ALBERT

Description: Abstract 2883 Background: Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 antibody conjugated to calicheamicin, a cytotoxic agent. CMC-544 targets CD22, which is expressed in the majority of B-cell non-Hodgkin lymphomas (NHL). CMC-544 alone and in combination with rituximab has demonstrated efficacy and tolerability in relapsed/refractory NHL patients including diffuse large B-cell lymphoma (DLBCL) patients who were ineligible for high-dose therapy and autologous stem cell transplant (HDT-aSCT). This trial is evaluating the safety and preliminary efficacy of CMC-544 plus rituximab (CMC-544+R) followed by HDT-aSCT. Objectives: Assess the safety and activity of CMC-544+R prior to HDT-aSCT in relapsed/refractory DLBCL patients using overall response rate (ORR), rate of successful peripheral blood stem cell (PBSC) collection, and aSCT rate as endpoints. Patients: Patients are eligible for this ongoing trial if they have CD20+/CD22+ B-cell DLBCL, have received 1 or 2 therapies, have at least 2 adverse prognostic factors (prior rituximab exposure, early (1), and are judged eligible for HDT-aSCT. Rituximab (375 mg/m2) is given on day 1, then CMC-544 (1.8 mg/m2) on day 2 every 21 days for up to 6 cycles; PBSC mobilization with G-CSF (+/− plerixafor injection [Mozobil®]) begins no earlier than day 8 of cycle 2. Chemo-primed mobilization (with cyclophosphamide [C] or etoposide [E]) is allowed if insufficient PBSCs are collected by G-CSF and is initiated only after disease response is observed. Patients responding to CMC-544+R and with sufficient PBSCs (〉2×106 CD34+ cells/kg) proceed to HDT-aSCT. Results: To date, 34 patients have been treated with CMC-544+R. Median age is 62 y (range: 19–75); 74% male; 50% had 1 prior chemotherapy regimen, 38% had 2, and 9% had ≥ 3. Most common adverse events during CMC-544+R treatment were: thrombocytopenia (38%), neutropenia (21%), lymphopenia (21%), nausea (27%), fatigue (29%), and increased aspartate aminotransferase (21%). Three deaths have been reported: 2 due to disease progression at days 76 and 126 after last dose of CMC-544; and 1 after HDT-aSCT. There have been no reports of veno-occlusive disease. To date, 19 patients have postbaseline disease assessment(s), with adverse prognostic factors as follows: 100% prior treatment with rituximab; 79% with sIPI 〉1 (range, 2–4); 37% had no response to their most recent prior therapy, 53% responded but had early relapse or required initiation of new anti-cancer treatment (CMC-544+R) 12 months). Additionally, all had prior treatment with both anthracyclines and alkylating agents. For these 19 patients (each with ≥ 2 adverse prognostic factors) and who received a median of 2 cycles, a best ORR of 21% was observed (2 complete and 2 partial responses); 26% showed stable disease, and 53% had disease progression. Of the 4 responders, 1 had no response to prior R-ICE, 1 had early relapse (~ 6 months) after prior R-CHOP, 1 relapsed 12 months after prior aSCT, and 1 had a complete response to R-DHAP 5 years prior to study treatment. To date, 7 patients have had PBSC collections: of these, 5 had successful collections (3 with G-CSF plus plerixafor, 1 with G-CSF alone, 1 with G-CSF plus chemo-priming); 2 patients, receiving G-CSF alone, did not have successful collections. Three patients have had both a response to CMC-544+R and sufficient PBSCs allowing HDT-aSCT: 1 patient had successful carmustine/E/cytarabine/C (BEAC)-aSCT (neutrophil, platelet recovery 11 and 29 days after aSCT, respectively); 1 patient did not have complete platelet recovery after busulfan/E/melphalan (M)-aSCT with 4.35×106 CD34+ cells/kg (platelet levels were as low as 19,000/μL ~60 days after aSCT, and transfusions were required to sustain levels ≥20,000/μL); and 1 patient, a 74-y old male, expired 39 days after BEAM-aSCT from neutropenic sepsis with multiorgan failure. Conclusion: In this patient population, CMC-544+R has a safety profile similar as previously reported. The preliminary ORR observed is notable given the poor prognosis of these patients. Current results suggest that successful PBSC mobilizations following CMC-544+R are possible. Additional data from this ongoing trial will be helpful to further assess the safety and efficacy of CMC-544+R prior to HDT-aSCT. Disclosures: Goy: Allos Therapeutics: Consultancy, Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goh:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Ciliag: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweetenham:Pfizer: Research Funding. Powell:Pfizer: Employment, Equity Ownership. Sullivan:Pfizer: Employment, Equity Ownership. Vandendries:Pfizer Inc.: Employment, Equity Ownership. Gisselbrecht:Allos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Introduction: Uncontrolled complement activation plays a pivotal role in a variety of disorders such as PNH and aHUS. ALN-CC5 is a subcutaneous (SC) investigational RNAi therapeutic targeting complement C5 (C5). In preclinical studies, ALN-CC5 has demonstrated decreased terminal complement activity. Based on the literature, preventing the generation of the terminal complex protects against intravascular hemolysis and complement-mediated tissue damage. The purpose of this study is to evaluate the safety and tolerability of ALN-CC5 in normal healthy volunteers. Material and methods: A multi-centered, placebo controlled, double blind phase 1 clinical study in healthy volunteers is ongoing. Several cohorts of healthy volunteers in Part A, a single ascending dose study and Part B, a weekly multiple ascending dose study have been completed. Primary endpoints are safety and tolerability. Secondary endpoints are pharmacokinetics, reduction of circulating C5, reduction in hemolytic, CAP and CCP activity. Results: In Part A, 20 healthy volunteers were randomized (1:3) to placebo or single SC dose of 50, 200, 400, 600 or 900mg of ALN-CC5 and followed for at least 70 days. In Part B, 12 healthy volunteers were randomized (1:3) to placebo or 5 weekly doses of 100, 200 or 400mg of ALN-CC5. No SAEs or study discontinuations occurred and overall ALN-CC5 was considered safe and generally well tolerated. A dose dependent and 94% mean maximum C5 knockdown was achieved following weekly administration. Updated safety and tolerability data as well as C5 knockdown, and changes in CAP, CCP and hemolytic activity from the study will be presented. Conclusion: Collectively, these initial results suggest that the use of a novel RNAi therapeutic targeting C5 is a promising approach for inhibiting complement in PNH, aHUS and other complement-mediated diseases. The subcutaneous route of administration and infrequent dosing make this a potentially encouraging therapy. Disclosures Hill: Alnylam: Consultancy. Off Label Use: ALN-CC5 is an investigational RNAi therapeutic targeting complement C5.. Borodovsky:Alnylam Pharmaceuticals: Employment, Equity Ownership. Kawahata:Alnylam Pharmaceuticals: Employment, Equity Ownership. Mclean:Alnylam Pharmaceuticals: Employment, Equity Ownership. Powell:Alnylam Pharmaceuticals: Employment, Equity Ownership. Chaturvedi:Alnylam Pharmaceuticals: Employment, Equity Ownership. Warner:Alnylam Pharmaceuticals: Employment, Equity Ownership. Garg:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership.

Description: Abstract 455 Introduction: Bosutinib (SKI-606) is an orally active, dual competitive inhibitor of the Src and Abl tyrosine kinases. The phase 3 BELA study compared bosutinib with imatinib in patients (pts) with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML). Methods: Pts were randomized 1:1 to open-label oral bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252) and stratified by Sokal score risk group (low, medium, high) and geographical region. The primary efficacy endpoint was complete cytogenetic response (CCyR) at 12 mo in the intent-to-treat population. Key secondary and exploratory efficacy endpoints included major molecular response (MMR) at 12 mo, time to CCyR and MMR, duration of CCyR and MMR, time to and incidence of transformation to accelerated/blast phase (AP/BP) CML, event-free survival (EFS), and overall survival. Safety analyses included all treated pts. Results: The median treatment duration was 19.3 mo for bosutinib and 19.5 mo for imatinib; 67% and 74% of pts, respectively, are still receiving therapy. The primary reason for discontinuation of bosutinib was toxicity (23%), while the primary reason for discontinuation of imatinib was disease progression (13%). Rates of CCyR and MMR are shown in the table. The rate of cumulative CCyR by 18 mo was 79% in both arms, and the cumulative rate of MMR by 18 mo was 55% in the bosutinib arm versus 45% in the imatinib arm. Median time to CCyR was faster for bosutinib versus imatinib (12.7 vs 24.6 wk); median time to MMR was also faster for bosutinib versus imatinib (36.9 vs 72.3 wk). Transformation to AP/BP CML while on treatment occurred in 4 (2%) pts on bosutinib and 13 (5%) pts on imatinib. On-study deaths from any cause occurred in 6 (2%) pts receiving bosutinib versus 13 (5%) pts receiving imatinib, and included 5 (2%) and 9 (4%) pts, respectively, who died due to CML progression. Median on-treatment EFS and overall survival were not yet reached for either arm. At 18 mo, the Kaplan-Meier estimates of EFS were 95% for bosutinib versus 91% for imatinib, and the estimates of overall survival were 99% versus 95%, respectively. Bosutinib was associated with higher incidences compared with imatinib of gastrointestinal events (diarrhea [69% vs 22%, respectively], vomiting [32% vs 14%], pyrexia [18% vs 10%], and abdominal pain [13% vs 7%]). In contrast, bosutinib was associated with lower incidences of edema (peripheral edema [4% vs 11%] and periorbital edema [1% vs 14%]) and musculoskeletal events (myalgia [5% vs 11%], muscle cramps [4% vs 22%], and bone pain [4% vs 10%]). Fewer pts on bosutinib experienced grade 3/4 laboratory abnormalities of neutropenia (11% vs 24% with imatinib), while the incidences of grade 3/4 anemia and thrombocytopenia were similar between treatment arms (8% with anemia and 14% with thrombocytopenia). Grade 3/4 liver function test abnormalities occurred more frequently with bosutinib versus imatinib (increased alanine aminotransferase [23% vs 4%] and aspartate aminotransferase [12% vs 3%]). Although common with bosutinib, gastrointestinal events and liver function test abnormalities were typically transient, managed with dose modifications, and not life threatening. Conclusions: The study did not meet the primary endpoint (CCyR at 12 mo); early discontinuation of bosutinib due to adverse events may have contributed to this observed lack of difference. However, bosutinib did result in a higher rate of MMR at 12 mo, faster times to MMR and CCyR, fewer events of transformation to AP/BP CML, and fewer overall and CML-related deaths compared with imatinib, suggesting superiority of bosutinib in pts with newly diagnosed CP CML. In addition, the 18-mo estimates for both EFS and OS currently favor bosutinib. Bosutinib and imatinib were each associated with acceptable but distinct toxicity profiles. Based on these results, bosutinib may offer a new therapeutic option for pts with newly diagnosed CP CML. Minimum of 24 mo of follow-up will be presented for all pts. Disclosures: Cortes: Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Guilhot:CHU de Poitiers: Employment; Pfizer Inc: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria. Duvillie:Pfizer Inc: Employment. Powell:Pfizer Inc: Employment, Equity Ownership. Countouriotis:Pfizer Inc: Employment. Gambacorti-Passerini:Pfizer Inc: Honoraria, Research Funding; BMS: Research Funding; Novartis: Honoraria; Biodiversity: Honoraria.

Description: Specifying the extent and location of rifted, crystalline Precambrian crust in the eastern United States is important for seismic hazard evaluation and for models that relate upper-mantle structure to ancient tectonic features and ongoing tectonism. As currently depicted in the National Seismic Hazard Maps (NSHM), the western limit of Iapetan rifted crust is beneath the Appalachian plateau physiographic province, west of the Valley and Ridge province. New estimates of crustal thickness using EarthScope Transportable Array and other data do not support the presence of rifted crust beneath the Blue Ridge, Valley and Ridge, and Appalachian plateau physiographic provinces. Crustal thicknesses exceed 45 km throughout most of this region. The crust thins to the southeast beneath the southeastern part of the Piedmont physiographic province and is only 36 km thick near the edge of the Atlantic coastal plain. We suggest that the western limit of Iapetan rift-extended crust is east of the Blue Ridge province and is associated with the prominent Appalachian gravity gradient. This location coincides with palinspastic reconstructions based on geologic data for the Iapetan rifted margin. Recognition of thick crust beneath the Blue Ridge and Valley and Ridge provinces, unextended by Iapetan rifting, will support more robust modeling of the effects of mantle structure (such as delamination and abrupt changes in lithospheric thickness) on ongoing tectonism and earthquake activity in the eastern United States and will provide more accurate seismotectonic zonation in the NSHM.

Description: Abstract 1685 Bosutinib (BOS) is an orally active, dual competitive Src/Abl kinase inhibitor. The phase 3 BELA study compared the safety and activity of BOS 500 mg/d with imatinib (IM) 400 mg/d in patients (pts) with newly diagnosed chronic phase chronic myeloid leukemia (CP CML). This analysis summarizes the safety profile of each agent, addressing management of gastrointestinal toxicities and liver function test changes. The median age was 48 y (range, 19–91 y) in the BOS arm and 47 y (range, 18–89 y) in the IM arm. Median treatment durations were 19.3 mo for BOS and 19.5 mo for IM; 67% and 74% of pts are still receiving therapy. The primary reason for BOS discontinuation was adverse events (AEs; 23% BOS [15/55 without prior dose adjustment] vs 6% IM). The primary reason for IM discontinuation was disease progression (4% BOS vs 13% IM). Deaths occurred in 6 (2%) BOS pts versus 13 (5%) IM pts; the majority occurred after treatment discontinuation. Non–CML-related deaths (1 pt each) included mesenteric embolia/intestinal necrosis (BOS), cardiovascular disease (IM), fatal septicemia (IM), lung embolism (IM), and pneumonia (IM). BOS was associated with higher incidences versus IM of all grades of gastrointestinal toxicities (diarrhea [69% vs 22%], vomiting [32% vs 14%], and abdominal pain [13% vs 6%]) and pyrexia (18% vs 10%). In contrast, BOS was associated with lower incidences of edema (peripheral edema [4% vs 11%] and periorbital edema [1% vs 14%]) and musculoskeletal events (myalgia [5% vs 11%], muscle cramps [4% vs 22%], and bone pain [4% vs 10%]). Diarrhea (11% vs 1%, respectively) and vomiting (3% vs 0%) were the most common grade 3/4 AEs. Elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reported as grade 3/4 AEs for 18% and 8% of pts on BOS, respectively, versus 2% and 2% of pts on IM. Diarrhea typically occurred during the initial month of treatment, with the median time to first event of 3 d (range, 1–589 d) on BOS (n = 172) and 26 d (range, 1–829 d) on IM (n = 56) and median duration of a diarrhea event of 3 d (range, 1–836 d) and 5 d (range, 1–771 d), respectively. Diarrhea was managed with antidiarrheal medication in 68% of BOS pts and 43% of IM pts; 22% and 9% of pts with diarrhea required temporary dose interruption, while 8% and 0% had a reduction of their dose. Of the pts who had a temporary dose interruption due to diarrhea, 34/38 pts on BOS and 5/5 pts on IM were rechallenged without recurrence of diarrhea or permanent discontinuation due to diarrhea. Grade 3/4 liver function test laboratory abnormalities were more common among pts receiving BOS versus IM, including elevation of ALT (23% vs 4%) and AST (12% vs 3%); the majority experienced grade 3 events. The median times to first ALT elevation were 28 d for BOS (n = 78) and 114 d for IM (n = 18); median times to first AST elevation were 28 d for BOS (n = 65) and 107 d for IM (n = 19). For BOS and IM, respectively, median durations for a grade 3/4 event to grade ≤1 severity were 21.0 versus 25.0 d for ALT elevation and 21.5 versus 25.0 d for AST elevation. Of the pts with ALT elevations, 35% versus 56% had a dose reduction and 56% versus 28% had a temporary dose interruption. Of the 40 pts who were rechallenged with BOS after dose interruption due to ALT elevation, 32 (80%) were successfully rechallenged without reoccurrence of their event or did not discontinue due to ALT elevation; all 4 pts who were rechallenged after IM interruption were successfully rechallenged. Of the pts with AST elevations, 17% versus 5% had a dose reduction and 43% versus 16% had a temporary dose interruption. All of the 26 pts who were rechallenged with BOS after dose interruption due to AST elevation were successfully rechallenged without reoccurrence of their event or discontinuation due to AST elevation; all 3 pts who were rechallenged after IM interruption were successfully rechallenged. No cases met the Hy's Law criteria. Ten pts discontinued BOS due to ALT elevation; no other discontinuations due to liver function test abnormalities were reported. In conclusion, BOS and IM were associated with acceptable but distinct safety profiles in pts with newly diagnosed CP CML. BOS was mainly associated with gastrointestinal AEs and transient liver function test elevations, both of which were managed with dose modifications and were not life threatening. Additional experience in managing the toxicities associated with BOS treatment may reduce the overall number of pts discontinuing BOS due to toxicity. Disclosures: Gambacorti-Passerini: Pfizer Inc: Honoraria, Research Funding; BMS: Research Funding; Novartis: Honoraria; Biodiversity: Honoraria. Cortes:Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Harris:Pfizer Inc: Employment. Powell:Pfizer Inc: Employment, Equity Ownership. Countouriotis:Pfizer Inc: Employment. Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer Inc: Research Funding; Ariad: Research Funding.

Description: Abstract 2769 In the phase 3 BELA study, bosutinib was associated with superior rates of major molecular response (MMR) at 12 months, faster times to MMR and complete cytogenetic response (CCyR), fewer on-treatment events of transformation to accelerated/blast phase CML, and fewer overall deaths on study when compared with imatinib; each agent was associated with an acceptable but distinct safety profile. However, clinical resistance to TKIs commonly results from development of Bcr-Abl mutations. Therefore, we investigated the incidence of Bcr-Abl mutations and their impact on clinical outcome in the BELA trial. Newly diagnosed patients (pts) with CP CML were randomized to bosutinib 500 mg/day (n = 250) or imatinib 400 mg/day (n = 252). Direct sequencing of Bcr-Abl kinase domain (10%-20% sensitivity) in a central laboratory was employed at baseline (bosutinib, n = 237; imatinib, n = 241) as well as at treatment discontinuation (bosutinib, n = 62; imatinib, n = 49). The median age was 48 years (range, 19–91 years) in the bosutinib arm and 47 years (range, 18–89 years) in the imatinib arm. Based on a minimum of 18 months from the last pt randomized, median treatment duration was 22.0 months for both treatment arms; 33% (n = 81) of pts in the bosutinib arm and 26% (n = 66) of pts in the imatinib arm have discontinued treatment. The primary reason for discontinuation of bosutinib was treatment-related toxicity (22% vs 6% with imatinib), while the primary reason for discontinuation of imatinib was disease progression (13% vs 4% with bosutinib); all other reasons for discontinuation were reported for ≤3% of pts in either arm. At baseline, already present Bcr-Abl polymorphisms were equally distributed among the 2 arms (bosutinib, n = 24; imatinib, n = 17). The most common baseline polymorphisms were E499E (bosutinib, n = 18; imatinib, n = 10), 499E/E or 499E/E variant (bosutinib, n = 3; imatinib, n = 1), and T83T (bosutinib, n = 0; imatinib, n = 4); additional polymorphisms detected in at least one of the treatment arms included E197K, K247R, T240T, and Y320C. As of the database snapshot, 81 pts had discontinued treatment in the BOS arm compared with 66 pts in the IM arm, of which 62 (77%) pts in the BOS arm and 49 (74%) pts in the IM arm had a sample collected at treatment discontinuation. Of these, 37/62 (60%) pts in the BOS arm did not have a detectable mutation and 28/49 (57%) pts in the IM arm did not have a detectable mutation. Four (6%) pts had a detectable mutation in the BOS arm (T315I [n = 2], E255K, and V299L [n = 1 each]) compared with 10 (21%) pts in the IM arm (G250E [n = 2], M244V [n = 2], Q252H, Y253H, E255K, M244V/M351T, D276G/H396R, and D276G/T277A/T315I [n = 1 each]) at the time of treatment discontinuation. In the BOS arm, 1 pt with the V299L mutation achieved CCyR (time to CCyR of 254 days). In the IM arm, 1 pt with the G250E mutation achieved both CCyR and MMR (time to response of 252 days for both) and 2 pts with the M244V and D276G/T277A/T315I mutations achieved CCyR (times to CCyR of 254 and 340 days, respectively). Treatment failure was experienced by 2/4 pts in the BOS arm with a mutation (E255K and T315I) compared with 7/10 pts in the IM arm (M244V [n = 2], G250E, Q252H, Y253H, M244V/M351T, and D276G/H396R). An on-treatment event of transformation to accelerated/blast phase CML was experienced by 2/4 pts in the BOS arm (E255K and T315I) versus 5/10 pts in the IM arm (G250E, Q252H, Y253H, M244V/M351T, and D276G/H396R). Among pts with a new mutation detected at treatment completion, 2 deaths were reported in each treatment arm; all 4 deaths occurred after discontinuation of study treatment. In conclusion, baseline and emergent Bcr-Abl kinase domain mutations were detected in both treatment arms, with polymorphisms at the E499 position the most common. In this analysis, imatinib was associated with a higher rate of progressive disease compared with bosutinib among pts with new mutations at treatment discontinuation; a similar trend has been observed in the overall study population. Additional follow-up will allow for more complete mutational analysis. Disclosures: Kim: Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Cortes:Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Wong:Pfizer Inc: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; GSK: Research Funding; Bayer: Honoraria, Research Funding; Sanofi: Research Funding; Biogen Idec: Honoraria, Research Funding; Roche: Research Funding; Leo Pharma: Honoraria. Duvillie:Pfizer Inc: Employment. Powell:Pfizer Inc: Employment, Equity Ownership. Countouriotis:Pfizer Inc: Employment. Brümmendorf:Pfizer Inc: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria.