Subcutaneous Veltuzumab Research Articles

Comparison Of Two Dosing Schedules For Subcutaneous Injections Of Low-Dose Anti-CD20 Veltuzumab In Relapsed Immune Thrombocytopenia: Final Results Of a Phase I Study

BackgroundAs a 2nd-generation humanized anti-CD20 monoclonal antibody, veltuzumab has structure-function differences from rituximab and has shown increased potency in comparative preclinical studies (Goldenberg et al., Blood. 113(5):1062-70, 2008). In non-Hodgkin lymphoma (NHL), subcutaneous (SC) injections of low-dose veltuzumab using a high-concentration formulation demonstrated activity (Negrea et al., Haematologica. 96:567-73, 2011) comparable to that achieved previously by intravenous infusions (Morschhauser et al., J Clin Oncol. 27:3346-53, 2009). The prospect of SC veltuzumab for treating autoimmune diseases is particularly attractive. We present final phase I results from a multicenter study comparing two dosing schedules of low-dose SC veltuzumab administered as a monotherapy in immune thrombocytopenia (ITP). MethodsAdults with primary ITP who failed ≥1 standard therapy were eligible if platelets were ≤30 K/μL without major bleeding. In Cohort 1, 80, 160, or 320 mg SC veltuzumab doses were given twice, 2 weeks apart (total dose 160, 320, 640 mg, respectively). All patients in Cohort 2 received once-weekly 320 mg doses for 4 weeks (total dose 1280 mg). Steroids or other premedications were not required. An objective response (OR, ≥30 K/μL platelets twice, one week apart, and at least doubled from baseline) was classified as complete (CR) if ≥100K μL, otherwise as partial (PR). For responders, time to relapse (TTR) was measured from first injection to relapse with platelets below 30K/μL, initiation of subsequent treatment, or lost to follow-up. Adverse events (AEs) and safety laboratories were evaluated by NCI CTC v3 toxicity grades. Other evaluations included circulating B-cell levels (CD19), veltuzumab serum levels, and human anti-veltuzumab antibody (HAHA) titers. ResultsA total of 50 patients (31 female/19 male, median 54-years old, 8 post splenectomy) were enrolled in Cohorts 1 (N=34) and 2 (N=18, including 2 rollovers). They were a median of 2 years from diagnosis of ITP; 14 patients had newly-diagnosed or persistent disease (ITP ≤ 1 year) treated with corticosteroids and/or immunoglobulins, and 36 patients had chronic disease (ITP > 1 year) and also had received azathioprine or danazol (N=15), thrombopoietin-receptor agonists (N=10), rituximab (n=7), platelets (N=5) or chemotherapy (N=4). SC veltuzumab was well tolerated with a limited number of AEs (all Grade 1-2 transient injection reactions) and no other safety issues. At all doses, B cells were depleted rapidly after the first administration of veltuzumab, with recovery starting 12 to 16 weeks after treatment. Veltuzumab serum levels increased with each injection, achieving mean Cmax values of 11.7, 19.3 and 40.6 µg/mL at dose levels of 80, 160, and 320 mg, respectively, in Cohort 1, and 67.0 µg/mL at 320 mg in Cohort 2. HAHA titers were positive in 7 patients; interestingly, 4 had ORs, including 3 CRs. Three patients given rescue medication for rapidly decreasing platelets at study entry were inevaluable for treatment response. Of 47 evaluable patients, 22 (47%) had ORs, including 13 (28%) CRs, which differed little with ITP duration (≤1 year: 51% OR, 29% CR; >1 year: 42% OR, 27% CR). For responders, median TTR was comparable for CRs and PRs (7.9 vs 7.6 months, respectively) but decreased with ITP duration (14.4 vs 6.9 mo. for ≤1 year vs >1 year, respectively). OR and PR rates tabulated below for each dose group show meaningful activity (including CRs) already achieved at the lowest dose level, with no evidence of dose-dependent response rates, although response duration appears increased with higher total doses delivered.DoseTotal DoseNORCROR Median TTR (mo.)80 mg x 2160 mg875%50%8.0160 mg x 2320 mg933%11%6.7320 mg x 2640 mg1553%27%14.2320 mg x 41280 mg1741%29%11.0 ConclusionsLow-dose SC veltuzumab was convenient, well-tolerated, with good B-cell depletion and therapeutic activity across all dose levels and with comparable outcome when administered as 2 doses, 2 weeks apart, or as 4 consecutive weekly doses. These results support further studies in ITP combining SC veltuzumab with other agents or given as a maintenance regimen. Disclosures:Liebman:Immunomedics: Research Funding. Off Label Use: Veltuzumab is investigational agent for treatment of ITP. Bussel:Immunomedics: Research Funding. Saleh:Immunomedics: Research Funding. Horne:Immunomedics: Employment, Equity Ownership. Wegener:Immunomedics: Employment, Equity Ownership. Goldenberg:Immunomedics: Employment, Equity Ownership.

Low‐dose anti‐CD20 veltuzumab given intravenously or subcutaneously is active in relapsed immune thrombocytopenia: a phase I study

Low doses of the humanized anti-CD20 monoclonal antibody, veltuzumab, were evaluated in 41 patients with immune thrombocytopenia (ITP), including 9 with ITP ≤1 year duration previously treated with steroids and/or immunoglobulins, and 32 with ITP >1 year and additional prior therapies. They received two doses of 80-320 mg veltuzumab 2 weeks apart, initially by intravenous (IV) infusion (N = 7), or later by subcutaneous (SC) injections (N = 34), with only one Grade 3 infusion reaction and no other safety issues. Thirty-eight response-assessable patients had 21 (55%) objective responses (platelet count ≥30 × 10(9) /l and ≥2 × baseline), including 11 (29%) complete responses (CRs) (platelet count ≥100 × 10(9) /l). Responses (including CRs) occurred with both IV and SC administration, at all veltuzumab dose levels, and regardless of ITP duration. Responders with ITP ≤1 year had a longer median time to relapse (14·4 months) than those with ITP >1 year (5·8 months). Three patients have maintained a response for up to 4·3 years. SC injections resulted in delayed and lower peak serum levels of veltuzumab, but B-cell depletion occurred after first administration even at the lowest doses. Eight patients, including 6 responders, developed anti-veltuzumab antibodies following treatment (human anti-veltuzumab antibody, 19·5%). Low-dose SC veltuzumab appears convenient, well-tolerated, and with promising clinical activity in relapsed ITP.(Clinicaltrials.gov identifier: NCT00547066.).

Phase I/II Study of Monotherapy with Subcutaneous Injections of Low-Dose Anti-CD20 Veltuzumab in Relapsed Immune Thrombocytopenia

AbstractAbstract 622 Background:Veltuzumab is a 2nd-generation humanized anti-CD20 monoclonal antibody with structure-function differences from rituximab, and evidence of higher potency preclinically (Goldenberg et al., Blood. 113(5):1062–70, 2008). In non-Hodgkin lymphoma (NHL), subcutaneous (SC) injections of low-dose veltuzumab were well-tolerated and demonstrated high activity (Negrea et al., Haematologica. 96:567–73, 2011), comparable to that achieved by intravenous infusions (Morschhauser et al., J Clin Oncol. 2009;27:3346–53). As such, we postulated that low-dose SC veltuzumab also may be effective and particularly convenient for treating autoimmune diseases, especially since a high-concentration formulation was developed. Hence, a multicenter, phase I/II study was undertaken to evaluate SC veltuzumab as a monotherapy administered in immune thrombocytopenia (ITP). Methods:Adults with primary ITP who failed ≥1 standard therapy were eligible if platelets were ≤30 K/μL without major bleeding. In Cohort 1, 80, 160, or 320 mg SC veltuzumab was given twice 2 weeks apart (total dose 160, 320, 640 mg, respectively). In Cohort 2, 320 mg veltuzumab was given weekly for 4 doses (total dose 1280 mg). Steroids or other premedications were not required. Best platelet response to treatment (on at least 2 occasions, one week apart) was classified as complete (CR, >150K/μL), partial (PR, 50–150K/μL), or minor (MR, 30–50K/μL). For responders, time to relapse was measured from first injection to relapse with platelets below 30K/μL, initiation of subsequent treatment, or lost to follow-up. Adverse events (AEs) and safety laboratories were evaluated by NCI CTC v3 toxicity grades. Other evaluations included circulating B-cell levels (CD19), veltuzumab serum levels, and human anti-veltuzumab antibody (HAHA) titers. Results:A total of 45 patients (28 female/17 male, median 54-years old, 8 post splenectomy) were enrolled in Cohorts 1 (N=34) and 2 (N=11). They were a median of 2 years from diagnosis of ITP; 12 patients had newly-diagnosed or persistent disease (ITP ≤ 1 year) treated with corticosteroids and/or immunoglobulins, and 33 patients had chronic disease (ITP > 1 year) and also had received azathioprine or danazol (N=14), thrombopoietin-receptor agonists (N=8), rituximab (n=6), platelets (N=6) or chemotherapy (N=4). SC veltuzumab was well tolerated with a limited number of AEs (all Grade 1–2 transient injection reactions) and no other safety issues. At all doses, B cells were depleted rapidly after the first administration of veltuzumab, with recovery starting 12 to 16 weeks after treatment. Veltuzumab serum levels increased with each injection, achieving mean Cmax values of 11.7, 19.3 and 40.6 μg/mL at dose levels of 80, 160, and 320 mg, respectively, in Cohort 1, and 67.0 μg/mL at 320 mg in Cohort 2. HAHA titers were positive in 7 patients; interestingly, 6 had objective responses (OR: CR+PR+MR), including 3 CRs. Five patients were inevaluable for treatment response (3 given rescue medication for rapidly decreasing platelets at study entry, 2 still continuing treatment). Of the 40 evaluable patients, 27 (68%) had ORs, including 7(18%) CRs, 14 (35%) PRs, and 6 (15%) MRs. Follow-up data is mature for Cohort 1, with median time to relapse for 23 responders increasing by response category (MR: 2.1, PR: 5.7, CR: 14.2 months) and 8 (35%) responding > 1 year (2 ≥ 3 years). Ignoring the generally short-lived MRs, CR and CR+PR rates are tabulated below. Results for all evaluable patients (as well as only those with potentially more refractory chronic disease) show no evidence of dose-dependence, with meaningful activity (including CRs) already achieved at the lowest dose level.DoseAll PatientsITP > YearTotal DoseNCRCR+PRNCRCR+PR80 mg × 2160 mg825%75%520%80%160 mg × 2320 mg90%33%80%38%320 mg × 2640 mg1520%60%1118%45%320 mg × 41280 mg825%38%425%50% Conclusions:Low-dose SC veltuzumab was convenient, well-tolerated, with good B-cell depletion and promising activity in relapsed ITP. As a single agent, SC veltuzumab appears potent across a variety of dose levels and dosing schedules even in more heavily treated patients with chronic disease. These results support further studies in ITP combining SC veltuzumab with other agents or given as a maintenance regimen. Disclosures:Horne:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.

Monotherapy with Subcutaneous (SC) Injections of Low Doses of Humanized Anti-CD20 Veltuzumab Is Active in Chronic Lymphocytic Leukemia (CLL)

AbstractAbstract 192 Background:Veltuzumab is a 2nd generation humanized anti-CD20 monoclonal antibody with structure-function differences and improved preclinical properties compared to chimeric rituximab. In non-Hodgkin lymphoma, 4 SC injections of low-dose veltuzumab administered every other week demonstrated clinical activity (Negrea et al., Haematologica 2011;96:567–73), comparable to that demonstrated earlier with low veltuzumab doses delivered intravenously (Morschhauser et al., J Clin Oncol, 2009;27:3346–53), but avoiding the need for lengthy IV administration and dedicated infusion suites. In CLL, with high levels of circulating leukemic cells, more frequent and prolonged veltuzumab dosing may be required, which was investigated. Methods:A multicenter, phase I/II study was undertaken to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of SC veltuzumab in patients with previously untreated or relapsed CD20+ CLL. Patients initially received the NHL dosing schedule with 4 doses administered every other week at 80, 160, or 320 mg (Cohort 1, cumulative dose range: 320 – 1280 mg). After protocol amendment, subsequent patients received 16 doses administered twice-weekly at levels of either 160 or 320 mg (Cohort 2, cumulative dose range: 2560 – 5120 mg). Evaluations included adverse events, routine safety assessments, CT scans, lymphocyte (ALC) and CD19+ B-cell blood levels, with serum veltuzumab levels and human anti-veltuzumab antibody (HAHA) titers measured by ELISA assays performed by the Sponsor. Efficacy was assessed by hematology-based NCI/IWCLL criteria 4 and 12 weeks post-treatment, with responding patients continuing follow-up until progression up to 2 years. Results:A total of 20 patients (10 males/10 females, 50 – 93 years old, 7.9 – 138.5 × 109/μL WBC) were entered in Cohorts 1 (N=11) and 2 (N=9). Thirteen patients were treatment naïve, while 7 had received 1–6 prior treatments (including a rituximab-containing regimen in 6 patients). Most patients had Rai intermediate risk scores (N=14) and presented with one or more B symptoms (N=16). Pre-treatment with antihistamines or steroids was not required before SC veltuzumab. Veltuzumab was well tolerated with only transient Grade 1–2 injection-site reactions. One patient developed bacterial meningitis and withdrew during treatment, while another patient with a complicated medical history developed malignant hypertension, transient ischemic attack, and pneumonia 6 months after treatment; no other SAEs or Grade 3–4 events occurred. One patient previously treated with rituximab had anti-veltuzumab antibodies at study entry; HAHA response results for the other patients have all been negative. Circulating leukemic cells decreased after treatment in all patients by 7.7 to 90.8%, with 13 patients having >50% decreases from baseline, and 3 patients achieving ALC values <4000 cells/μL. Consistent with high and widely varying baseline ALC levels (5 – 116 cells x109/μL), veltuzumab serum levels were often low and variable at all except the highest dose level, with mean Cmax values, respectively, of 1.8, 4.5, and 30.8 μg/mL at dose levels of 80, 160, or 320 mg in Cohort 1, and 36.2 and 199.5 μg/mL at dose levels of 160 and 320 mg in Cohort 2. By IWCLL criteria, 3 patients had partial responses (PR) (including 2 continuing relapse-free at 12 and 24 months) and 12 patients had stable disease (SD) as best response (most progressing within 12 weeks, but 4 remaining relapse-free for 6 – 12 months). Three patients progressed by first evaluation and 2 patients withdrew consent prior to any response assessment. As such, 15 (83%) of 18 evaluable patients achieved either PR or SD after treatment. Veltuzumab appeared active at all dose groups, and, despite increasing cumulative doses from 320 to 5120 mg delivered with these 5 dose groups, treatment responses and percent ALC decreases appeared similar regardless of dose level (80 vs. 160 vs. 320 mg) or dosing schedule (Cohort 1 vs. 2). Conclusions:In CLL, with high levels of circulating leukemic cells, SC administration of veltuzumab is convenient, well-tolerated, and shows evidence of single-agent pharmacologic activity across a variety of dose levels and dosing schedules. These results support further studies in CLL, including combining veltuzumab with chemotherapy or given as a maintenance regimen. Disclosures:Horne:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.

Phase I/II Study of Subcutaneous Injections of Low-Dose Anti-CD20 Veltuzumab in Relapsed Immune Thrombocytopenia,

Abstract 3302▪▪This icon denotes a clinically relevant abstract Background:Subcutaneous (SC) injections of veltuzumab, a 2nd-generation humanized anti-CD20 monoclonal antibody with structure-function differences from rituximab, may offer potential benefits to both patients and the healthcare system. In non-Hodgkin’s lymphoma, SC veltuzumab was well tolerated and demonstrated activity (Negrea et al., Haematologica, 96:567–73, 2011) comparable to that demonstrated earlier with low veltuzumab doses delivered intravenously (Morschhauser et al., J Clin Oncol, 2009;27:3346–53). Since this route of administration may also be effective and particularly convenient for treating autoimmune disease, a clinical study of SC veltuzumab was undertaken in immune thrombocytopenia (ITP). Methods:A multicenter, phase I/II study was conducted to evaluate veltuzumab in adults with primary ITP who failed ≥1 standard therapy and presented with platelets ≤30K/μL, but without major bleeding. All patients received 2 doses of veltuzumab 2 weeks apart (without steroids or other premedications required). Veltuzumab was initially administered IV, but then by SC injection after a higher concentration formulation became available. By recent international working group categories, efficacy was evaluated separately for patients with newly-diagnosed or persistent disease (≤1 year duration) compared to patients with chronic disease (>1 year), with best responses (on at least 2 occasions, one week apart) classified as complete (CR, >150K/μL), partial (PR, 50–150K/μL), or minor (MR, 30–50K/μL). Adverse events (AEs) and safety laboratories were evaluated by NCI CTC v3 toxicity grades. Other evaluations included circulating B-cell levels (CD19), veltuzumab serum levels, and human anti-veltuzumab antibody (HAHA) titers. Results:A total of 41 patients were entered in this study, with 7 patients receiving 2 IV veltuzumab doses of 80 (N=3), 120 (N=3), or 200 mg (N=1), and 34 receiving 2 SC doses of 80 (N=9), 160 (N=10), or 320 mg (N=15). 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 AEs (All NCI CTC v3.0 Grade 1–2 transient infusion/injection reactions) and no other safety issues. ORs and CRs occurred with both SC and IV administrations, and across all dose levels. Of 9 patients (6 female/3 male; median 54-years old) with ITP ≤1 year and treated with steroids and/or immunoglobulins, 7 (78%) achieved an objective response (OR: CR+PR+MR), including 3 (33%) CRs. Of 32 patients (19 female/13 male; median 51-years old) with ITP > 1 year, (47% 5 – 31 years) and additional therapies [splenectomy (N=8), azathioprine (N=9), rituximab (N=6), tpo-receptor agonists (N=5), chemotherapy (N=5)], 19 (59%) still achieved ORs, including CRs in 4 (13%) patients with ITP for 1.4, 2.0, 2.4 and 25 years. Of 7 CRs, the median relapse-free survival was 1.2 years, and 3 still continue 1.8 – 3.5 years after treatment. Most PRs and MRs relapsed by 6 months. However, of 6 such patients who were then retreated, 4 patients achieved responses comparable to their initial response, while another patient (with a 31-year history of ITP) achieved a CR after receiving veltuzumab in combination with prednisone. With both IV and SC dosing, and at all doses, B cells were depleted rapidly after the first administration of veltuzumab, with recovery starting 12 to 16 weeks after treatment. Compared to IV dosing, SC veltuzumab had slower release over several days with lower serum levels, but approximately comparable availability/exposure. Four patients developed low-level HAHA titers of uncertain clinical significance. Conclusions:Low-dose SC veltuzumab was convenient, well tolerated and with promising activity in relapsed ITP. With only 2 SC doses, patients with limited disease duration of ≤1 year achieved high rates of objective responses [78%], including 33% durable CR’s. In patients with long-standing disease (47% with ITP for 5 – 31 years) and who were often heavily pretreated, CRs occurred less frequently, but there was still activity [59% ORs]. Higher doses and extended dosing SC regimens may be more effective in this more refractory population. Disclosures:Liebman:Immunomedics: Research Funding. Saleh:Immunomedics: Research Funding. Bussel:Immunomedics: Research Funding. Bernstein:Immunomedics: Research Funding. Negrea:Immunomedics: Research Funding. Onyegbula:Immunomedics: Research Funding. Farber:Immunomedics: Research Funding. Horne:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics, Inc.: Consultancy, Employment, Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Subcutaneous injections of low-dose veltuzumab (humanized anti-CD20 antibody) are safe and active in patients with indolent non-Hodgkin's lymphoma

Subcutaneous injections of anti-CD20 antibodies may offer benefits to both patients and the healthcare system for treatment of B-cell malignancies. A pilot study was undertaken to evaluate the potential for subcutaneous dosing with 2(nd) 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. 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. 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 identifier: NCT00546793).

Subcutaneous Injections of Low Doses of Humanized Anti-CD20 Veltuzumab for Treatment of Indolent B-Cell Malignancies.

Abstract 3757Poster Board III-693 BackgroundLow 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. MethodsA 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. ResultsTwenty-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. ConclusionsSC 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.

Subcutaneous Injections of Low-Dose Anti-CD20 Veltuzumab for Treatment of Relapsed Immune Thrombocytopenia (ITP).

Abstract 1322Poster Board I-344 BackgroundVeltuzumab, 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. MethodsA 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. ResultsThe 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.) ConclusionsLow-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. DisclosuresSaleh: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.

Subcutaneous injections of low doses of veltuzumab (humanized anti-CD20 antibody): Objective responses in B-cell malignancies

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]