ALBERT

Description: Chronic myelogenous leukemia (CML), a malignancy of a hematopoietic stem cell, is caused by the Bcr-Abl tyrosine kinase. STI571(formerly CGP 57148B), an Abl tyrosine kinase inhibitor, has specific in vitro antileukemic activity against Bcr-Abl–positive cells and is currently in Phase II clinical trials. As it is likely that resistance to a single agent would be observed, combinations of STI571 with other antileukemic agents have been evaluated for activity against Bcr-Abl–positive cell lines and in colony-forming assays in vitro. The specific antileukemic agents tested included several agents currently used for the treatment of CML: interferon-alpha (IFN), hydroxyurea (HU), daunorubicin (DNR), and cytosine arabinoside (Ara-C). In proliferation assays that use Bcr-Abl–expressing cells lines, the combination of STI571 with IFN, DNR, and Ara-C showed additive or synergistic effects, whereas the combination of STI571 and HU demonstrated antagonistic effects. However, in colony-forming assays that use CML patient samples, all combinations showed increased antiproliferative effects as compared with STI571 alone. These data indicate that combinations of STI571 with IFN, DNR, or Ara-C may be more useful than STI571 alone in the treatment of CML and suggest consideration of clinical trials of these combinations.

Description: Abstract 964 Introduction: Bruton's tyrosine kinase (Btk) is a downstream mediator of B-cell receptor signaling. PCI-32765 is a potent, selective, irreversible and orally bioavailable small molecule inhibitor of Btk. We have previously reported initial efficacy and safety data with this agent in various B-cell malignancies (ASCO 2010 abstract # 8012). We now report updated efficacy and safety of PCI-32765 in patients (pts) with long-term dosing. Pts and Methods: Pts on the Phase 1 study were treated with escalating doses over 6 cohorts. Cohort 1 was dosed at 1.25 mg/kg/day with subsequent dose escalation (2.5, 5.0, 8.3, 8.3 continuous dosing, and 12.5 mg/kg/day) based on safety evaluation. Pts were analyzed according to histology, pretreatment clinical and laboratory characteristics, PCI-32765 dose levels, overall response (OR), and response duration. Results: Responses and time on study (≥ 6 months) are summarized in Table 1. Of 47 pts enrolled in the Phase 1 study, 20 pts (43%) achieved an OR including 3 complete remissions (CR) and 17 partial remissions (PR). Fourteen of 47 pts have been on study ≥ 6 months; of these 8 pts demonstrated a PR or better and 6 pts maintained stable disease (SD). Responses were observed irrespective of pretreatment risk factors such as performance status, lactate dehydrogenase (LDH) levels, or disease burden. Durable responses were seen at all dose levels and across various histologic subtypes (Table 1) and currently 9 of 14 pts with treatment ≥ 6 months are still on study. Study-drug related Grade ≥ 3 toxicities were reported in 9/47 pts (19%). Five of 47 pts discontinued study drug due to adverse events: neutropenia (Grade 3) lasting 〉 7 days, hypersensitivity reaction (Grade 3), small bowel obstruction (Grade 3), anemia (Grade 2), and exacerbation of chronic obstructive pulmonary disease (Grade 3). No evidence of cumulative hematologic toxicity or long-term safety signals have been observed. No treatment-related deaths have been reported. Conclusion: PCI-32765 is a novel oral Btk inhibitor that induces durable objective responses in various relapsed or refractory B-cell malignancies. The favorable safety profile and lack of cumulative hematologic toxicities support further studies of both monotherapy and combination treatment with PCI-32765. Disclosures: Fowler: Pharmacyclics: Consultancy, Research Funding. Off Label Use: This phase I trial describes the results of a first in human Phase I trial. This drug is not FDA approved for the treatment of malignancy. Sharman:Pharmacyclics, Inc: Honoraria, PI grant. Smith:pharmacyclics: Research Funding. Boyd:pharmacyclics: Research Funding. Grant:pharmacyclics: Research Funding. Kolibaba:pharmacyclics: Research Funding. Furman:Pharmacyclics, Inc: Research Funding. Buggy:pharmacyclics: Employment. Loury:Pharmacyclics: Employment, Equity Ownership. Hamdy:pharmacyclics: Employment. Advani:Pharmacyclics, Inc: Honoraria, PI grant.

Description: This study was designed to evaluate the efficacy and safety of bortezomib as monotherapy in patients (pts) with indolent B-cell lymphoma who have relapsed following, or who are refractory to, rituximab therapy. A total of 60 patients enrolled and 59 were treated with 1.3 mg/m2 of bortezomib (IV bolus over 3–5 secs) Days 1, 4, 8, and 11 for up to eight 21-day cycles; pts with a CR could receive 4 additional cycles. Pts with

Description: Key Points Obinutuzumab monotherapy demonstrates an increased ORR with 2000 mg over 1000 mg, but no difference in progression-free survival. No meaningful difference was observed in the overall safety profile across the 2 treatment arms.

Description: Background: Spleen tyrosine kinase (Syk) is a mediator of B-cell receptor signaling in normal and transformed B-cells. Entospletinib is an orally bioavailable, selective inhibitor of Syk. Methods: This Phase 2 trial is evaluating entospletinib 800 mg BID in a study of 204 patients with previously treated lymphoid malignancies. Tumor imaging was planned at weeks 8, 16, 24 and then every 12. Tumor response was assessed per Cheson 2007 criteria. Results: A cohort of 69 patients with iNHL (41 follicular lymphoma [FL], 11 lymphoplasmacytoid lymphoma [LPL], 17 marginal zone lymphoma [MZL]) are included in this analysis. Median age was 66 years (range 41 - 89). 58% were male. The median number of prior treatments (Rxs) regimens was 3 (range 1- 14). Prior Rxs included anti-CD20 antibodies (rituximab 99%, ofatumumab 4%), alkylating agents (90%; bendamustine 51%) and anthracyclines (35%). Baseline risk factors: Ann Arbor Stg III-IV (70%), Gr 3a FL (29%), FLIPI ≥3 (34%). Median duration of Rx was 16 weeks with 10 patients continuing on Rx. Entospletinib was generally well tolerated. The most common TEAEs (any Grade/≥Gr 3, independent of causality) were fatigue (54%/13%), nausea (49%/4%), diarrhea(36%/0%), vomiting (26%/0%), headache (23%/1%), pyrexia (23%/3%), decreased appetite (22%/0%), constipation (22%/1%) and common laboratory abnormalities were increased AST (33%/15%), increased ALT (41%/19%), increased total bilirubin (32%/16%), anemia (36%/13%) and neutropenia (38%/13%). 4 patients died while on study from progressive disease. At the time of this analysis, 66 of 69 patients have been treated through first response assessment (1 patient ongoing not reaching first response assessment, 1 patient discontinued due to AE and 1 patient withdrew consent prior to it). 38 out of 61 (62%) patients evaluable for SPD experienced reduced tumor burden, with median duration of Rx 28 weeks (range 4-92). 9/61 (15%) achieved a decrease of ≥ 50% in SPD. The ORR was 13.0% (95% CI: 6.1%, 23.3%), with 7 patients achieving a PR, one LPL patient achieving MR and one patient achieving a CR. Forty-one patients (59.4%) had stable disease. The primary end point of 24 weeks PFS was 48.9% (95% CI: 34.6%, 61.7%). Median PFS was 5.5 months (95% CI: 4.4 months, 8.2 months). There were 39 patients (56.5%) with events of disease progression. Conclusions: Entospletinib monotherapy given with this dose and schedule was well tolerated and demonstrated activity in patients with advanced relapsed iNHL, including those with poor prognostic features. Further development of entospletinib in iNHL will focus on the development of combination approaches with chemotherapy and targeted agents. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Sharman: Calistoga: Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Roche: Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Off Label Use: Management of CLL/SLL and follicular lymphoma. Kolibaba:Takeda Pharmaceuticals International Co.: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Janssen: Research Funding; GSK: Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding. Abella:Gilead: Employment. Eng:Gilead: Employment. He:Gilead Sciences: Employment. Hu:gilead: Employment. Yasenchak:Seattle Genetics, Inc.: Research Funding.

Description: Introduction: Rituximab-CHOP (R-CHOP) has resulted in significantly improved outcomes for patients (pts) with untreated DLBCL. Despite this progress, approximately 30% of pts are not cured with R-CHOP, especially those with high risk disease as defined by the IPI. Polatuzumab vedotin (PoV) is an antibody drug conjugate (ADC) designed for the targeted delivery of the potent microtubule inhibitor MMAE to cells expressing CD79b. Because ADCs may possess a therapeutic index superior to that of many systemically administered chemotherapies, PoV has the potential to replace vincristine with a targeted agent and potentially increase the potency of the standard R-CHOP regimen. We report preliminary results from the dose-escalation portion of this Phase Ib/II study of PoV combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) (ClinicalTrials.gov NCT01992653). Methods: This multicenter, open-label study will evaluate the safety, tolerability, and pharmacokinetics of escalating doses of PoV with standard doses of R-CHP. Adults, ages 60-80 years, with newly diagnosed or relapsed/refractory B-cell NHL were given PoV intravenously 1.0, 1.4, or 1.8 mg/kg with R-CHP every 21 days for a total of 6 or 8 cycles. Doses were escalated in a 3+3 design based on dose limiting toxicity assessment during cycle 1. Assessments for anti-tumor activity were performed following 4 cycles of study treatment (tx) and at the end of study tx (EOT). Results: 13 pts (46% male) enrolled in the R-CHP + PoV dose-escalation phase of the study. Median age was 68 years (range 60-73). Pts had untreated DLBCL (n=10), relapsed FL (n=2), and untreated MZL (n=1). At baseline, pts had stage I/II (5), III/IV (8) disease and ECOG status of 1-2 (6). Of 10 DLBCL pts, 4 had age adjusted IPI (aaIPI) 2, and 6 had aaIPI 0-1. At the time of this report, all pts in the 1.0 mg/kg (n=3), 1.4 mg/kg (n=3) and 4 of 7 pts in the 1.8 mg/kg cohort completed study tx. The most common adverse events (AEs) in 〉3 pts were nausea (8), fatigue (7), diarrhea (6), neutropenia (5), dizziness (4), peripheral neuropathy (PN; 4), and insomnia (4). Across all dose levels, 8 pts had a total of 18 grade (Gr) 3/4 AEs including neutropenia (10), thrombocytopenia (1), febrile neutropenia, pneumonia (2 each), DVT, PE, and ophthalmic herpes zoster (1 each). Six pts experienced a serious AE (SAE). Four pts in the 1.8 mg/kg cohort had SAEs: 1 pt with Gr 2 dysphagia (not attributed to tx), 1 pt with Gr 4 pulmonary embolism (PE) and neutropenia and Gr 3 pneumonia (all tx-related), 1 pt with 2 episodes of Gr 4 neutropenia (tx-related that investigator deemed life-threatening), and 1 pt with Gr 4 pneumonia (not attributed to tx). The PE event was determined to be a DLT by the investigator. This pt had a concurrent event of deep vein thrombosis (non-serious). Seven of 13 pts experienced PN (Gr 1 [n=6] and Gr 2 [n=1]). The pt who had the Gr 2 PN received 2.4 mg/kg of PoV with R-CHP in error for 4 cycles and had additional risk factors for PN including history of diabetes mellitus, prior vincristine therapy. One tx discontinuation due to AE occurred due to Gr 2 PN in this pt who received PoV 2.4 mg/kg. One pt had a dose reduction for Gr 3 neutropenia. No deaths were reported. Of the 10 pts with DLBCL, 8 were assessed for interim response by PET/CT: 5 CR [1 at 1.0 mg/kg, 3 at 1.4 mg/kg, and 1 at 1.8 mg/kg], 3 PR [1 at 1.0 mg/kg and 2 at 1.8 mg/kg]). Two of 10 had not completed 3 cycles of tx and therefore not assessable for interim response. At the EOT, 7 were assessed for response: 5 CR (1 at 1.0 mg/kg, 3 at 1.4 mg/kg, and 1 at 1.8 mg/kg), 1 PR (at 1.0 mg/kg), 1 unevaluable (at 1.8 mg/kg). The 3 other pts were not assessed because they did not have a PET scan at EOT. Of the 2 pts with FL: one had SD (1.0 mg/kg) and one was not evaluable at the time of this report (2.4 mg/kg) at the EOT. One pt with MZL had CR at the EOT, then progressed at month 3 follow-up with biopsy proven transformed DLBCL. Conclusions: Early results show that PoV plus R-CHP has an acceptable safety profile in pts with previously untreated DLBCL. The PoV doses tested (1.0, 1.4, and 1.8 mg/kg) in this study showed acceptable toxicity in previous studies with relapsed NHL pts. Although the protocol-specified MTD was not formally reached, the recommended phase 2 dose of PoV was established at 1.8 mg/kg based on the overall safety and tolerability profile at that dose. The study's Phase 2 PoV+R-CHP expansion and the Phase Ib PoV+obinutuzumab-CHP dose escalation are ongoing. Disclosures Bartlett: AstraZeneca: Research Funding; Janssen: Research Funding; ImaginAb: Research Funding; Pharmacyclics: Research Funding; Genentech, Inc.: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Celgene: Research Funding; Medimmune: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy. Off Label Use: Polatuzumab vedotin is an investigational agent and not approved for DLBCL. Chen:Genentech, Inc.: Consultancy, Other: Advisory Board; Seattle Genetics: Consultancy, Other: Advisory Board; Janssen: Consultancy, Other: Advisory Board; Gilead: Consultancy, Other: Advisory Board. Kolibaba:Seattle Genetics: Research Funding; TG Therapeutics: Research Funding; GSK: Research Funding; Acerta: Research Funding; Genentech, Inc.: Research Funding; Novartis: Research Funding; Cell therapeutics: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Consultancy, Research Funding; Amgen: Research Funding; Pharmacyclics: Research Funding. Jones:Genentech, Inc.: Employment. Hirata:Genentech, Inc.: Employment, Equity Ownership. Sharman:TG Therapeutics, Inc.: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Roche: Research Funding; Janssen: Research Funding; Calistoga: Honoraria.

Description: Background Entospletinib (GS-9973) is an orally bioavailable, selective inhibitor of spleen tyrosine kinase (Syk). Syk is a mediator of B-cell receptor signaling in normal and transformed B-cells. Targeting the B-cell receptor (BCR) signaling pathway has been a successful therapeutic strategy for chronic lymphocytic leukemia (CLL), with both ibrutinib, an inhibitor of BTK (BTKi) and idelalisib, an inhibitor of PI3Kdelta (PI3Ki), approved for this indication. Entospletinib activity in CLL was recently reported, and preclinical data suggested that entospletinib may be effective even in the context of resistance to BTK therapy, including that conferred by activation of PLCγ2. (Liu, Blood -2015-02-626846) Methods GS-US-339-0102 is an ongoing phase2 trial of entospletinib in CLL and NHL (NCT01799889). The study protocol was amended to add 40 patients in each of 2 CLL cohorts who have been previously treated with BCR signaling pathway (BTK/PI3K) inhibitors. These patients were treated with entospletinib monotherapy (400mg BID) and evaluated using modified Hallek/IWG-CLL criteria every 2-3 months as previously described in Sharman, Blood 2015:125(5). Results As of July 20, 2015, 8 patients with preceding BCR pathway signaling inhibitor treatment have been enrolled, 5 with preceding BTKi therapy (4 with ibrutinib, 1 with AVL-292) and 3 with preceding PI3Ki therapy (idelalisib). The median duration of preceding BTKi treatment was 51 weeks (range 2-85 weeks) and the median duration of preceding PI3Ki treatment was 106 weeks (range 74-168 weeks). Two patients had progressed on prior BTKi and 2 were intolerant (cause missing for 1 patient), while 2 patients progressed on PI3Ki and 1 was intolerant. All 5 patients with preceding BTKi and 2 out of 3 patients with prior PI3Ki remain on entospletinib treatment. Of the 5 patients who were previously treated with BTKi, the ongoing duration of treatment with entospletinib is 8, 8, 13, 25, and 39 weeks. For the 3 patients with preceding PI3Ki, two patients have ongoing treatment of 18 and 26 weeks; one patient stopped treatment and died after 23 weeks due to a cardiac arrest that is not believed to be related to the study drug. The most common treatment-emergent AEs (N=number; any Grade/≥Gr 3, independent of causality) were decreased appetite (3/0), contusion (2/0), dyspepsia (2/0), fatigue (2/0), dehydration (1/1), cardiac arrest (1/1); common laboratory abnormalities were anemia (5/1), neutropenia (4/1), thrombocytopenia (3/2), increased lipase (1/1). Early responses were seen with entospletinib treatment (3 partial response (PR), 1 stable disease, & 3 patients were too early to evaluate) and 1 PD. PR occurred in 1 BTKi and 2 PI3Ki previously treated patients. One patient with preceding PI3Ki developed progressive disease after 8 weeks. Conclusions Early experience from this trial with ongoing enrollment demonstrates that entospletinib has clinical activity following therapy with either BTKi or PI3Ki. No additional safety signals were seen from earlier studies. Additional investigation of treatment with entospletinib following progression with B-cell receptor signaling pathway inhibitors is warranted. Disclosures Sharman: Celgene Corporation: Consultancy, Research Funding; TG Therapeutics, Inc.: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Calistoga: Honoraria; Janssen: Research Funding. Shustov:Celegene, BMS: Consultancy, Honoraria, Research Funding. Smith:celegene, spectrum, genentech: Honoraria. Boyd:US Oncology: Research Funding; Celgene: Speakers Bureau; Genentech, Inc.: Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; GSK: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding. Abella:Gilead: Employment. He:Gilead Sciences: Employment. Eng:Gilead: Employment. Hu:gilead: Employment. Reddy:gilead: Employment. Mitra:Gilead: Employment. Yasenchak:Seattle Genetics, Inc.: Research Funding.

Description: Background: Spleen tyrosine kinase (Syk) is a mediator of B-cell receptor signaling in normal and transformed B-cells. GS-9973 is an orally bioavailable, selective inhibitor of Syk. Methods: This Phase 2 trial enrolled 41 patients with CLL and 15 patients with SLL treated with GS-9973 800 mg BID. Tumor imaging occurred at weeks 8, 16, 24 and then every 12. Response was independently evaluated according to Hallek 2008 as modified by Cheson 2012 for patients with CLL and Cheson 2007 for patients with SLL. Primary endpoint for the study was PFS at 24 weeks. Results: The median ages of CLL and SLL patients were 73 (range 51-89) and 70 (range 57-84), respectively. 68% of CLL subjects and 60% of SLL subjects were male. Ten patients had 17p deletions/TP53 mutations and 17 had SF3B1 or NOTCH1 mutation, or 11q22.3 deletion. The median number of prior regimens for CLL was 2 (range 1-8) and for SLL was 2 (range 1-10). Prior therapies included anti-CD20 antibodies (98%), alkylating agents (86%, [bendamustine 63%]) and fludarabine (66%). 12 CLL and 6 SLL patients are still on treatment; the median duration of treatment for all CLL and SLL patients was 36 weeks The most common treatment emergent AEs (any Grade/≥Gr 3, independent of causality) were fatigue (70%/7%), nausea (54%/2%), diarrhea(48%/0%), cough(34%/0%), dizziness (32%/2%), headache (29%/0%), pyrexia (29%/0%), decreased appetite (27%/2%), upper respiratory tract infection(27%/0%), constipation (23%/0%). Common laboratory abnormalities were increased AST (30%/5%), increased ALT (43%/4%), increased total bilirubin (41%/16%), anemia (50%/7%) and neutropenia (54%/29%). Forty-nine patients were treated for at least 8 weeks and 54 patients had ≥ 1 efficacy assessment, two patients discontinued prior to the first response assessment, one due to AE and one withdrew consent. Per investigator assessment, 51 out of 52 (98%) patients evaluable for SPD experienced reduced tumor bulk; 38 (73%) achieved a decrease of ≥ 50%. The ORR was 62.5% (95% CI: 48.6%, 75.1%), with 35 patients achieving a PR and no subject achieving a CR. Thirteen patients (23.2%) had stable disease. The primary end point of 24 weeks PFS was 72.3% (95% CI: 57.1%, 83.0%). Median PFS was 20.5 months (95% CI: 7.7 months, not reached). There were 24 patients (42.9%) with events, 22 (39%) with disease progression and two deaths (4%) attributed to septic pneumonia and pseudomonal infection which was unrelated to entospletinib by investigator assessment. Among the 35 responding patients, median DOR was 21.3 months (95% CI: 13.2 months, not reached). Results of an independent response assessment are pending and will be presented. Entospletinib was well tolerated and demonstrated substantial activity in patients with CLL, and SLL including those with poor prognostic features. Entospletinib activity seems comparable to that reported by other approved BCR pathway inhibitors with the median PFS reported for Idela of 15.8 months (Blood. 2014;123(22):3390-3397) and Ibrutinib reported 42.6% overall response rate and a PFS of 70-80% @ 12 months (ibrutinib PI) Current studies plans include studying Entospletinib in combination therapy. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Sharman: Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Research Funding; Calistoga: Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Research Funding; TG Therapeutics, Inc.: Research Funding; Janssen: Research Funding. Kolibaba:Janssen: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; GSK: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Gilead: Consultancy, Research Funding. Abella:Gilead: Employment. Di Paolo:Gilead Sciences: Employment, Equity Ownership. Eng:Gilead: Employment. Hu:gilead: Employment. He:Gilead Sciences: Employment. Reddy:gilead: Employment. Yasenchak:Seattle Genetics, Inc.: Research Funding.

Description: Background Outcomes for patients with DLBCL have improved over the past decade, with the addition of rituximab to CHOP or CHOP-like multi-agent chemotherapy regimens improving the 3-year overall survival (OS) of patients by 10-16% compared to multi-agent chemotherapy alone (Coiffier 2002; Pfreundschuh 2010). However, patients with high-intermediate or high-risk disease have relatively poor outcomes with the standard RCHOP regimen (Ziepert 2010); in a recent prospective trial of intermediate- and high-risk DLBCL patients, complete response (CR) rate for RCHOP alone was 26% (Hainsworth 2011). Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising the antibody cAC10, specific for human CD30, covalently attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. Brentuximab vedotin has demonstrated compelling activity as a single agent in patients with relapsed or refractory DLBCL, even those with low CD30 expression (Bartlett 2013). This phase 2, randomized, open label study is designed to evaluate the antitumor activity and safety of brentuximab vedotin (1.2 or 1.8 mg/kg) when administered in combination with standard RCHOP chemotherapy (A+RCHOP) for the front-line treatment of patients with CD30-unselected high-intermediate/high-risk (standard IPI score 3–5 or age-adjusted IPI [aaIPI] score 2–3) DLBCL (ClinicalTrials.gov NCT01925612). Methods Patients were randomized to receive up to 6 cycles of either 1.2 or 1.8 mg/kg brentuximab vedotin administered IV on Day 1 of every 21-day cycle in combination with RCHOP; prednisone was administered orally on Days 1-5 of every 21-day cycle. Assessments included disease response per Cheson 2007, as evaluated by the investigator, surveillance of adverse events (AEs), physical examination findings, and laboratory testing. The primary endpoints for this study are the CR rate at the end of treatment (EOT) and the type, incidence, and severity of AEs. Key secondary endpoints include objective response rate (ORR), progression-free survival (PFS), and OS. Results At the time of the planned interim analysis, 33 patients were enrolled (17 patients, 1.2 mg/kg A+RCHOP; 16 patients, 1.8 mg/kg A+RCHOP). Median age for all patients was 66 years (range, 21 to 81). At baseline, 36% were high-risk (IPI 4-5, aaIPI 3) and 64% were high-intermediate risk (IPI 3, aaIPI 2). The majority of patients (73%) had Stage IV disease and 33% had an ECOG status of 2. At the time of interim analysis, a total of 12 patients (6 patients in each arm) had completed EOT. Across both dose levels, ORR was 92% (11/12), with 7 CRs (58%), 4 PRs (33%), and 1 PD. The patient with PD subsequently died. Patients with PR had a median reduction of baseline tumor size of 84% (range, 92% to 83%), as measured by SPD. The only patient with follow-up after EOT converted from PR to CR without subsequent therapy. Treatment-emergent AEs occurring in ≥30% of patients treated (26/33) were nausea, diarrhea, peripheral sensory neuropathy, fatigue, and decreased appetite. Grade 3 or higher events occurring in more than 2 patients were febrile neutropenia and neutropenia. Events of peripheral neuropathy occurred equally per arm (46%, 1.2 mg/kg A+RCHOP; 46% 1.8 mg/kg A+RCHOP) and were generally Grade 1 or 2 (15% and 23%, respectively); events were of similar grade across dose levels. The median time to onset of any grade of peripheral neuropathy was 6 weeks (range, 2 to 10 weeks). Five patients (19%) had dose reductions due to peripheral neuropathy and 3 patients (12%) had dose reductions due to febrile neutropenia. One patient who received 1.2 mg/kg A+RCHOP discontinued study drug due to an AE (thrombocytopenia). Conclusions At doses of 1.2 or 1.8 mg/kg, A+RCHOP exhibited manageable toxicity in the treatment of newly-diagnosed DLBCL; the incidence of peripheral neuropathy was similar to single-agent administration of brentuximab vedotin (Pro 2012, Younes 2012) and RCHOP alone (Rummel 2013, Flinn 2014). In 12 patients with response-assessable, high-intermediate and high-risk DLBCL, A+RCHOP showed encouraging antitumor activity, with an ORR of 92% and a CR rate of 58%. Disclosures Yasenchak: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. . Farber:Seattle Genetics, Inc.: Research Funding. Budde:Seattle Genetics, Inc.: Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding. Advani:Takeda Pharmaceuticals International Co.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Jansseen Pharmaceuticals: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other. Holkova:Seattle Genetics, Inc.: Research Funding. Halwani:Seattle Genetics, Inc.: Research Funding. Knapp:Takeda Pharmaceuticals International Co.: Research Funding; EMD Serono: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Merck: Research Funding; Heron Pharmaceuticals: Research Funding, Travel expenses, Travel expenses Other; Genentech: Research Funding, Travel expenses, Travel expenses Other; Seattle Genetics, Inc.: Research Funding; Pharmacyclics: Research Funding. Fayad:Seattle Genetics, Inc.: Consultancy, Research Funding. Kolibaba:Genentech: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Research Funding. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Seetharam:Seattle Genetics, Inc.: Research Funding. Manley:Seattle Genetics, Inc.: Employment, Equity Ownership. Bartlett:Genentech: Research Funding; ImaginAb: Research Funding; Celgene: Research Funding; MedImmune: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Janssen: Research Funding; Astra Zeneca: Research Funding.