ALBERT

Description: Introduction. The NCIC CTG is conducting phase II testing to establish the tolerability and estimate the efficacy of combining lenalidomide (L) + melphalan (M) over multiple cycles for previously untreated patients with multiple myeloma who are ineligible for stem cell transplantation. We report the data from the preliminary safety phase of this trial. Methods. The MY.11 trial was initially designed as a randomized phase II test of M 9 mg/m2 given on days 1–4 (M9) plus either L 10 mg (L10) or 20 mg given on days 1–21 of a 28 day cycle. Primary prophylaxis with G-CSF was not included, but use of G-CSF for established neutropenia was permitted; our intent was to determine dose levels that could be given independently of G-CSF. A dose attenuation schedule was developed for neutropenia and/or thrombocytopenia that was severe and occurred during the administration of L or was persistent and caused a delay in the next treatment cycle. A hematologic dose limiting toxicity (H-DLT) was defined as the need for 2 dose attenuations of L or 1 dose attenuation of M. Prior to the randomized phase of the trial, a safety run-in phase testing M9+L10 in 6 patients was planned; closure of this arm was to occur if, during the first 3 treatment cycles, there were ≥ 3 H-DLTs or any non-hematologic serious adverse event (SAE) judged to be treatment related. Four of the planned 6 patients were entered; during their first 3 treatment cycles, each experienced a H-DLT and one died from sepsis. The study was therefore amended with the intent to conduct a randomized phase II test of M 4 mg/m2 days 1–4 plus L 15 mg days 1–21 (M4L15) and M 6 mg/m2 days 1–4 plus L 10 mg days 1–21 (M6L10). Prior to the randomized phase of testing, each regimen was tested in non-randomized safety run-ins that included 6 patients per arm. The same parameters as above for study arm closure were applied. If the M6L10 arm was closed, the trial would proceed to test M 5 mg/m2 days 1–4 and L 10 mg days 1–21 (M5L10). Results. Six patients were enrolled to M4L15: during their first 3 treatment cycles, 4 patients experienced H-DLTs related to severe or persistent grade 3–4 neutropenia and one other patient experienced an SAE related to hallucinations and multiple constitutional complaints. This arm was therefore closed to accrual. Six patients were enrolled to M6L10: during their first 3 treatment cycles, 3 patients experienced H-DLTs related to severe or persistent grade 3–4 neutropenia. One of these patients was hospitalized with pulmonary edema and another with febrile neutropenia. This arm was therefore closed and the MY.11 trial amended to proceed as a single-arm phase II testing M5L10. Conclusion. Although M + L holds promise as an effective combination for previously untreated myeloma patients, the regimen is associated with considerable myelosuppression. The efficacy of the combination when given at tolerable doses remains to be established.

Description: Key Points Patients with relapsed or refractory transformed indolent lymphoma and DLBCL have similar outcomes with salvage therapy and ASCT. This therapy should be considered the standard of care for previously treated transformed indolent lymphoma.

Description: Background: The outcome of peripheral T-cell lymphomas (PTCLs) remains poor and improved therapies are needed. Retrospective data suggest that integration of anthracyclines in the primary therapy may not impact outcome, providing the rationale to explore alternative regimens. Histone deacetylase inhibitors appear to have a class effect in PTCLs andromidepsin monotherapy demonstrates activity in a proportion of patients with relapsed/refractory PTCLs and can induce durable remissions. Gemcitabine is reported to be a highly active agent in PTCL, and the GDP (gemcitabine, dexamethasone, cisplatin) regimen has become a standard chemotherapy backbone for relapsed aggressive lymphomas (Crump, JCO 2014). We investigated the feasibility, safety and efficacy of GDP combined with romidepsin in a phase I dose escalation trial. Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) were also included. Methods: Patients with relapsed/refractory PTCL or DLBCL, PS 0-2, with measurable disease and who had received one or two prior lines of systemic therapy, were treated with standard doses of GDP (gemcitabine, 1000 mg/m2 d1, d8; dexamethasone, 40 mg po d1-4; cisplatin, 75 mg/m2 d1) every 21 days, plus escalating doses of romidepsin (6, 8, 10 and 12 mg/m2) on days 1 and 8 to a maximum of 6 cycles in a standard 3+3 design. After the first 4 patients were enrolled, based on the observed pattern of thrombocytopenia, the treatment schedule was modified so that gemcitabine and romidepsin were given on days 1 and 15 and cycles extended to every 28 days. Dose-limiting toxicities (DLTs) were assessed during the first 2 cycles and defined as requiring platelet transfusion for bleeding, grade 3 hematological toxicity lasting 〉10 days, grade 4 hematological toxicity lasting 〉7 days, febrile neutropenia, or grade 3-4 non-hematological toxicity attributable to romidepsin. Responses were as per Cheson, JCO 2007 excluding PET scans. Results: 20 eligible patients (PTCL n=10; DLBCL n=10) were enrolled between 10/2013 and 01/2016 and treated with GDP plus romidepsin. The main PTCL subtype was PTCL, not otherwise specified (50%). Median age was 65 years (24-74); 9 were female; ECOG performance status was 0 (n=2), 1 (n=13), or 2 (n=5). Number of prior therapies was 1 (n=17) or 2 (n=3). 17 (85%) patients received 〉90% of the planned dose each cycle. The median number of cycles was 2 (range, 1-6); one patient is still on therapy. The reasons for treatment discontinuation were lymphoma progression (n=10), toxicity (n=2), proceeding to autologous stem cell transplant (ASCT, n=3), intercurrent illness (n=1), or completion of 6 cycles (n=3). On the 21-day schedule at 6 mg/m2 romidepsin, there were 3 DLTs among four patients (2 with grade 3-4 thrombocytopenia, 1 venous thromboembolic event). On the 28-day schedule, there were no DLTs observed in the three patients treated at each of the 6, 8 or 10 mg/m2 dose levels. At 12 mg/m2 there were 4 observed grade 3 DLTs among six evaluable patients (hypotension, acute kidney injury, anorexia, thrombocytopenia 〉10 days). Notable toxicities during any cycle were: febrile neutropenia (n=2); grade 3-4 thrombocytopenia (n=9); grade 3-4 neutropenia (n=4); and grade 3-4 anemia (n=4); grade 2 atrial fibrillation (n=2); grade 2 QTc prolongation (n=1); grade 1 sinus tachycardia (n=1); grade 2-3 infections (n=16); grade 1-3 cutaneous toxicity (n=9); grade 1-3 thromboembolic events (n=2); TIA (n=2) or stroke (n=1). One patient died after cycle 1 due to sepsis. 7 other patients have died of progressive lymphoma. The overall response rate was 9/20 (45%), all were partial remissions (PR), 3 had stable disease (SD), 4 had progressive disease (PD), and 4 were not objectively evaluable. Of the responders, 5 had PTCL and 4 had DLBCL. Four patients went on to ASCT. With a median follow-up of 5.8 months, the median duration of response was 2.8 months and median PFS is 2.2 months. For all patients, the 1 year PFS was 6% and 1 year OS was 43% Discussion: Full doses of GDP can be combined with a recommended phase II romidepsin dose of 10 mg/m2 given on a day 1, 15 every 28 days schedule. Thrombocytopenia prohibits this combination on a 21-day schedule. Toxicity is otherwise acceptable and as expected. Further study at the recommended dose and schedule would be required to properly define the activity of this regimen in PTCLs and DLBCL. Disclosures Reiman: Celgene: Honoraria, Research Funding. Buckstein:Novartis: Honoraria; Celgene: Honoraria, Research Funding. Kuruvilla:Merck & Co., Inc.: Consultancy, Honoraria. Villa:Lundbeck: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria. Hay:Amgen: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Kite Pharmaceuticals: Research Funding.

Description: Abstract 1633 Background: Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent antitumor antibiotic. CD22 is expressed on the majority of B-cell non-Hodgkin's lymphomas (NHL). This phase 1 study was conducted to identify the maximum tolerated dose (MTD) of INO when given in combination with R-CVP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.4 mg/m2 all on Day 1 and prednisone 40 mg/m2on Days 1–5) every 21 days, and to obtain preliminary safety and efficacy data for this regimen. Patients and methods: The study enrolled patients with relapsed/refractory CD22+ B-cell NHL. The dose-escalation part (Part 1; previously presented) identified the MTD as INO 0.8 mg/m2 given on Day 2 with R-CVP q3wks [Blood. 2011;118:3715]. Subsequent cohorts included the MTD confirmation cohort (Part 2) and MTD expansion cohort (Part 3), for collection of additional safety and preliminary efficacy data. Untreated patients who were not candidates for anthracyclines were allowed in Part 2 and Part 3 of the study. In Part 2 (n = 10), confirmation of the MTD required a dose-limiting toxicity (DLT) rate of

Description: Abstract 3715 Background: Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent antitumor antibiotic. CD22 is expressed on the majority of B-cell non-Hodgkin lymphomas (NHL). Although safety and preliminary efficacy data of INO as monotherapy and in combination with rituximab have previously been reported, there is no report of combination use of INO with chemotherapy. This phase I study evaluated the safety of INO in combination with chemotherapy (R-CVP regimen) in patients with relapsed or refractory CD22+ B-cell NHL. Preliminary efficacy data were also collected. Patients and Methods: Patients with either relapsed or refractory CD22+ B-cell NHL and at least 1 prior treatment regimen, including rituximab and chemotherapy, were enrolled in a phase I dose-finding study (part 1), with a planned expansion cohort (n = 10) to confirm the safety and tolerability of the maximum tolerated dose (MTD; part 2), and a further expansion cohort (n = 20) to estimate antitumor activity (part 3). In the dose-escalation study, INO (0.8 mg/m2) was given on Day 2 with R-CVP (rituximab 375 mg/m2, vincristine 1.4 mg/m2, and escalating doses of cyclophosphamide 375, 550, and 750 mg/m2 all on Day 1; prednisone 40 mg/m2 on Days 1–5) q3wks. After the highest dose of cyclophosphamide was evaluated for safety, INO was escalated to 1.3 mg/m2. Dose reductions and/or dose delays were performed, as needed, based on toxicities. The current analysis presents the completed dose-escalation phase, with preliminary safety and efficacy data. Results: 23 patients with follicular (FL; n = 15), mantle cell (n = 3), diffuse large B-cell (n = 3), or small lymphocytic (n = 1) lymphomas (missing diagnosis, n = 1) have been enrolled so far: 65% of patients were male, and the median age was 62 years (range, 42–74 years). In part 1 of the study, approximately 50% of patients had received 2 or more prior chemotherapy regimens, and all had received prior rituximab. As of the time of this analysis, 11 patients had completed at least 5 treatment cycles (ie, ≥105 days on study drug). No dose-limiting toxicities (DLTs) were reported with INO 0.8 mg/m2 plus R-CVP at the lower doses of cyclophosphamide (375 and 550 mg/m2). At a dose level of INO 0.8 mg/m2 plus full-dose R-CVP (cyclophosphamide 750 mg/m2), 1 out of 6 patients had a DLT of grade 4 neutropenia requiring treatment with granulocyte colony-stimulating factor (G-CSF). At a dose level of INO 1.3 mg/m2 plus R-CVP, 2 out of 3 patients had a total of 3 DLTs (acute hepatitis, thrombocytopenia, and neutropenia requiring G-CSF). Therefore, the MTD was determined to be rituximab 375 mg/m2, vincristine 1.4 mg/m2, and cyclophosphamide 750 mg/m2 all given on Day 1, INO 0.8 mg/m2 given on Day 2, and prednisone 40 mg/m2 given on Days 1 through 5 of each 3-week cycle. Treatment-emergent grade ≥3 adverse events included neutropenia (57%), lymphopenia (52%), leukopenia (35%), thrombocytopenia (30%), increased alanine aminotransferase (9%), increased aspartate aminotransferase (4%), decreased blood sodium (4%), fatigue (4%), febrile neutropenia (4%), hyperbilirubinemia (4%), hypoxia (4%), lethargy (4%), pleural effusion (4%), and pollakiuria (4%). Enrollment is continuing in parts 2 and 3 of the study. Preliminary efficacy data from the escalation portion of the study (n = 15 evaluable patients) is notable for an overall response rate (ORR) of 87% (33% with complete response; 53% with partial response). In patients with FL, the ORR was 100% (45% with complete response). Conclusions: INO 0.8 mg/m2 appears to be tolerable when given in combination with full dose R-CVP chemotherapy. DLTs were hematologic and hepatic, and encouraging signs of antitumor activity have been reported. Disclosures: MacDonald: Roche Canada: Honoraria, Research Funding. Davies:Pfizer Inc: Research Funding. Sangha:Roche: Honoraria; Boehringer Ingelheim: Honoraria. Crump:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche Canada: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria. Thieblemont:Assistance Publique - Hôpitaux de Paris: Employment; Institut National du Cancer - INCa [French National Cancer Institute]: Research Funding. Ishibashi:Pfizer Inc: Employment, Equity Ownership. Hua:Pfizer Inc: Employment, Equity Ownership. Paccagnella:Pfizer Inc: Employment, Equity Ownership, Patents & Royalties. Vandendries:Pfizer Inc: Employment, Equity Ownership. Kobayashi:Ohtsuka Pharmaceutical: Research Funding; Nippon Shiyaku: Honoraria; BMS: Honoraria. Tobinai:Bayer: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Eli Lilly: Research Funding; Genzyme: Research Funding; GSK: Research Funding; Kyowa Hakko Kirin: Research Funding; Janssen: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Pfizer Inc: Research Funding; Symbio: Research Funding; Zenyaku: Research Funding.

Description: Background NCIC CTG LY.12 was an international randomized trial evaluating two treatment strategies for patients (pts) with aggressive lymphoma relapsing after or with progressive disease following primary therapy. The first randomization demonstrated that gemcitabine, dexamethasone, cisplatin (GDP) was non-inferior to and significantly less toxic than dexamethasone, cytarabine, cisplatin (DHAP) as salvage therapy (ASH 2012). Here we report the results of the second randomization, testing the ability of the CD20 antibody rituximab (R) administered post-ASCT to improve event-free survival (EFS) compared to no further therapy. Methods Pts with CD20-positive aggressive lymphoma who underwent ASCT after GDP or DHAP who had recovered from ASCT-related toxicities and who remained clinically progression-free within 3-5 weeks post-transplant were stratified by centre, salvage regimen received, response to salvage therapy (CR vs PR/SD) and prior treatment with R, and were randomized using a minimization algorithm to receive R 375 mg/m2every 2 months for 6 doses, or observation. Response assessment by CT scanning was required at 3,7,13 and 25 mos post-ASCT or as needed to evaluate possible disease recurrence. The primary endpoint of the second randomization was 2 year EFS; to detect an improvement by 15% (from 50 to 65%, hazard ratio 0.62) required 142 events, with a 2-sided α 0.05 and power 0.80. Because of the low event rate over the last year and a projected time of many years to reach the protocol specified event rate, the Data Safety Monitoring Committee approved a request for study closure and analysis, with 118 events recorded. Results 230 patients were randomized to R maintenance (115) or observation (115). Baseline patients and disease characteristics were well balanced between treatment arms: median age was 53 yrs, 28% were age 〉65 and 40% were female; 52% received GDP and 48% DHAP; 55% had an IPI score of 2 or more at relapse/progression, and 17% had transformed (TR) from previous indolent lymphoma. Response to salvage pre-ASCT: CR 24%, PR 58%; 70% had received R with chemotherapy prior to study enrolment, and 69% received R with protocol salvage treatment. All analyses are by intention to treat (ITT). To date, there have been 118 EFS events (R 53, observation 65). After a median follow-up of 63 months, 2 year EFS was 64% for pts treated with maintenance R vs 51% for those on observation (HR 0.74, 95% CI 0.48-1.14, p= 0.11); there was no difference in overall survival (OS) at 4 years (R 69%, observation 68%, p=0.64). Grade 3-4 neutropenia was reported in 36% of pts on R maintenance vs 25% during observation; and Gr 3-4 thrombocytopenia in 11% and 16%, respectively. Febrile neutropenia occurred in 10 pts (9%) on R maintenance and 2 pts (2%) on observation. Two year EFS was similar in subsets defined by stratification variables at randomization: GDP salvage therapy: R 57.0% vs observation 45.9% (HR 0.84, 95% CI 0.52-1.36), DHAP: R 70.0% vs observation 57.1% (HR 0.68, 0.39-1.18); response to salvage CR/CRu: R 69.0% vs 52.9% (HR 0.71, 0.32-1.6), PR: R 64.5% vs observation 57.4% (HR 0.90, 0.55-1.46); R use with prior treatment: R 53.7% vs observation 42.0% (HR 0.81, 0.54-1.22); no prior R: R 83.3% vs observation 70.6% (HR 0.64, 0.29-1.38). In multivariable analysis, only age 〉60 was significantly associated with EFS; ECOG performance status, treatment arm, stage and extra-nodal disease were not significant. Conclusion This evaluation of rituximab maintenance treatment every 2 mos for one year after ASCT for aggressive lymphoma failed to meet the study endpoint of improved EFS, compared to observation. Disclosures: Crump: Roche: Honoraria; Jansen-Ortho: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Novartis: Research Funding; Seattle Genetics: Honoraria. Off Label Use: rituximab for maintenance therapy post autolgous transplant for lymphoma. Kuruvilla:Roche Canada Seattle Genetics, Janssen, Celgene, Lundbeck, Karyopharm: Honoraria. Kouroukis:Roche: Honoraria. Federico:MedImmune: Research Funding. Meyer:Lilly: Consultancy; Celgene: Consultancy.

Description: Background CD22 is expressed on most B-NHL. Inotuzumab ozogamicin (InO) is a humanized anti-CD22 antibody conjugated with calicheamicin, a potent cytotoxic antitumor antibiotic with activity in relapsed/refractory B-NHL. This study explored the safety, tolerability and preliminary efficacy of InO plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) for subjects with CD22+ B-NHL. Methods Part 1 (dose escalation phase, n = 27) enrolled patients (pts) with relapsed or refractory CD22+ B-NHL treated with ≥1 prior R-chemo regimen using an up-and-down independent dose-escalation schema for G and P. InO (0.8 mg/m2 day 2) was combined with R-GDP (R 375 mg/m2, G, and P day 1; oral D 40 mg days 1-4) on a 21-day cycle for up to 6 cycles. R-GDP (R 375 mg/m2 day 1; G 1000 mg/m2 days 1 and 8; D 40 mg days 1-4; P 75 mg/m2 day 1) is a regimen used in some patients with relapsed/refractory B-NHL. Part 2 (MTD confirmation cohort, n = 10) enrolled additional pts to further evaluate the safety and tolerability of the MTD determined in Part 1. Confirmation of the MTD required a dose-limiting toxicity (DLT) rate of 〈 33% in Cycle 1 and 〈 4 pts discontinuing prior to Cycle 3 due to adverse event (AE). Part 3 (MTD expansion cohort, n = 18) enrolled additional pts to further evaluate the preliminary efficacy of InO when given in combination with R-GDP. Results Fifty-five pts were treated: 21 DLBCL, 14 FL, 12 MCL, 4 SLL, 1 MZL, and 3 other indolent B-NHL. Characteristics: aged 25 to 81 y (median 65 y); 51 with ECOG PS ≤1; median of 2 prior chemo regimens (range 1-6); 8 refractory to prior therapy. The dose-escalation phase (Part 1) identified the MTD as InO 0.8 mg/m2, R 375mg/m2, G 500 mg/m2 (day 1 only), D 40 mg, P 50 mg/m2. This MTD was confirmed in Part 2, in which 3 pts had DLTs (2 with grade 4 platelets, 1 with febrile neutropenia). The most common treatment-related grade ≥3 AEs included thrombocytopenia (69%), neutropenia (56%), lymphopenia (22%), leukopenia (18%), anemia (16%), and febrile neutropenia (11%). Twenty-one pts completed all 6 treatment cycles; the median number of cycles completed was 4 (range 1-6). The most common AEs leading to dose reductions and temporary dose delays included thrombocytopenia, febrile neutropenia, and neutropenia. For the 55 pts enrolled, the overall response rate (ORR) was 45% (n = 25), including 22% of pts (n = 12) who achieved a complete response (CR). Of the 55 pts enrolled, 46 had both a baseline and at least 1 post-baseline assessment reported. In this population to date, the ORR was 54%, including 26% who achieved a CR. 2 pts remain on treatment at the time of data collection. Additional efficacy data are summarized in Table 1 . Pharmacokinetic samples were collected for pts enrolled in the MTD confirmation and expansion cohorts. Fifty-three pts have discontinued treatment, including 21 who completed the planned number of cycles, 12 due to AE (including 8 pts with grade 2/3 thrombocytopenia that did not resolve to grade 1 or better within the 28-day dose delay window allowed per protocol, and 1 each grade 5 oesophageal obstruction, grade 2 skin lesion and grade 4 tumor lysis syndrome) and 12 due to PD. Fifteen deaths have been reported, 12 due to disease progression and 3 due to other causes, including graft-versus-host disease, toxicity after allograft, and sequelae of subdural hematoma not related to study drug (n = 1 each). Conclusions InO 0.8 mg/m2 with R-GDP is tolerable at reduced doses of G (500 mg/m2 day 1 only) and P (50 mg/m2). Preliminary efficacy in the MTD expansion cohort is encouraging. Follow-up for PFS and OS is currently ongoing. Disclosures: Sangha: Boehringer Ingelheim: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria; Pfizer: Honoraria. Off Label Use: This abstract presents findings from a phase I study of inotuzumab ozogamicin in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma; this drug is investigational and is not approved for use in any indication in any country. Davies:Pfizer: Research Funding; Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Ogura:Eli Lilly: Research Funding. Volkert:Pfizer Inc: Employment. Ananthakrishnan:Pfizer Inc: Employment. Luu:Pfizer Inc: Employment. Boni:Pfizer Inc: Employment. Vandendries:Pfizer Inc: Employment. Goh:Gilead Scienes: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Jannsen: Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Hospira: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Description: Abstract 2729 Poster Board II-705 Background: There are limited effective treatment options for patients with diffuse large B cell lymphoma who relapse post autologous stem cell transplant or are transplant-ineligible. The detection of vascular endothelial growth factor (VEGF )A, B and C isoforms and their receptors on many large cell lymphoma samples suggests that the VEGF pathway is critically important and may contribute to disease progression. Sunitinib maleate, is an orally bioavailable inhibitor of VEGF receptor-1 (VEGFR-1), -2, and -3, PDGFR-α and β as well as KIT, FLT3, RET and CSF-1 (Chow, LQ JCO 2007). We tested the efficacy, safety and biomarker activity of sunitinib in patients with relapsed diffuse large B cell lymphoma in a multi-center prospective phase II study. Methods: Eligibility included age 18 or older, histologically confirmed relapsed or refractory diffuse large B-cell (DLBCL), primary mediastinal (PMBCL), or transformed indolent lymphoma, at least one and no more than 2 prior chemotherapy regimens (one anthracycline-containing). The primary endpoint was objective response defined by 1999 Cheson criteria. The secondary endpoints were progression-free and overall survival, toxicity and the effect of sunitinib on peripheral blood circulating endothelial cells (CECs) and their precursors (CEPs). Patients self administered sunitinib 37.5 mg po daily with no breaks in 4 week cycles for up to 1 year. CT imaging was performed every 2 cycles and CEC/CEP assays were done at baseline, day 1 of cycles 2, 3 then q 3 months thereafter. A Simon 2-stage design was used with at least 1 response needed after 15 evaluable patients to complete a planned accrual of 25 patients total. Results: Between Feb 2007 and September 2008 we enrolled 19 patients at 7 Canadian sites - 17 were eligible and are evaluable for toxicity and 15 are evaluable for response. The median age was 65 and patients were a median of 20.3 months(m) from diagnosis (range 5.8–132 m). Fourteen (82%) had a diagnosis of DLBCL, 10 (58%) had responded to their preceding line of chemotherapy - 5 (29%) had relapsed post high dose chemotherapy. The median number of cycles of sunitinib received was 2 (1–5) with only 5 patients remaining on drug for 3 or more cycles. Only 35% of patients received 〉 90% planned dose intensity with 14 patients missing doses and 5 undergoing dose reductions necessitated by toxicities. Hematological toxicity (grade 3 neutropenia in 5 pts, grades 3–4 thrombocytopenia in 6 pts) and was the most common reason for dose omission. Of the 15 evaluable pts, no objective responses were seen, and 9 achieved stable disease (median duration 3.4 m); and 6 had primary progressive disease. As a result, the study was closed at the end of the first stage. With limited serial sampling, there was no discernable relationship between the change in absolute or apoptotic CEC over time with clinical response as measured by best response or change in bi-dimensional measurements. Conclusions: Sunitinib 37.5 mg po daily showed no evidence of anti-tumour activity in relapsed/refractory large B cell lymphoma and is associated with greater than expected hematological toxicity. Disclosures: Buckstein: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Off Label Use: It is being tested in NHL.

Description: Background: Despite recent improvements in therapy, follicular lymphoma (FL) remains incurable with standard treatment, warranting investigation of new approaches. Bortezomib, the first-in-class proteasome inhibitor has demonstrated promising efficacy as a single agent in heavily pretreated patients (pts) with FL. This is the first study to evaluate the safety and efficacy of the addition of bortezomib to cyclophosphamide, vincristine, prednisone and rituximab (CVP-R). Methods: This is a phase II multi-center open-label trial adding bortezomib (1.3 mg/m2 day 1&8) to standard dose C(750 mg/m2) V(1.4 mg/m2, capped at 2 mg) P(40 mg/m2 × 5) –R(375 mg/m2) for up to 8 cycles in pts with newly diagnosed stage III/IV FL requiring therapy. Planned accrual is 90 patients. A two-stage design was employed with a planned interim analysis of the first 28 patients to ensure an acceptable level of neurotoxicity (defined as less than 5/28 patients with grade 3/4 neurotoxicity after the first 4 cycles) and meaningful response rate (more than 12/28 patients with a complete response following 8 cycles), prior to enrolling remaining patients. Results: Median age of the first 28 patients was 55 years (range, 30–73). Fifty percent were male and 79% had stage IV disease. FLIPI score at study entry: low 14%, intermediate 43%, high 43%. Overall, the combination of bortezomib and CVP-R was extremely well tolerated. To date, no pts have developed grade 4 neurotoxicity and only 1/28 (4%) has developed grade 3 neurotoxicity within the first 4 cycles (neuropathic pain which resolved without need for treatment modification). The incidence of grade 1 and 2 neurotoxicity was 54% and 25% respectively. Only 3 pts discontinued therapy prematurely (2 pt refusal, 1 progressive disease). Ninety-four percent of planned bortezomib treatments in the first four cycles and 93% of vincristine doses were administered without dose reduction. Hematologic toxicity was mild, with no pts experiencing grade 3/4 anemia or thrombocytopenia. Only 2 episodes of febrile neutropenia occurred and no grade 3/4 infections were noted. Although it is too early to report on efficacy in this ongoing trial, response objectives for stage I have been met, and enrollment to stage 2 is underway. Conclusions: The addition of bortezomib to standard dose CVP-R is very well tolerated, with an acceptable level of neurotoxicity, without compromising the delivery of bortezomib or vincristine. This ongoing study will provide toxicity and efficacy data to facilitate the development of a planned phase III trial.