Advani, Ranjana H.

Abstract Background: Bortezomib has efficacy in follicular lymphoma (FL). Though generally well tolerated, it is associated with a few known toxicities, including neurotoxicity. As a chronically administered agent, it is important to investigate the tolerability of bortezomib over time as a single agent and in combination with chemotherapy. The current method of summarizing adverse events (AEs) -focusing on the maximum grade and reporting only grade 3 or higher incidences- fails to capture toxicity that evolves over time or chronic low grade AEs that may occur at significant expense to patients' quality of life. In this study, we applied the Toxicity over Time (ToxT) analytic approach (Thanarajasingam et al, Lancet Oncol 2016), which graphically and analytically depicts AEs longitudinally, to a randomized Phase 2 ECOG-ACRIN sponsored study, E2408, to characterize chronic toxicity of bortezomib (V) when added to standard bendamustine-rituximab (BR) induction in previously untreated high risk FL. Methods: In E2408, patients (pts) were randomized to one of 3 arms at a 1:2:2 ratio: A) BR x 6 followed by maintenance rituximab (MR) x 2 years (yrs) vs B) BVR x 6 (bortezomib 1.3 mg/m2 IV/SQ days 1, 4, 8, 11) then MR x 2 yrs vs C) BR x 6 then MR x 2 yrs + lenalidomide 20mg/day x 1 yr. Pts enrolled 1/2011-5/2015. This analysis focuses on the 6 cycles of induction only, with arms A and C combined. Six AEs of interests were selected, 4 symptomatic (subjective) AEs (peripheral sensory neuropathy (PSN), diarrhea, febrile neutropenia, fatigue); and 2 non-symptomatic (objective) AEs (neutropenia and thrombocytopenia). Treatment-related post baseline AEs of any grade were investigated by conventional maximum grade toxicity analysis (ToxC) and ToxT methods. The mean AE grades over cycles were analyzed by repeated measures models, time to grade 2 or higher (gr2+)AE were analyzed with time-to-event analysis; and AE profile over the entire course of the study was summarized by area under the curve (AUC) analyses. Comparisons were performed between treatment arms (BVR vs. BR). Results: All 280 randomized treated pts (187 on BR, 93 on BVR) were included in the analysis regardless of eligibility status; 87% (163/187 BR, 81/93 BVR) completed all 6 cycles. Analyzing the symptomatic AEs,ToxC indicates that the overall incidence of grade 3+ PSN was significantly higher in BVR (12%) than BR (1%) (p<.0001). Additional, ToxT captures the trajectory, demonstrating a rapid, rising incidence and worsening grade of PSN on BVR vs BR over 6 cycles in a steam plot of mean gr. by cycle (Fig 1a) and bar chart of incidence and grade per cycle (c1: 13% gr1 3% gr2, c6: 36% gr1 12% gr2 6% gr3 on BVR; c1: 3% gr1, c6: 10% gr1 1% gr2 on BR, Fig. 1b). Risk of developing gr2+ PSN was significantly higher in BVR than BR with 28% vs 0.5% by day 100 (HR=0.01, p<.0001, Fig. 1c). ToxC captures a higher incidence of grade 3+ diarrhea on BVR (7% vs. 1% , p=.01) while AUC from ToxT includes chronic lower grade diarrhea, that is substantial over time on BVR vs. BR (p<.0001), but is not cumulative. Furthermore, the risk of developing gr2+ diarrhea affecting drug tolerability is significantly higher on BVR than BR(13% vs 5% by day 100) (HR=0.3, p=.05). Febrile neutropenia appeared to be similar, and fatigue was marginally more severe under BVR (p=.06 by AUC). For objective AEs, ToxC reveals no significant difference in neutropenia or thrombocytopenia BVR vs BR (neutropenia gr 3+: 36% vs 31%, p=.4; thrombocytopenia gr3+: 10% vs. 5%, p=.12). However, ToxT illustrates that neutropenia is cumulative, worsening over repeated exposure to drug (c1: 2% gr1 5% gr2 5% gr 3+ , c6: 7% gr1 10% gr2 12% gr3+ both arms combined; p<.0001) on mean grade over time (Fig. 2a). In contrast, thrombocytopenia does not worsen with continued treatment (Fig 2b, p=.73). Conclusions: Compared with conventional toxicity analysis (ToxC), ToxT delineated important additional and clinically relevant depictions of both symptomatic and laboratory AEs over time for bortezomib added to BR in FL pts. In patients receiving BVR, close monitoring is suggested for PSN, diarrhea and neutropenia for reassessment of risks and benefits, symptom interventions and dose modification. Longitudinal toxicity analyses such as ToxT can guide AE interventions as well as patient and clinician education, and provide a more patient-centered toxicity assessment of chronically administered therapies for lymphoma. Disclosures Hong: Merck: Consultancy. Evens:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Affimed: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees. Advani:Kura: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Takeda: Consultancy, 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, Other: Participated in an advisory board, Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Infinity: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Janssen: Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Forty Seven Inc.: Research Funding; Merck: Research Funding; Millenium: Research Funding; Agensys: Research Funding; Celgene: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dueck:Bayer: Employment; Pfizer: Honoraria; Phytogine: Employment. Kahl:Genentech: Consultancy; Acerta: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; Abbvie: Consultancy; Juno: Consultancy; Gilead: Consultancy; Celgene: Consultancy; CTI: Consultancy; AstraZeneca: Consultancy.

Abstract Background: There remains a critical need to identify untreated HR FL patients (pts) who are at increased risk of early progression and death with conventional treatment. Data examining baseline PET has been reported to be prognostic in FL, however, there remains a paucity of data analyzing this in the context of bendamustine/rituximab (BR) induction followed by maintenance rituximab (MR). We examined the prognostic impact of baseline PET metabolic imaging from the randomized BIONIC study for pts with untreated HR FL. Methods: The BIONIC study conducted by the ECOG-ACRIN Cancer Research Group enrolled untreated grade I/II or IIIa FL pts with HR disease defined as GELF high tumor burden and/or FLIPI score of 3-5. Pts were randomized to: a) standard BR induction x 6 followed by maintenance rituximab (MR) q 2 months x 2 years vs b) bortezomib + BR x 6 followed by MR q 2 months x 2 years vs c) BR x 6 followed by q 2 months MR x 2 years + lenalidomide given concurrently with the first year of MR. Survival analyses showed no significant differences in 4-year progression-free survival (PFS) or overall survival (OS) for any study arm (Evens AM et al, ASH 2017). All pts were thus pooled for the purpose of analyzing baseline PET imaging and other characteristics and for correlation with clinical outcomes. Kruskal-Wallis & Wilcoxon Rank Sum test were used to assess differences in distribution of: metabolic measurements (SUVmax and SUVmean of the dominant mass (i.e., the mass/lesion with the highest SUV uptake); metabolic tumor volume (MTV); and total lesion glycolysis (TLG) by categorical variables); induction treatment response; and end-of-induction (EOI) PET response vis-à-vis Deauville scoring (1-3 = negative). Cox proportional hazards regression was used to correlate these metabolic measurements with PFS & OS and multivariable analyses were conducted. An optimal cutoff threshold (grouping into 'High' or 'Low' categories) was used for the metabolic measurements that were significantly associated with PFS & OS. Results: Metabolic data were received and measurements were analyzed centrally on 182 (71%) of 257 eligible pts. The EOI overall response rate (ORR) for all pts on study was 92% with a complete remission (CR) rate of 73%. Additionally, 12% of pts experienced early progression of disease (POD) within 2 years. SUVmax was borderline for association with PFS (P=0.06) and MTV and TLG were not associated with PFS or OS. We demonstrated a statistically significant linear relationship between continuous SUVmean score with PFS and OS, and thereafter, used the minimum p-vlaue approach to determine the optimal cutoff threshold of 7.03 to group pts into 'High' and 'Low' risk groups; with this threshold, baseline SUVmean of the dominant mass was categorized as high risk in 27% pts. The 4-year PFS rates for SUVmean low vs high groups were 80% (95% CI 72, 90%) vs 55% (40, 74%), respectively, P<0.001; and the corresponding 4-year OS rates were 93% (89, 98)% vs 80% (95% CI 69, 93%), respectively, P=0.01 (see Fig. 1). Sensitivity analyses showed no differences in baseline SUVmean by study arm, GELF or FLIPI. The only clinical characteristic that varied among patients with low vs high baseline SUVmean was Black race (0.8 vs 8.0%, respectively, Chi-square P=0.08); there were no other differences based on age, sex, stage, FLIPI, GELF status, ECOG PS, LDH, or # of extranodal sites. In addition, baseline SUVmean correlated with EOI PET (negative EOI PET with baseline SUVmean Low vs High: 81% vs 62%, respectively, P=0.03). In multivariable analyses, both baseline SUVmean and EOI PET remained significant (SUVmean: PFS HR 2.62 (95% CI 1.40-4.92), P=0.001, OS HR 2.37 (95% CI 1.01-5.56), P=0.02; EOI PET PFS HR 4.70 (95% CI 2.74-9.54), P<0.001, OS HR 2.78 (95% CI 1.18-6.56), P=0.01). Finally, baseline SUVmean was also strongly predictive of FL pts who experienced early 2-year POD (Chi-square P<0.001). Conclusions: High baseline SUVmean of the dominant mass was a strong independent prognostic factor for survival for untreated HR FL pts treated with BR-based induction with rituximab maintenance and significance was independent of FLIP or GELF criteria. Collectively, this represents a novel and simple method to identify FL pts at increased risk of early POD and poor survival with standard therapy. Continued investigation of combined PET imaging analyses and other correlative studies to enrich prognostication are warranted. Disclosures Hong: Merck: Consultancy. Advani:Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Kyowa: Other: Consulting/Advisory Role; Infinity: Other: Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Millenium: Other: Institutional Research Support; Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Autolus: Other: Consultancy/Advisory Role; Takeda: Other: Consultancy/Advisory Role; Celgene: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; AstraZeneca: Other: Consultancy/Advisory Role; Cell Medica: Other: Consultancy/Advisory Role; Gilead/Kite: Other: Consultancy/Advisory Role; Agensys: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Janssen Pharmaceutical: Other: Institutional Research Support. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kahl:Acerta: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Juno: Consultancy; CTI: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy. Evens:Affimed: Consultancy; Novartis: Consultancy; Acerta: Consultancy; Bayer: Consultancy; Tesaro: Research Funding; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy.

Abstract Background: Relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical challenge. We hypothesized that using immune checkpoint blockade to activate the immune cells in the tumor microenvironment, and concurrently targeting tumor cells with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) could overcome tumor resistance. E4412 is a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of BV, nivolumab (Nivo), and ipilimumab (Ipi) in patients with R/R HL. Here we present the preliminary safety and response data on the full cohort of patients treated in Phase 1 with BV + Ipi + Nivo (Arms G-I). Methods: Patients with confirmed R/R HL were treated with Nivo 3mg/kg, Ipi 1mg/kg and BV 1.2mg/kg (Arm G) or 1.8mg/kg (Arm H) with a 3+3 design, and an expansion cohort (Arm I) of 9 patients with BV at 1.8mg/kg. BV and Nivo are given every 21 days for 16 cycles; Nivo may be continued for an additional 12 months. Ipi is given every 12 weeks except for the first 2 patients in Arm G who received Ipi every 6 weeks for the first 3 cycles. Dose limiting toxicity (DLT) was defined within the first cycle of therapy. Results: As of 6/30/18 22 patients with a median of 2 prior therapies (range 1-5) have been treated; 7 in Arm G, 6 in Arm H, and 9 in Arm I. Median age was 35, range (19-60); 11 patients were male. Nine patients had prior SCT (1 alloSCT, 8 autoSCT); 1 patient had prior BV. Safety: All 22 enrolled patients are evaluable for safety. There were 3 DLTs, one in each arm. In Arm G one patient experienced grade 4 diabetic ketoacidosis and hyperglycemia, and went off treatment after cycle 1. In Arm H, one patient had transient grade 3 AST elevation; this was of no clinical significance and did not require a delay in therapy. In Arm I a post AlloSCT patient had grade 4 Steven-Johnson syndrome with grade 3 pruritis, rash, and GVHD, and came off therapy. Common toxicities considered at least possibly related to drug, are shown in Table 1, and grade 3 or greater toxicity in Table 2. There were no grade 5 AEs or additional grade 4 AEs. Significant grade 3 AEs were: rash, colitis, gastritis, pancreatitis, and arthritis each in one patient, resulting in dose delays but not discontinuation of therapy. One patient experienced grade 2 angioedema in cycle 1 and came off therapy. No significant infusion reactions were noted. Response: Nineteen of 22 patients are evaluable for response. Three patients discontinued treatment after cycle 1 and are not evaluable for response. For the full population the overall response rate (ORR) was 82% (18/22), with a complete response (CR) rate of 68% (15/22). For patients treated with at least 3 cycles of therapy who were evaluable for response, the ORR is 95% (18/19) with a CR rate of 79% (15/19). Six patients went from treatment to SCT. With a median follow-up of 0.52 years median progression free survival (PFS) has not been reached (Figure 1), and with a median follow-up of 0.82 years overall survival (OS) has not been reached (Figure 2). Conclusion: In this study of the triplet combination of BV, Ipi and Nivo for R/R HL, therapy was generally well tolerated, although more grade 3 AEs were seen than in the doublets. In a heavily pretreated patient population, with 9 patients post SCT, the ORR of 95% and CR rate of 79% in evaluable patients is extremely promising. Data will be updated to include longer term PFS and OS by the time of the meeting. Optimization of this strategy is ongoing in E4412, now a randomized phase 2 study comparing the doublet of BV-Nivo to the triplet of BV-Ipi-Nivo. Disclosures Diefenbach: Trillium: Research Funding; Incyte: Research Funding; Genentech: Consultancy; Seattle Genetics: Consultancy, Research Funding; Denovo: Research Funding; Acerta: Research Funding; Millenium/Takeda: Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Hong:Merck: Consultancy. Cohen:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Merck: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kura: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Janssen: Research Funding; Millenium: Research Funding; Infinity: Research Funding; Regeneron: Research Funding; Agensys: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Forty Seven: Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Svoboda:Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Kyowa: Consultancy; TG Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; KITE: Consultancy. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Kahl:Genentech: Consultancy; Abbvie: Consultancy; Acerta: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; Juno: Consultancy; CTI: Consultancy; Gilead: Consultancy. Ansell:LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Merck & Co: Research Funding; Takeda: Research Funding.

Abstract Introduction: Lenalidomide (len) is an immunomodulatory agent with single agent activity in relapsed and refractory peripheral T-cell lymphoma (PTCL). CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) is a common initial regimen. Herein, we report the completed phase II results of the combination of len-CHOEP. Methods: Eligible patients (pts) had newly diagnosed PTCL, ANC ≥1000 cells/mm3, platelets ≥100 K/mm3, and adequate organ function. Based on phase I results [Lunning et al. T-cell Forum 2018] 10 mg of len was chosen for phase II. CHOEP was administered at standard doses with len given on days 1-10 of 21-day cycle for six planned cycles. Mandatory prophylaxis included aspirin (ASA) or alternative thromboprophylaxis and growth factor support per institutional guidelines with each cycle. A PET/CT after two cycles (PET-2) for interim response assessment was required per protocol. The primary endpoint was complete response (CR) by PET/CT after 6 cycles (PET-6) of len-CHOEP utilizing the revised Cheson 2007 criteria with secondary endpoints to include toxicity, overall response rate (ORR), progression free survival (PFS), 2-year PFS, and overall survival (OS). Pts who had CR or partial response (PR) at the end of therapy had the option of len maintenance (10 mg/day for 21 out of 28 days) for 1-year or consolidative autologous stem cell transplant (ASCT) without len maintenance. Per protocol pts dosed at 10 mg in phase I (N=8) were included in the phase II analysis. Results: Forty pts with PTCL-NOS (23), ALK negative ALCL (5) and AITL (12) enrolled into the phase II portion. Median age was 62 years (range 24-79) and 21 were male. Thirty (75%) pts completed all 6 cycles. Reasons for discontinuing len-CHOEP early were toxicity (n=6) and progressive disease (PD; n=4). PET-2 was not done in 4/40 pts (n=2 each either not performed or PD). In an intent to treat (ITT) analysis the CR rate at the end of treatment was 48% (19/40; 95CI-32-64%) with an ORR of 68%. In pts who completed 6 cycles (n=30) the CR/ORR rate was 63%/87% respectively. Seven pts (18%) experienced primary treatment failure. Of the 19 pts in CR at end of initial therapy, 14 were in a CR at PET-2 assessment. Two pts in a PET-2 CR discontinued prior to cycle 6 due to toxicity and have not progressed. Five pts converted from a PR to CR after PET-2, but 7 of 13 PRs remained PRs. Responding pts (CR/PR; n=30) proceeded either to an ASCT (n=18), len maintenance (n=10) or neither (investigator/pts preference; n=2). At a median follow up of 13 months (range: 4-23 months), the 1-year estimated PFS and OS is 68% [95% CI--50-80%] and 89% [95%CI--73-96%] respectively. There were five grade (G) 5 events including PD (n=1), secondary malignancy (n=1; AML), sepsis (n=2), and cardiac arrest (n=1). Serious or recurrent adverse events (SAEs or AEs) of interest occurring during any cycle included 38% G 3-4 febrile neutropenia despite mandated GCSF use, 43% G 3-4 anemia, 43% G 3-4 thrombocytopenia (without report of G 3-4 bleeding or bruising despite ASA use), 3% G3-4 rash (all G 23%), and 8% G 3-4 diarrhea (all G 43%). Conclusions: The phase II portion of the study in an ITT population noted an unexpectedly modest 48% CR rate and a high discontinuation rate (15%) due to AEs or SAE. The utility of response at PET-2 and post initial therapy strategy (len maintenance vs ASCT) continue to be monitored for PFS and OS in this limited cohort. Improving frontline outcomes for pts with PTCL remains an unmet need. Disclosures Lunning: Celgene: Consultancy; TG Therapeutics: Consultancy; Genentech: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Spectrum: Consultancy; Kite: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy; Astra-Zeneca: Consultancy; Genzyme: Consultancy; Juno: Consultancy; Genentech: Consultancy; Verastem: Consultancy. Horwitz:Millennium/Takeda: Consultancy, Research Funding; Trillium: Consultancy; Mundipharma: Consultancy; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Portola: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; Innate Pharma: Consultancy; Corvus: Consultancy; Spectrum: Research Funding; Seattle Genetics: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Advani:Janssen Pharmaceutical: Other: Institutional Research Support; Cell Medica: Other: Consultancy/Advisory Role; Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Merck: Other: Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Millenium: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Celgene: Other: Institutional Research Support; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Infinity: Other: Institutional Research Support; Autolus: Other: Consultancy/Advisory Role; Kyowa: Other: Consulting/Advisory Role; Takeda: Other: Consultancy/Advisory Role; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Agensys: Other: Institutional Research Support; Gilead/Kite: Other: Consultancy/Advisory Role; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; AstraZeneca: Other: Consultancy/Advisory Role. Vose:Epizyme: Honoraria; Roche: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Incyte Corp.: Research Funding; Legend Pharmaceuticals: Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics, Inc.: Research Funding; Abbvie: Honoraria; Acerta Pharma: Research Funding; Kite Pharma: Research Funding; Merck Sharp & Dohme Corp.: Research Funding. Mehta-Shah:Verastem: Research Funding; Genetech: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Spectrum: Consultancy. Haverkos:Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Moskowitz:ADC Therapeutics: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Takeda: Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Ansell:Merck & Co: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Takeda: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Celldex: Research Funding; Regeneron: Research Funding.

Abstract Background: The phase 3 ECHELON-1 study assessed frontline brentuximab vedotin administered with doxorubicin, vinblastine, and dacarbazine (A+AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients (pts) with advanced cHL (NCT01712490). The primary endpoint of ECHELON-1, modified PFS (mPFS) per independent review facility (IRF), is defined as (1) progressive disease, (2) death, or (3) subsequent anticancer therapy (chemotherapy [chemo] and/or radiotherapy [RT]) following detection of a non-complete response (non-CR = Deauville score 3-5) at end of frontline therapy. A+AVD was superior to ABVD (hazard ratio [HR]=0.77; p=0.035) with 2-year mPFS rates of 82.1% and 77.2%; as previously reported. In pts with newly diagnosed cHL, the aim of frontline therapy is curative. Pts who do not achieve a satisfactory response to frontline therapy may initiate subsequent anticancer therapy prior to response criteria-defined progression. The measurement of traditional PFS becomes confounded, as pts may effectively be rescued from criteria-defined progression by subsequent treatment, resulting in an overestimation of PFS with frontline therapy (Connors et al. Haematologica 2016;101[s5]:22-3[P007]). To further evaluate modified and traditional PFS in the ECHELON-1 study, two sensitivity analyses were conducted. Methods: 1334 pts with Stage III (36%) or IV (64%) cHL were randomized 1:1 to receive A+AVD (n=664) or ABVD (n=670) on days 1 and 15, for up to six 28-day cycles. In addition to mPFS per IRF, mPFS per investigator (INV) was collected. A sensitivity analysis (mPFS-chemo) was performed in which RT following a non-CR at the completion of frontline therapy was not counted as an event: in this case, mPFS-chemo was defined as (1) progression, (2) death, or (3) receipt of additional anticancer chemo excluding RT for pts who are not in CR after completion of frontline therapy. A second sensitivity analysis of traditional PFS (PFS-traditional), defined as (1) progression or (2) death, was also performed. All analyses were performed per INV as, per protocol, IRF follow up of pts was not conducted after the initiation of subsequent therapy. Results: At 2 years, the rates of mPFS per INV (95% CI) for A+AVD vs ABVD were 81.0% (77.6-83.9%) vs 74.4% (70.7-77.7%), respectively; HR=0.72 (95% CI: 0.573, 0.914; p=0.006). Concordance between IRF and INV mPFS assessments was high among all pts in both arms, at 91%. A total of 123 mPFS events per INV were observed among pts treated with A+AVD, including 73 pts with PD, 15 deaths, and 35 who received additional anticancer therapy following evidence of non-CR at the end of frontline therapy, vs 164 per INV mPFS events among pts treated with ABVD, of which 103 were PD, 22 were deaths, and 39 were additional anticancer therapy following evidence of non-CR at the end of frontline therapy. Of the 35 (A+AVD) and 39 (ABVD) additional anticancer therapy events, chemo/RT following evidence of non-CR at the end of frontline therapy accounted for 11/24 and 17/22 of these events, respectively. For mPFS-chemo, a larger benefit in favor of A+AVD vs ABVD, with a HR=0.687 (95% CI: 0.534, 0.885; p=0.003), was observed. The 2-year mPFS-chemo (95% CI) was estimated as 84.0% (80.9-86.7%) for pts treated with A+AVD vs 77.3% (73.7-80.4%) for pts treated with ABVD. A total of 103 events were observed among pts in the A+AVD arm, including 78 pts with PD, 15 deaths, and 10 who received additional chemo following evidence of a non-CR at the end of frontline therapy, vs 145 events among pts treated with ABVD, of which 106 were PD, 22 were deaths, and 17 were additional chemo following evidence of non-CR at the end of frontline therapy. For PFS-traditional, an advantage in favor of A+AVD vs ABVD was also observed: HR=0.70 (95% CI: 0.54-0.91; p=0.006). The 2-year PFS estimate (95% CI) was 84.2% (81.1-86.9%) for A+AVD vs 78.0% (74.4-81.1%) for ABVD. In total, there were 101 PFS events in the A+AVD arm, including 86 pts with PD and 15 deaths; vs 140 PFS events in the ABVD arm, including 118 pts with PD and 22 deaths. Conclusions: Consistent with the primary outcome of ECHELON-1, a benefit in favor of A+AVD vs ABVD was observed independent of the inclusion of additional anticancer RT or chemo as survival events, in addition to progression or death. A traditional PFS assessment including only progression or death events demonstrated that A+AVD resulted in a 30% reduction in the risk of progression or death compared to ABVD. Figure. Figure. Disclosures Connors: Lilly: Research Funding; Bayer Healthcare: Research Funding; Janssen: Research Funding; Bristol Myers-Squibb: Research Funding; Merck: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Seattle Genetics: Honoraria, Research Funding; Roche Canada: Research Funding; Amgen: Research Funding; Genentech: Research Funding; F Hoffmann-La Roche: Research Funding; Cephalon: Research Funding; Takeda: Research Funding. Younes:J&J: Research Funding; Celgene: Honoraria; BMS: Honoraria, Research Funding; Sanofi: Honoraria; Abbvie: Honoraria; Curis: Research Funding; Genentech: Research Funding; Merck: Honoraria; Bayer: Honoraria; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding; Incyte: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria, Research Funding; Astra Zeneca: Research Funding; Takeda: Honoraria. Gallamini:Takeda: Consultancy, Speakers Bureau. Ansell:Pfizer: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Takeda: Research Funding; Merck & Co: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding. Kim:J&J: Research Funding; Kyowa-Kirin: Research Funding; Mundipharma: Research Funding; Celltrion: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Roche: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Celgene: Research Funding; Merck: Research Funding. Advani:Janssen: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Forty Seven Inc.: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kura: Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Merck: Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Celgene: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Millenium: Research Funding; Agensys: Research Funding; Infinity: Research Funding; Regeneron: Research Funding; Celgene: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Bartlett:KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; ImaginAB: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Pharmacyclics: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Research Funding; Immune Design: Research Funding; Astra Zeneca: Research Funding; Forty Seven: Research Funding; Affimed: Research Funding; Genentech: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck & Co: Research Funding; Janssen: Research Funding. Straus:Onco Tracker: Consultancy; Roch China: Speakers Bureau; Memorial Sloan Kettering Cancer Center: Employment; JUNO: Consultancy; Medical Crossfire: Speakers Bureau; DAVA Oncology: Consultancy, Honoraria; Bayer: Consultancy; InPractice Elselvier: Consultancy; Millenium (Takeda): Consultancy, Research Funding; Seattle Genetics: Consultancy. Sureda:BMS: Consultancy, Honoraria; Sanofi: Honoraria; Roche: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria. Hutchings:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dlugosz-Danecka:Servier: Consultancy; Roche: Consultancy. Engley:Seattle Genetics: Employment. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Liu:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Miao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jolin:Takeda Pharmaceuticals International Co.: Employment. Gautam:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Radford:Novartis: Consultancy, Speakers Bureau; Celgene: Research Funding; Pfizer: Research Funding; GlaxoSmithKline: Equity Ownership; Takeda: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Equity Ownership; Seattle Genetics: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding.

Abstract Background We have previously reported and validated that the E-IPI, provided better discrimination of overall survival (OS) than the IPI for DLBCL patients > 60 years of age treated with R-CHOP (Advani et al., BJH 2010 and 12-ICML 2013 Abstract 222). Recent reports suggest that males > 60 years treated with R-CHOP have worse outcomes likely related to differences in rituximab clearance (Muller et al., Blood 2012). In this study, we explored if the addition of male sex to the E-IPI further improved risk stratification. Methods DLBCL patients > 60 years treated with R-CHOP on the E4494, RICOVER-60 and GELA 98-5 trials were included. A multivariate analysis was performed to assess whether male sex is an independent prognostic factor for OS in addition to the five E-IPI risk factors, E-IPI score, and E-IPI risk group. Male sex (S) was added as an additional risk factor to the E-IPI (S-EIPI, 0-6) and patients regrouped according to the number of risk factors: low (L)=0-1, low intermediate (LI)=2, high intermediate (HI)=3 and high (H)=4-6 based on the observed OS using Kaplan-Meier curves. C-statistic was used to compare the discrimination ability. The 5 year OS was estimated using the Kaplan-Meier method. Results 1079 patients (E4494, n=267; RICOVER-60, n=610; GELA 98-5, n=202) with a median follow-up of 8.9 years were included. In multivariate analyses, male sex was a significant independent predictor for OS adjusting for all five E-IPI factors, (HR 1.5, p < 0.0001), E-IPI score (HR 1.42, p < 0.001), and E-IPI risk group (HR 1.42, p < 0.001) (Table 1). C-statistic was 0.66 for S-EIPI and 0.64 for EIPI. Incorporation of sex into the E-IPI shifted 35% patients to higher risk groups, including 110 patients into the highest risk group (Table 2). The estimated 5 year OS for the S-EIPI L, LI, HI, and H risk groups was 87%, 70%, 58%, and 40%, respectively (Table 3). Compared to E-IPI, the 95% C.I. did not overlap among S-EIPI risk groups. Conclusion For DLBCL patients >60 years treated with R-CHOP, our results suggest the addition of male sex to the E-IPI may improve categorization of patients into well-defined clinically relevant risk groups. Patients with low risk S-EIPI have an excellent outcome (5 year OS 87%). Patients with high risk S-EIPI have a 5 year OS of only 40% and therapies beyond standard R-CHOP need to be explored. Disclosures: Horning: Genentech: Employment; Roche: Equity Ownership.

Abstract Background Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin’s lymphomas (NHL) characterized by poor treatment outcomes with conventional chemotherapy, including CHOP [complete remission (CR) ∼40%]. Retrospective studies suggest that the incorporation of etoposide into chemotherapy regimens may improve outcomes compared to CHOP. In contrast, anthracyclines appear to have a limited role in PTCL, largely attributed to p-glycoprotein related resistance. Pralatrexate was the first drug approved for patients (pts) with relapsed PTCL, providing a rationale to evaluate it in the front-line setting. Herein, we evaluated the efficacy of a novel combination for the primary therapy of pts with PTCL whereby the anthracycline in CHOP backbone was replaced with etoposide (CEOP) alternating with pralatrexate (P). Methods Pts > 18 years (yrs) with PTCL stages II-IV with no prior therapy and adequate end organ function were eligible. Eligible histologies included, PTCL-NOS, AILT, ALCL (ALK positive pts only allowed if IPI >3). CEOP (Cycle A) was administered as: cyclophosphamide 750 mg/m2 IV d1, etoposide 100 mg/m2 IV d1-3 (or 100 mg/m2 IV d1 and 200 mg/m2 PO days 2-3), vincristine 2 mg IV day 1 and prednisone 100 mg/day X 5 alternating with P (cycle B) 30 mg/m2 IV d 15, 22 and 29 (with vitamin B12 and folate supplementation). Growth factors were used to support both cycles of therapy. Imaging to assess response was done after cycle 2B, 4B and 6B. Pts achieving a remission were eligible for consolidative autologous stem cell transplant (ASCT) after cycle 4B at physician discretion. The primary statistical aim was to improve the CR rate from 40 to 63% with CEOP-P and optional transplant. Secondary objectives included assessment of event free survival (EFS), overall survival (OS) and toxicity of the regimen. A two-stage Simon design (alpha=0.10, 90% power) tested the null hypothesis that the CR rate would be </= to 40%. For the first stage of 20 evaluable pts, the trial would be terminated if 8 or fewer pts experienced a CR after course 2B of chemotherapy. For the second stage, a total of 34 pts were required with at least 17 achieving a CR at the end of therapy to consider the regimen useful. Results 34 pts were enrolled and one withdrew consent before starting therapy, leaving 33 pts enrolled between 7/2011 and 1/2013. Characteristics are shown in Table 1. 27 pts received at least 2 cycles of therapy. 6 pts received only 1 cycle due to early disease progression in 4 and adverse events in 2. Grade 3-4 toxicities attributed to therapy included, anemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). At the end of stage 1, 10 of 20 pts (50%) achieved a CR; therefore accrual proceeded to stage 2. At the time of this initial analysis, the overall response rate is 70%. To date 15 pts (45%) have achieved a CR with two additional pts pending evaluation. Overall, the 1-yr EFS is 48% (95% CI 28-64), and 1-yr OS 70% (95% CI 47-84) (Figures 1 and 2). 6 pts (18%) to date (n=3 CR, n=2 PR and 1 with stable disease) have received consolidation with ASCT and all are in CR post-transplant. Pts who proceeded to ASCT were younger than the non-transplant cohort (median age 58 versus 64 yrs) with other clinical characteristics being similar. On exploratory bivariate analyses, age <60 yrs, absence of B symptoms, low IPI score (0,1), achieving a CR, and receiving a ASCT were associated with better EFS. Attaining a CR was the only factor associated with better OS and was highest in patients with low IPI (78%) and those with ALCL histology (75%). Conclusions CEOP-P met the pre-defined stage 1 response criteria. Longer follow-up is needed to assess the impact on the final CR rate and secondary objectives of EFS and OS. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need. Disclosures: Advani: Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Research Funding. Off Label Use: Pralatrexate is currently only approved for relapsed/refractory PTCL. Lechowicz:Allos Therapeutics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Carson:Spectrum Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau. Foss:merck: Research Funding; spectrum: Research Funding; eisai: Membership on an entity’s Board of Directors or advisory committees; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees; celgene: Honoraria, Research Funding; seattle genetics: Research Funding. Horwitz:Celgene : Consultancy, Research Funding; Spectrum Pharamaceuticals: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Kyowa Hakko Kirn Pharma: Consultancy; Genzyme : Research Funding; Janssen: Research Funding; Millennium: Consultancy, Research Funding. Pro:Spectrum Pharmaceuticals: Honoraria. Pinter-Brown:Spectrum Pharmaceuticals: Consultancy, Honoraria. Smith:Micromet: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Allos: Consultancy; Genentech: Consultancy; Onyx: Consultancy. Shustov:Spectrum Pharmaceuticals: Consultancy, Honoraria. Savage:Spectrum Pharmaceuticals: Research Funding. Vose:Spectrum Pharmaceuticals: Research Funding.

Abstract Introduction This phase 1/2 study evaluated the safety and antitumor activity of brentuximab vedotin (BV) administered in combination with nivolumab (Nivo) in adult patients (pts) with relapsed/refractory classic Hodgkin lymphoma (R/R cHL) who have failed frontline therapy (NCT02572167). Results from Parts 1 & 2 have been previously reported, wherein safety, efficacy, and biomarkers consistent with immune activation were observed in pts with R/R cHL (Herrera et al., Blood 2018). In Part 3, patients were treated with BV + Nivo on Day 1 of each cycle. In contrast, pts in Parts 1 & 2 received BV on C1D1 and Nivo on C1D8 with concurrent admin on subsequent cycles. Herein we present safety, efficacy, and biomarker results for Part 3 and updated progression free survival (PFS) from Parts 1 & 2. Methods Pts in Parts 1 & 2 received up to four 21-day cycles of staggered dosing (day 1 BV 1.8 mg/kg, day 8 Nivo 3 mg/kg in Cycle 1) and concurrent thereafter, with steroid and antihistamine premedication. Pts in Part 3 received up to four 21-day cycles of concurrent BV + Nivo on Day 1 with antihistamine premedication. Following Cycle 4 response assessment (Lugano Classification Revised Staging System with the incorporation of the Lymphoma Response to Immunomodulatory Therapy Criteria [LYRIC, 2016]) responding pts were eligible to undergo autologous stem cell transplant (ASCT). Results 30 pts were treated in Part 3 and all were evaluable for efficacy. Pt characteristics included the following: median age 31.5 yrs (range; 20 - 66), 63% female, 93% prior ABVD, 37% primary refractory HL, 30% relapsed within 1year of frontline therapy, 30% with extranodal disease and 17% with bulky disease at enrollment. 28 pts completed all 4 cycles. 1 pt discontinued treatment (tx) due to an adverse event (AE; Grade 3 [G3] elevated Gamma-Glutamyltransferase) and 1 pt due to progressive disease (PD). The latter pt eventually died due to PD. All pts are off tx and have been observed through the safety reporting period. 37% of pts experienced a G3 or higher tx emergent AE prior to ASCT. 30% of the pts experienced infusion related reactions (IRRs), which occurred most frequently during Cycle 2. Potential G3 or higher immune-related AEs (IRAEs), excluding IRRs, occurred in 2 pts, one of whom required steroids for G4 pneumonitis, which subsequently resolved. Among the 30 efficacy evaluable pts, the complete response (CR) rate was 80% (24/30), with an objective response rate (ORR) of 93%. 47% of pts (14) had a Deauville ≤2, and 17% (5) had Deauville 3. 5 pts with CR had a Deauville >3 and met LYRIC criteria for IR-2. 4/5 pts had a negative follow-up biopsy that confirmed CR and in 1 pt the PET finding was considered to be a false positive as contrast enhanced CT did not reveal any abnormality. All 5 pts proceeded directly to ASCT and remain in CR at follow-up. Among all treated patients, 25 went directly to ASCT after completing BV + Nivo tx with a median 6.8 x 106 CD34+ cells/kg (range 1-20) collected. Median times to neutrophil and platelet engraftment were 12 and 14 days, respectively. 4 pts required additional salvage therapy subsequent to study tx. Patients were followed for a median of 6 months from ASCT (N=25, range 0.8-8.8) and 10 months from first dose (N=30, range 1.8-12.7). The estimated 9-month PFS rate in all-treated pts was 88%. This is comparable to all-treated pts in Parts 1 & 2, whose estimated 9 and 15 month PFS were 86% and 82%, respectively (Fig 2). Biomarker testing was performed on peripheral blood samples, included immunophenotyping, serum cytokine analysis, and TCRβ sequencing. Concurrent dosing of BV+ Nivo resulted in increased levels of both activated and dividing CD4+ and CD8+ T cells, as well as increased regulatory T-cells and circulating plasmablasts. Cytokines and chemokines associated with innate and adaptive immune activation, including Type I and Type II interferons, IL-18, and IP-10, were significantly upregulated following BV + Nivo, while TARC levels were significantly diminished following therapy. TCRβ sequencing revealed clonal expansion in the periphery following BV + Nivo. Conclusion A concurrent dosing schedule of BV + Nivo was well tolerated with a high CR rate of 80%. Biomarkers evaluated in Part 3 indicate immune activation in the periphery following BV + Nivo. Cumulatively, the results in Part 3, along with the durable remissions noted in Parts 1 & 2, support BV + Nivo combination as an encouraging first salvage therapy prior to ASCT in pts with R/R cHL. Disclosures Advani: Forty Seven: Research Funding; Infinity: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Merck: Research Funding; Agensys: Research Funding; Millenium: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding. Moskowitz:Bristol Myers-Squibb: Consultancy, Research Funding; Incyte: Research Funding; Takeda: Honoraria; Merck: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Bartlett:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vose:Celgene: Research Funding; Legend Pharmaceuticals: Honoraria; Bristol Myers Squibb: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Incyte Corp.: Research Funding; Roche: Honoraria; Novartis: Honoraria, Research Funding; Seattle Genetics, Inc.: Research Funding; Acerta Pharma: Research Funding; Abbvie: Honoraria; Epizyme: Honoraria; Kite Pharma: Research Funding. Ramchandren:Merck: Research Funding; Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Feldman:Johnson and Johnson: Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Portola: Research Funding; Janssen: Speakers Bureau; KITE: Speakers Bureau. LaCasce:Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria. Christian:Acerta: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:LAM Therapeutics: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Takeda: Research Funding. Moskowitz:Celgene: Consultancy; Merck & Co: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Ogden:Seattle Genetics, Inc: Employment, Equity Ownership. Taft:Seattle Genetics: Employment, Equity Ownership. Zak:Seattle Genetics: Employment, Equity Ownership. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Galderisi:Seattle Genetics: Employment, Equity Ownership. Herrera:Immune Design: Research Funding; Merck, Inc.: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences: Research Funding.

Abstract Background Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post-translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T-cell lymphoma (AITL) and CXCL12+ peripheral T-cell lymphoma (PTCL) patients (pts). Methods This Phase 2 study is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) cohort to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL, age >/=18 years and a performance status of 0-2. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) pts with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1-21 of 28-day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Ancillary studies are also ongoing to investigate the prognostic value of CXCL12 expression in patients who received standard of care treatment. Results As of 25 July 2018, 34 PTCL pts (13 AITL, 1 ALK- ALCL, 20 PTCL-NOS) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 15 pts in the ongoing AITL histology and CXCL12 cohorts. Median number of prior treatment regimens was 3. The most common treatment-related adverse events (AE) (grade ≥ 3) are hematological, including neutropenia (50%), thrombocytopenia (43%), leukopenia (33%), febrile neutropenia (27%), and anemia (20%). Skin and subcutaneous tissue disorders were reported in 9 pts, 6 of them with AITL histology. One pt with AITL experienced an episode of possible Stevens Johnson Syndrome that resolved with dose discontinuation and did not recur upon re-challenge at one dose level reduction. Of 18 evaluable patients enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. Pre-treatment tumor tissue CXCL12 expression correlated with favorable pt outcomes. In the AITL cohort (10 evaluable pts), 1 PR and 1 SD have been observed so far, with 5 pts pending cycle 2 response evaluation. In the CXCL12+ cohort (n=3 evaluable pts), 1 SD has been observed, with 2 pts pending cycle 2 response evaluation. Plasma levels of CXCL12 decreased over time with tipifarnib treatment. Expression of CXCL12 mRNA and other biomarkers in pre-treatment biopsies of pts in the AITL and CXCL12+ cohorts are being evaluated using RT-PCR assays. In addition, the prognostic value of CXCL12 is being investigated in approximately 100 diagnostic specimens of PTCL pts who received standard therapy. Preliminary data suggest that CXCL12 overexpression is observed in approximately 25% of PTCL and negatively affects pt survival. Conclusion Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment continues. Disclosures Witzig: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. Kim:Takeda: Research Funding; J&J: Research Funding; Mundipharma: Research Funding; Roche: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Celltrion: Research Funding. Foss:Miragen: Consultancy, Speakers Bureau; Spectrum: Consultancy; Seattle genetics: Consultancy; Mallinkrodt: Consultancy. Advani:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Merck: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Janssen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Research Funding; Agensys: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Infinity: Research Funding. Marin Niebla:Amgen: Other: Medical education of Staff, Speakers Bureau; Roche: Consultancy, Other: Medical education of Staff, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Other: Medical education of Staff, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Medical education of Staff, Speakers Bureau. Piris:Kura: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Curry:Kura Oncology: Employment, Equity Ownership. Gualberto:Kura Oncology: Employment, Equity Ownership.

Abstract Abstract 94 Background: Lymphoma diagnosed during pregnancy is a rare occurrence. Further, there is heterogeneity in clinical presentation and a range of lymphoma histologies resulting in a continued deficiency of lymphoma-specific data in the literature regarding prognosis, optimal therapy, maternal complications, and fetal outcome. Methods: A comprehensive retrospective analysis was completed for patients (pts) diagnosed (dx) with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) during pregnancy at 9 large U.S. academic centers over a 13-year period (1998–2011). The vast majority of cases were co-managed with high-risk maternal fetal medicine. Data on maternal disease characteristics, treatment details, obstetric complications, and fetal outcomes were analyzed. Results: 88 cases were identified with complete data available in 82. The median age of pts was 31 yrs (18–40). Lymphoma dx occurred at a median of 24 weeks (wks) gestation (5–40). 15% of pts were dx during the 1st trimester, 46% during the 2nd trimester, 35% during the 3rd trimester, while 4% (n=3) of pts had a pre-existing NHL dx (follicular lymphoma (FL)). 52% (n=43) of pts had NHL and 48% (n=39) HL. Of NHL cases, 83% (n=33) were B-cell and 17% (n=10) T-cell. B-cell histologies were DLBCL n=23 (including 2 primary CNS and 1 'double hit' NHL), FL n=5 (including 1 leukemic phase FL), Burkitt's lymphoma n=3, and mixed histology n=1; T-cell histologies were anaplastic large cell n=6, PTCL not otherwise specified n=2, and T-cell/NK NHL n=2. Pts with B-cell NHL and HL were dx at a median age of 29 yrs (range, 18–40), while T-cell NHL pts were dx at a median of 34 years (19–37). MRI without gadolinium was the most common imaging modality utilized for staging. 63% of NHL and 19% of HL pts had stage III/IV disease (25% of HL with stage IIB). Pregnancy was terminated in 6 pts (n=4 aggressive NHL and n=2 HD) to enable immediate chemotherapy (five in the 1st trimester [at 5, 8, 10, 10, and 12 wks] and 1 pt in the early 2nd trimester who required high-dose methotrexate). 48 pts (63%) initiated anti-lymphoma therapy at a median of 25 wks gestation (range, 13–37) with 79% of pts initiating therapy in the 2nd trimester (see Table 1). The median gestation at time of lymphoma dx for pts who received intra-partum treatment was 20 wks vs 34 wks for pts who had therapy deferred to post-delivery (p<0.0001). The overall response rate among pts who received therapy was 87% (74% complete remission). Notably, gestation went to full-term in 54% with delivery occurring at a median of 37 wks (31–40). Therapy was deferred until post-delivery in 28 pts (37%) and the majority of these pregnancies were also carried to term (median delivery at 38 wks). At a median follow-up of 41 months (6–157), the 3-year PFS and OS for all pts were 79% and 89% respectively. Histology-specific 3-year PFS and OS were: B-cell NHL: 73% and 82%, respectively; T-cell NHL: 50% and 90%, respectively; and HL: 90% and 95%, respectively (Figure 1). Detailed obstetrical information was available in 59 pts. There were minimal pre-term complications, the most common being induction of labor in 45%. Perinatal events included spontaneous rupture of membranes in 5% and pre-eclampsia in 8%. Further, there were no differences in these events detected among pts who received intra-partum treatment vs deferred therapy. No episodes of chorioamnionitis or endometritis were noted. There was 1 stillbirth that occurred at 19 wks gestation in a 34-year-old pt with double-hit NHL following 1 cycle of R-CHOP. The median birth weight of infants was 2427 grams (1005–5262) with no difference among pts who received intra-partum chemotherapy vs not (2637 grams vs 2212 grams, respectively; p=NS). Microcephaly was reported in 1 case following 4 intra-partum cycles of CHOP for DLBCL; there were otherwise no malformations detected. Conclusions: To our knowledge, this represents one of the largest experiences reported of lymphoma in pregnancy. Our data show that standard NHL and HL chemotherapeutic regimens (without anti-metabolites) administered during the 2nd and 3rd trimester, including as early as 13 wks gestation in select cases, is associated with minimal maternal complications or fetal detriment. In addition, pts with low risk clinical scenarios (e.g., indolent NHL and/or late gestational dx) had therapy safely deferred to post-partum. In our experience, this approach was associated with overall expected lymphoma-related survival. Disclosures: No relevant conflicts of interest to declare.