follicular and diffuse large B-cell lymphoma) were evaluated. Thirty-five (71%) were rituximab-naive, with the remainder having previously received and responded to then relapsed from rituximab (single agent or with chemotherapy). Patients received 360 mg/m2 IV of epratuzumab, followed by 375 mg/m2 IV of rituximab, weekly for 4 consecutive weeks. RESULTS: As preliminarily reported (Emmanouilides et al, Blood2003; 102/11:69a), the combination therapy was well tolerated, without notable additive toxicity over that expected with single-agent rituximab. Twenty-two of the 41 (54%, 95% CI: 37% – 69%) follicular NHL (FL) patients achieved an objective response (OR) using IWG response criteria, including 10 (24%) patients with complete responses (CR), half of whom remained in remission at the last evaluation with a median duration of follow-up of 44.3 months (range: 18.2 – 52.4 months). The median duration of response (DR) was 13.4 months (95% CI: 8.4 – 28.2 months) and the median progression-free survival (PFS) was 10.2 months (95% CI: 6.3 – 13.6 months), with a Kaplan-Meier estimated median DR of 33.4 months (range: 11.2 – 47.9 months) and an estimated median PFS of 35.1 months (range: 12.9 – 52.4 months) for the 10 patients who achieved CR. Importantly, 4/7 SLL patients (57%) experienced OR, including 2 CR, 1 CRu and 1 PR. Furthermore, while the rituximab-naive FL and SLL patients (n=34) showed an OR of 50% (26% CR/CRu, 24% PR), those patients who had responded to prior rituximab (n=14) had an OR of 64% (29% CR, 36% PR). CONCLUSIONS: Overall, this study confirms that the combination of epratuzumab and rituximab, in addition to being well tolerated, demonstrates promising anti-lymphoma activity for indolent NHL, and can result in durable complete remissions in a subset of patients. Further evaluation of this combination regimen as initial therapy for indolent NHL is planned (CALGB 50701), and in diffuse large B cell lymphoma (CHOP + epratuzumab + rituximab) is ongoing (NCCTG N0489).

Background: An open-label, multicenter, dose-escalation study in patients with recurrent NHL was initially undertaken to establish the safety, tolerance, PK, and immunogenicity (HAHA) of humanized anti-CD20 antibody, IMMU-106 (hA20), administered once-weekly for 4 weeks at different doses. Additional patients have now been entered to confirm the efficacy of 120 and 375 mg/m2 dosing, and to determine the feasibility of using even lower hA20 doses. Methods: A total of 55 patients (23 male, 32 female; 51 Caucasian; 40–84 years old) received hA20 at 120 (N=21), 200 (N=6), 375 (N=25) or 750 mg/m2 (N=3). They had follicular (FL, N=37) or other (N=18) B-cell lymphomas, were predominantly stage III/IV (N=44) at study entry, and had received 1–7 prior treatments (median, 2), including 1 (N=34) or more (N=14) rituximab regimens (without progression within 6 months). Results: Fifty-two patients completed all 4 infusions, 2 are currently being treated, and one patient with hives and chills after prior rituximab discontinued treatment after similar NCI CTC v.3 grade 1–2 reactions at 1st hA20 infusion. hA20 was generally well tolerated with a median infusion time at the lowest dose of 120 mg/m2 of 2.2 h for 1st infusion and 1.2 h for subsequent infusions. Twenty-one patients had drug-related adverse events; these were all transient, mild-to-moderate (Grade 1–2) events, most occurring only at first infusion. No consistent pattern of abnormal laboratory changes occurred, and there was no evidence of immunogenicity in 29 patients now evaluated for HAHA. Mean antibody serum levels increased with dose and with repeated infusions, and limited post-treatment data indicate the serum clearance at 375 mg/m2 dosing is similar to rituximab. Even at 120 mg/m2, peripheral blood B-cell depletion occurred after the first infusion and persists after 4th infusion, with analysis continuing > 6 mo. Thirty-nine patients with at least 12 wks follow-up had one or more responses evaluated by Cheson criteria (Table), with all CR/CRu occurring in follicular lymphoma except for one patient with marginal zone lymphoma; 6 pts progressed by week 4. Of 18 pts with OR’s, 9 have continuing responses (median follow-up, 9 mos post-treatment), including 4 with long-lived responses (12–18 mos). Conclusions: hA20 is well tolerated, with no evidence of significant toxicity or pattern of adverse events other than minor infusion reactions, even at short infusion times. All dose levels studied so far, including the lowest dose of 120 mg/m2, resulted in B-cell depletion and objective responses (including CR/CRu), with no clear-cut evidence of dose response in efficacy. As such, further dose de-escalation is ongoing. Treatment Response hA20 Dose OR CR/CRu All patients (n = 39) 46% (18/39) 21% (8/39) 120 mg/m2 (n = 11) 36% (4/11) 27% (3/11) 200 mg/m2 (n = 6) 67% (4/6) 33% (2/6) 375 mg/m2 (n =19) 42% (8/19) 11% (2/19) 750 mg/m2 (n = 3) 67% (2/3) 33% (1/3)

B cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE), so the safety and activity of anti-B cell immunotherapy with the humanized anti-CD22 antibody epratuzumab was evaluated in SLE patients. An open-label, single-center study of 14 patients with moderately active SLE (total British Isles Lupus Assessment Group (BILAG) score 6 to 12) was conducted. Patients received 360 mg/m2 epratuzumab intravenously every 2 weeks for 4 doses with analgesic/antihistamine premedication (but no steroids) prior to each dose. Evaluations at 6, 10, 18 and 32 weeks (6 months post-treatment) follow-up included safety, SLE activity (BILAG score), blood levels of epratuzumab, B and T cells, immunoglobulins, and human anti-epratuzumab antibody (HAHA) titers. Total BILAG scores decreased by ≥ 50% in all 14 patients at some point during the study (including 77% with a ≥ 50% decrease at 6 weeks), with 92% having decreases of various amounts continuing to at least 18 weeks (where 38% showed a ≥ 50% decrease). Almost all patients (93%) experienced improvements in at least one BILAG B- or C-level disease activity at 6, 10 and 18 weeks. Additionally, 3 patients with multiple BILAG B involvement at baseline had completely resolved all B-level disease activities by 18 weeks. Epratuzumab was well tolerated, with a median infusion time of 32 minutes. Drug serum levels were measurable for at least 4 weeks post-treatment and detectable in most samples at 18 weeks. B cell levels decreased by an average of 35% at 18 weeks and remained depressed at 6 months post-treatment. Changes in routine safety laboratory tests were infrequent and without any consistent pattern, and there was no evidence of immunogenicity or significant changes in T cells, immunoglobulins, or autoantibody levels. In patients with mild to moderate active lupus, 360 mg/m2 epratuzumab was well tolerated, with evidence of clinical improvement after the first infusion and durable clinical benefit across most body systems. As such, multicenter controlled studies are being conducted in broader patient populations.

This open-label, phase I/II study investigated the safety and efficacy of epratuzumab, a humanised anti-CD22 monoclonal antibody, in the treatment of patients with active primary Sjogren's syndrome (pSS). Sixteen Caucasian patients (14 females/2 males, 33–72 years) were to receive 4 infusions of 360 mg/m2 epratuzumab once every 2 weeks, with 6 months of follow-up. A composite endpoint involving the Schirmer-I test, unstimulated whole salivary flow, fatigue, erythrocyte sedimentation rate (ESR), and immunoglobulin G (IgG) was devised to provide a clinically meaningful assessment of response, defined as a ≥20% improvement in at least two of the aforementioned parameters, with ≥20% reduction in ESR and/or IgG considered as a single combined criterion. Fourteen patients received all infusions without significant reactions, 1 patient received 3, and another was discontinued due to a mild acute reaction after receiving a partial infusion. Three patients showed moderately elevated levels of Human anti-human (epratuzumab) antibody not associated with clinical manifestations. B-cell levels had mean reductions of 54% and 39% at 6 and 18 weeks, respectively, but T-cell levels, immunoglobulins, and routine safety laboratory tests did not change significantly. Fifty-three percent achieved a clinical response (at ≥20% improvement level) at 6 weeks, with 53%, 47%, and 67% responding at 10, 18, and 32 weeks, respectively. Approximately 40%–50% responded at the ≥30% level, while 10%–45% responded at the ≥50% level for 10–32 weeks. Additionally, statistically significant improvements were observed in fatigue, and patient and physician global assessments. Further, we determined that pSS patients have a CD22 over-expression in their peripheral B cells, which was downregulated by epratuzumab for at least 12 weeks after the therapy. Thus, epratuzumab appears to be a promising therapy in active pSS, suggesting that further studies be conducted.

Background: FLIPI has been proposed as an accurate, simple, and validated prognostic index on the basis of routinely performed tests (age > 60 yrs, Ann Arbor stage III-IV, serum LDH level increased, Hg < 12g/dL, and more than four nodal areas involved (Solal-Celigny et al., Blood 2004; 104: 1258–1265). FLIPI has reliably predicted outcome for many follicular lymphoma (FL) patients (pts) treated with chemotherapy and rituximab. Currently, monoclonal antibody (Mab) therapy and a number of radioimmunoconjugates are considered important components of the treatment of FL; therefore, evaluating FLIPI in clinical trials of these modalities is of interest for optimizing therapy. Methods: A subset analysis was performed to assess the impact of FLIPI on the outcome of patients with relapsed/refractory FL enrolled in a larger, multi-center, open label, single-arm study of epratuzumab (humanized anti-CD22 Mab) in combination with rituximab (chimeric anti-CD20 Mab) (Strauss et al., ASCO 2004). Results: A total of 32 pts with FL were treated according to this protocol (4 weekly infusions at full dose of each agent), including 16 pts who had received > 2 prior chemotherapy regimens and 11 pts who had previously received rituximab. Twenty pts (62%) achieved an objective response (OR), including 8 pts (25%) with complete responses (CR, CRu) and 12 (37%) with partial responses, with a median response duration of 16.5 months (95% CI: 6.3 - 25.4) and median time-to-progression (TTP) of 11 months (95% CI: 9.9 - 19.2). Conclusion: Our data indicate that high OR rates and durable CR/CRu’s can be achieved with a combination of rituximab and epratuzumab in pts with low- (0–1) and intermediate-risk (2) FL, who failed multiple prior therapies. OR, CR rates and TTP are similar to rituximab front-line therapy for pts with low tumor burden FL (Solal-Celigny et al., Blood 104: 169a, 2004). The combination of rituximab and epratuzumab was significantly less efficacious for pts with high-risk (3–5) FLIPI ( P =.0.0023 for TTP). This small Phase-II study supports the prognostic value of FLIPI for pts with recurrent FL who are treated with MAbs. Prospective use of FLIPI may facilitate the optimal design of randomized trials using rituximab in combination with epratuzumab in pts with FL. | FLIPI score (No. of pts) | OR (%) | CR/CRu (%) | Median Duration in months (95% CI) | Median TTP in months (95% CI) | TTP P-value* | |:----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------:| ------ | ---------- | ---------------------------------- | ----------------------------- | ------------ | | N/A - Not available due to patients with long TTPs that are still censored (i.e. not reached progression of disease). * - Patients with high (3–5) FLIPI scores versus others, based on the log-rank test. | | 0–1 (11) | 9 (82) | 4 (36) | 15.7 (N/A) | 19.2 (10.3 – 21.3) | 0.0023 | | 2 (9) | 6 (67) | 3 (33) | 18.3 (17.2 – 25.4) | 18.8 (10 – 26.7) | | | 3–5 (12) | 5 (42) | 1 (8) | 6.3 (N/A) | 7.7 (7.1 – 10.2) | | Results stratified by FLIPI risk groups

Background. Infusion reactions, prolonged infusion times and immunogenicity of the chimeric anti-CD20 antibody, rituximab, may in part be related to its murine component. The humanized anti-CD20 antibody, IMMU-106 (hA20), may offer potential advantages because only the CDRs are of murine origin and the remaining >90% human framework regions are identical to humanized anti-CD22 IgG1 antibody epratuzumab, whose safety and short infusion times have been reported. Methods. An open-label, multicenter, phase I/II, dose escalation study conducted in patients with recurrent B cell lymphoma to establish the safety, tolerance, pharmacokinetics, and immunogenicity of hA20 administered once weekly for 4 doses. Results. Twenty patients (11 M/9 F, 40–81 y.o) with grade 1–2 follicular (n=16) or other CD20+ B-cell lymphomas (mantle cell, small lymphocytic, marginal zone x 2) were enrolled in the dose escalation portion of this study, receiving 120 mg/m2 (n=7), 200 mg/m2 (n=6), 375 mg/m2 (n=4) or 750 mg/m2 (n=3) weekly x 4. These patients had previously received 1-7 prior therapies (median, 2.5), including treatments with one (n=12) or 2–4 (n=6) rituximab-containing regimens (without progression within 6 months). Five patients (25%) had grade 1–2 infusion reactions predominantly with first hA20 infusion. Median infusion times for 375 mg/m2 of hA20 were 3.3 hours for first infusion, 2.0 hours for subsequent infusions, and were generally shorter at lower doses. Standard laboratory values obtained at each infusion were generally observed to be within normal limits, and human anti-human antibody (HAHA) serum evaluations are negative to date. Peripheral blood B-cell depletion occurred after first infusion and persisted for samples obtained up to 12 weeks following fourth infusion with analysis ongoing. Pharmacokinetic results after first and fourth infusions demonstrate a mean antibody serum half-life of 5.3 ± 5.3 and 12.0 ± 8.7 days, respectively. To date, of 15 pts with at least one post-treatment assessments now completed, there are at least 8 objective responses (53%) by Cheson criteria, including 6 patients (40%) with complete responses [CR, CRu] at a median follow-up of 12 weeks. Complete responses have been observed at all dose levels, including 3/7 patients receiving 120 mg/m2/wk. Conclusion. This study demonstrates the safety, tolerability, and preliminary efficacy of this humanized anti-CD20 antibody administered weekly for 4 doses, mostly to patients with follicular lymphomas who relapsed after rituximab-containing regimens. The demonstration of CRs, tolerability, and relatively short infusion times is encouraging. This study is continuing and expanding to assess the durability of responses and the optimal dose for subsequent studies.