ALBERT

Description: Background: Pediatric pts with cHL have better responses to therapy compared with adult pts; however, the combination regimens and radiotherapy used in treatment can result in significant morbidity. Including brentuximab vedotin as a component of multi-agent chemotherapy for pediatric pts with newly diagnosed HL may provide clinical benefit by decreasing the need for radiotherapy following chemotherapy, and reducing the risks of late effects associated with radiotherapy, including secondary malignancies, cardiac toxicity and thyroid dysfunction. The phase 1 portion of the study assessed the safety, tolerability, and RP2D of brentuximab vedotin when combined with doxorubicin, vinblastine, and dacarbazine (AVD) for frontline treatment of advanced stage cHL in pediatric pts. Methods: Eligible pts were aged 5 to

Description: Background PTCL is an aggressive subgroup of NHL. Outcomes in R/R PTCL remain poor and alternative therapies are needed. Alisertib is an investigational, oral, selective inhibitor of Aurora A kinase, a key mitotic regulator that is overexpressed/amplified in various cancers, including lymphomas. Phase 2 data with single-agent alisertib in R/R NHL (Friedberg et al JCO 2014) and R/R PTCL (Barr et al JCO 2015) suggested promising antitumor activity. This international phase 3 trial evaluated single-agent alisertib vs investigator's choice in pts with R/R PTCL, and was the first initiated randomized trial in this setting. Methods Adult pts with R/R PTCL (WHO criteria) after ≥1 prior conventional systemic cytotoxic therapy, who had measurable disease by 2007 IWG criteria, tumor biopsy for central hematopathology review, and ECOG PS 0-2, were eligible. Pts were randomized 1:1 (stratified by nodal vs extranodal disease, IPI score [0/1/2 vs 3/4/5], and region [North America + EU vs Rest of World]) to receive alisertib 50 mg twice daily as an enteric coated tablet on d 1-7 in 21-d cycles (alisertib arm), or investigator's choice of: pralatrexate 30 mg/m2 IV once weekly for 6 weeks in 7-week cycles; romidepsin 14 mg/m2 IV on d 1, 8, and 15 in 28-d cycles; or gemcitabine 1000 mg/m2 IV on d 1, 8, and 15 in 28-d cycles (comparator arm), until disease progression, unacceptable toxicity, or 2 yrs (extendable if benefit shown). Selected comparator drug could not have been previously received by the pt, and crossover to another study drug was not permitted. The primary endpoints were ORR (CR+PR) and PFS by IWG criteria per central (IRC) assessment. Secondary endpoints included OS, CR rate, DOR, and safety. The study employed an adaptive sample size reassessment approach, with two interim analyses (IA1, futility analysis; IA2) plus a planned final analysis. Sample size was determined to give 80% power to detect a difference in ORR (assumed 55% alisertib vs 30% comparator) at IA2, and ~85% power to detect a reduction in HR for PFS in favor of alisertib at the final analysis with a maximum of 354 randomized pts and a maximum of 261 PFS events. Conditional power calculation based on PFS at IA2 could determine whether the study would be stopped for futility or if sample size would be expanded for the final analysis. Here we report data from IA2 (17Sep2014 data cut-off). Results 238 pts were randomized across 27 countries (120 alisertib, 118 comparator). Baseline characteristics were balanced between arms (alisertib vs comparator): median age 63 vs 64 yrs; male 68% vs 64%; Ann Arbor stage III/IV 74% vs 72%; bone marrow involvement at study entry 29% vs 35%. Efficacy data are shown in the Table. ORR by IRC with alisertib vs comparator was 33% vs 43% (OR 0.65 [95% CI: 0.34-1.23]), including 16% vs 25% CR. Median duration of follow-up was 9.5 vs 9.2 mos with alisertib vs comparator. Median PFS by IRC was 3.7 vs 3.4 mos (HR 0.939 [95% CI: 0.681-1.293]; Figure) and median OS was 9.9 vs 12.2 mos (HR 0.901 [95% CI: 0.607-1.337]; OS data not mature at current follow-up). Median treatment duration with alisertib vs comparator was 12 vs 10 weeks and 15% vs 5% of pts remained on treatment at data cut-off. With alisertib vs comparator, rates of Gr ≥3 AEs were 85% vs 81%, serious AEs 53% vs 55%, discontinuations due to AEs 9% vs 13%, and on-study treatment-related deaths 2% vs 2%. Gr ≥3 AEs (〉20% all pts) were neutropenia 44% vs 27%, thrombocytopenia 29% vs 27%, and anemia 30% vs 11%. Conclusion While alisertib showed activity in R/R PTCL, there was no significant efficacy benefit vs comparator. Based on IA2, there was a low probability of claiming superiority of alisertib for PFS at the final analysis; therefore, per IDMC recommendation enrollment was stopped at 271 pts and pts deriving benefit continue on treatment. The study was unblinded and final data are pending. Table. Efficacy Alisertib Comparator All Pralatrexate Romidepsin Gemcitabine Response, n (%)*† n=83 n=80 n=40 n=17 n=23 ORR (CR+PR) 27 ( 33) 34 (43) 16 (40) 10 (59) 8 (35) CR 13 (16) 20 (25) 10 (25) 5 (29) 5 (22) PR 14 (17) 14 (18) 6 (15) 5 (29) 3 (13) SD 26 (31) 18 (23) 13 (33) 2 (12) 3 (13) PD 30 (36) 27 (34) 11 (28) 4 (24) 12 (52) Median DOR*† (responders), mos 5.0 5.8 - - - PFS*‡ n=120 n=118 n=67 n=21 n=30 Events, n (%) 78 (65) 73 (62) 45 (67) 7 (33) 21 (70) Median, mos 3.7 3.4 3.4 8.0 1.9 *IRC assessment †Response-evaluable pts (n=163); n=75 not evaluable (not dosed/ no post-baseline IRC assessment/ no central confirmation of PTCL) ‡ITT analysis (n=238) Disclosures O'Connor: Spectrum: Research Funding; Seattle Genetics: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding. Off Label Use: Investigational Aurora A kinase inhibitor, alisertib, for patients with relapsed/refractory peripheral T-cell lymphoma.. Demeter:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Masszi:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ramchandren:Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. d'Amore:Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Foss:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kim:Merck: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Donga: Research Funding; Roche: Research Funding. Zinzani:J&J: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jung:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Zhou:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Leonard:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dansky Ullmann:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shustov:Seattle Genetics: Research Funding.

Description: Background The incidence of and mortality from coronary heart disease (CHD) is significantly higher among African Americans (AAs) compared to Whites, even after adjusting for traditional CHD risk factors. Studies suggests that the unexplained excess risk might be the result of genetic modifiers associated with African ancestry conferring a higher risk of CHD. One such gene variant is the sickle cell mutation. The heterozygous state, or sickle cell trait (SCT), with a prevalence of 8 - 12% among AAs, was previously deemed clinically benign; however, recent evidence indicates that SCT is associated with increased risk of chronic kidney disease venous thromboembolism and sudden death following exertion. Individuals with SCT have higher circulating levels of C-reactive protein, fibrinogen, prothrombin fragment 1.2 and D-dimer. We hypothesized that AAs with SCT have a higher risk for myocardial infarction (MI) and coronary heart disease (CHD) than AAs who are homozygous for wild-type hemoglobin. Methods We obtained genotype and phenotype data from the Women's Health Initiative (WHI) REasonsfor Geographic and Racial Differences in Stroke (REGARDS), Multi-Ethnic Study of Atherosclerosis (MESA), Jackson Heart Study (JHS) and Atherosclerosis Risk In Communities (ARIC) cohorts. The outcomes were incident MI or CHD. Incident MI was defined as adjudicated non-fatal or fatal MI, while incident CHD was defined as 1) adjudicated non-fatal MI, 2) fatal MI, 3) documented coronary revascularization procedures or 4) non-MI CHD death. SCT status was determined by either direct genotyping or imputation for rs334 using the 1000Genome reference panel. Homozygous individuals and those with a prior history of CHD were excluded. Individuals with incident “micro MI”, only defined in REGARDS, were also excluded from the analysis. Analysis was performed separately in each cohort using a Cox proportional hazard models to estimate the hazard ratio (HR) for incident MI or CHD comparing SCT carriers to non-carriers. Models in each cohort were adjusted for age, sex, study site or region of residence, hypertension or systolic blood pressure, diabetes, serum LDL or HDL or total cholesterol, and population stratification (using principal components of global ancestry). The results from each cohorts were then meta-analyzed using a random effect model due to significant heterogeneity between studies (I2 = 39.1%, p = 0.02 for MI meta-analysis and I2 = 56%, p = 0.01 for CHD meta-analysis). Results A total of 20,053 African American men and women were included in the combined sample; 1503 with SCT (7.5% prevalence). Average ages in years at baseline were: 65.0±6.0 in WHI (N = 2248), 62.0 ± 9.2 in REGARDS (N = 10573); 62.2±10.2 in MESA (N = 1556); 50.0 ± 11.9 in JHS (N = 2133); and 54.0 ± 6.0 in ARIC (N = 3543). There were no statistically significant differences in the distribution of traditional cardiovascular risk factors by SCT status within cohorts, except that atrial fibrillation was more prevalent among REGARDS participants with SCT compared to those without SCT (9.9% vs. 7.8%, p = 0.03). The crude incidence rate of MI per 1000 person years in those with SCT compared to those without SCT was: 4.0 vs. 5.2 in WHI; 5.7 vs. 5.0 in REGARDS; 5.8 vs 4.3 in MESA, 2.0 vs 2.1 in JHS; and 4.1 vs 5.9 in ARIC. For CHD, the crude incidence rate was: 5.8 vs. 7.2 in WHI, 8.9 vs. 7.4 in REGARDS; 15.4 vs. 6.4 in MESA; 3.4 vs. 3.4 in JHS; and 10.5 vs. 9.5 in ARIC. The HR (95% CI) for MI was: 0.96 (0.49 - 1.89) in WHI; 1.27 (0.8 - 2.0) in REGARDS; 1.84 (0.74 - 4.60) in MESA; 1.24 (0.28 - 5.44) in JHS; and 0.68 (0.42 - 1.10) in ARIC. And that for CHD was: 1.05 (0.63 - 1.74) in WHI; 1.49 (1.01 - 2.18) in REGARDS; 2.82 (1.48 - 5.38) in MESA; 1.45 (0.50 - 4.19) in JHS; and 1.10 (0.80 - 1.50) in ARIC. Meta-analysis showed that, while SCT status was not significantly associated with incident MI (1.10 [0.73 - 1.64]), it was significantly associated with incident CHD (1.42 [1.02 - 1.98] Figures 1a and 1b). Conclusions This study showed a significant association between SCT and incident CHD, but not MI. Our conclusion is limited by the significant heterogeneity that existed between studies. Since SCT status was not associated with MI, but was associated with CHD, further work is needed to confirm these findings, determine which CHD component(s) explain the observed association and elucidate the possible mechanism(s) involved. Disclosures No relevant conflicts of interest to declare.