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This study evaluated venetoclax population pharmacokinetics (popPK) in patients with treatment-naïve acute myeloid leukemia and assessed the relationship between venetoclax exposure and clinical response for venetoclax in combination with either a hypomethylating agent (HMA) or low-dose cytarabine (LDAC). A total of 771 patients who received venetoclax from 5 Phase 1-3 studies were included in the popPK model. Exposure-response analyses included data from 575 patients for venetoclax/placebo plus HMA and 279 patients for venetoclax/placebo plus LDAC. The popPK model successfully characterized venetoclax plasma concentrations over time and confirmed venetoclax exposure did not vary significantly with age, weight, sex, mild to moderate hepatic impairment, or mild to severe renal impairment. Asian patients had 67% higher mean relative bioavailability than non-Asian patients, however the range of exposures in Asian patients was similar to non-Asian patients. For all efficacy endpoints with both treatment combinations, efficacy was higher in the venetoclax treatment groups compared with the respective control arm of placebo plus azacitidine or LDAC. Within patients who received venetoclax, no significant exposure-efficacy relationships were identified for either treatment combination, indicating that the beneficial effects of venetoclax were already maximized in the dose ranges studied. There was no apparent effect of venetoclax exposure on treatment-emergent Grade ≥3 thrombocytopenia or infections for either combination. Rates of treatment-emergent Grade ≥3 neutropenia were higher in the venetoclax treatment arms compared with the respective control arms; however, within patients who received venetoclax, there was only a shallow relationship or no apparent relationship with venetoclax exposure for venetoclax plus HMA or LDAC, respectively. Along with the efficacy and safety data previously published, the exposure-response analyses support the venetoclax dose regimens of 400 mg once daily (QD) plus HMA and 600 mg QD plus LDAC in treatment-naïve AML patients who are ineligible for intensive chemotherapy.

Purpose:The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL.Patients and Methods:Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue.Results:Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n = 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non–germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL).Conclusions:The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

Immunohistochemical staining of Bcl2, cMyc, Ki67, and CD3 in DLBCL subtype representative tumor samples (same as Supplementary Figure S1). Note that AD091967 is positive for both Bcl2 and cMyc. Cases AB189717, AD550620, and AE575816 show high proliferation rates (80%, 80%, 60%) Scale bars represent 50 µm.

VIALE-C compared the safety and efficacy of venetoclax or placebo plus low-dose cytarabine (+LDAC) in patients with untreated AML ineligible for intensive chemotherapy. Overall, 211 patients were enrolled (n = 143, venetoclax; n = 68, placebo). At the primary analysis, the study did not meet its primary endpoint of a statistically significant improvement in overall survival (OS), however, ~60% of patients had been on study for ≤6-months. Here, we present an additional 6-months of follow-up of VIALE-C (median follow-up 17.5 months; range 0.1–23.5). Median OS was (venetoclax +LDAC vs. placebo +LDAC) 8.4 vs. 4.1 months (HR = 0.70, 95% CI 0.50,0.99; P = 0.040); a 30% reduction in the risk of death with venetoclax. Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 48.3% vs. 13.2%. Transfusion independence rates (RBC) were 43% vs.19% and median event-free survival was 4.9 vs. 2.1 months (HR = 0.61; 95% CI 0.44,0.84; P = 0.002). These results represent improved efficacy over the primary analysis. Incidence of grade ≥3 adverse events were similar between study arms and overall safety profiles were comparable to the primary analysis. These data support venetoclax +LDAC as a frontline treatment option for patients with AML ineligible for intensive chemotherapy.This trial was registered at www.clinicaltrials.gov as #NCT03069352.

The objective of this research was to characterize the venetoclax exposure-efficacy and exposure-safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low-dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure-safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure-efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure-response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400-mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure-response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.

Navitoclax, a novel BCL-2 and BCL-X(L) inhibitor, demonstrated promising antitumor activity in the dose-escalation part of a phase 1/2a study (NCT00406809) in lymphoid tumors. Herein, we report the continued safety and efficacy results of the phase 2a portion. Twenty-six adult patients with relapsed/refractory follicular lymphoma (n = 11, Arm A) and other relapsed/refractory lymphoid malignancies (n = 15, Arm B) were enrolled. Navitoclax administration schedule consisted of a 150-mg 7-day lead-in dose followed by 250-mg daily dosing with the option to further increase to 325 mg after 14 days if the 250-mg dose was tolerated. All patients experienced at least 1 treatment-related adverse event (TRAE). Seventeen (65.4%) patients reported grade 3/4 TRAEs; thrombocytopenia (38.5%) and neutropenia (30.8%) were the most common. Two patients reported serious AEs; none were fatal (no deaths occurred within 30 days of last dose of study drug). The objective response rate (complete and partial) was 23.1% (6/26; Arm A: 9.1%, Arm B: 33.3%). Median progression-free survival and time to progression were identical: 4.9 months (95% CI: 3.0, 8.2); median overall survival: 24.8 months (95% CI could not be computed). Navitoclax monotherapy has an acceptable safety profile and meaningful clinical activity in a minority of patients with relapsed/refractory lymphoid malignancies.

Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS); secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.52-1.07; P = .11), although not statistically significant; median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70; 95% CI, 0.50-0.98; P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.

Summary Background MYC gene rearrangement is present in approximately 10% of aggressive B-cell lymphomas, with half also harbouring a BCL2 gene rearrangement. Multiple retrospective studies of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) have shown a worse outcome in patients with MYC rearrangement (alone or with rearrangement of BCL2 or BCL6, or both) than in patients without MYC rearrangement, and suggest improved outcomes after more intensive treatment. We aimed to determine the outcome of dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; DA-EPOCH-R), an intensive infusional treatment regimen, in untreated aggressive B-cell lymphoma with MYC rearrangement. Methods We present the final analysis of a prospective, multicentre, single-arm, phase 2 study of DA-EPOCH-R in patients with untreated aggressive B-cell lymphoma with MYC rearrangement. DA-EPOCH-R was scheduled to be administered with CNS prophylaxis for six cycles. Primary endpoints included event-free and overall survival. This study is registered with ClinicalTrials.gov ( NCT01092182 ). Findings 53 patients were enrolled, with median age of 61 years (range 29–80; IQR 50–70); 43 (81%) patients had stage III–IV disease and 26 (49%) had high-intermediate or high international prognostic index (IPI) scores. 19 patients had confirmed MYC rearrangement alone (single-hit) and 24 also had rearrangement of BCL2, BCL6, or both (double-hit), with similar characteristics between these two groups. After a median follow-up of 55·6 months (IQR 50·5–61·1), 48-month event-free survival was 71·0% (95% CI 56·5–81·4) and 48-month overall survival was 76·7% (95% CI 62·6–86·1) for all patients. Toxicity included grade 4 neutropenia in 160 (53%) of 301 cycles, grade 4 thrombocytopenia in 40 (13%) cycles, and any grade of fever with neutropenia in 56 (19%) cycles. There were three treatment-related deaths (all infections). Interpretation In this study, DA-EPOCH-R produced durable remission in patients with MYC-rearranged aggressive B-cell lymphomas and should be considered for the treatment of these diseases. Funding Cancer Trials Support Unit and Center for Cancer Research of the National Cancer Institute and Genentech.

PURPOSE Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. An international phase Ib/II study evaluated the safety and preliminary efficacy of venetoclax, a selective B-cell leukemia/lymphoma-2 inhibitor, together with low-dose cytarabine (LDAC) in older adults with AML. PATIENTS AND METHODS Adults 60 years or older with previously untreated AML ineligible for intensive chemotherapy were enrolled. Prior treatment of myelodysplastic syndrome, including hypomethylating agents (HMA), was permitted. Eighty-two patients were treated at the recommended phase II dose: venetoclax 600 mg per day orally in 28-day cycles, with LDAC (20 mg/m2 per day) administered subcutaneously on days 1 to 10. Key end points were tolerability, safety, response rates, duration of response (DOR), and overall survival (OS). RESULTS Median age was 74 years (range, 63 to 90 years), 49% had secondary AML, 29% had prior HMA treatment, and 32% had poor-risk cytogenetic features. Common grade 3 or greater adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and WBC count decreased (34%). Early (30-day) mortality was 6%. Fifty-four percent achieved complete remission (CR)/CR with incomplete blood count recovery (median time to first response, 1.4 months). The median OS was 10.1 months (95% CI, 5.7 to 14.2), and median DOR was 8.1 months (95% CI, 5.3 to 14.9 months). Among patients without prior HMA exposure, CR/CR with incomplete blood count recovery was achieved in 62%, median DOR was 14.8 months (95% CI, 5.5 months to not reached), and median OS was 13.5 months (95% CI, 7.0 to 18.4 months). CONCLUSION Venetoclax plus LDAC has a manageable safety profile, producing rapid and durable remissions in older adults with AML ineligible for intensive chemotherapy. High remission rate and low early mortality combined with rapid and durable remission make venetoclax and LDAC an attractive and novel treatment for older adults not suitable for intensive chemotherapy.

Introduction: Venetoclax (VEN), an orally bioavailable selective BCL-2 inhibitor, was granted accelerated approval by the FDA for the treatment of acute myeloid leukemia (AML) in combination with a hypomethylating agent (HMA) or low-dose cytarabine (LDAC). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships using data from the nonrandomized Phase 1/2 studies and the confirmatory Phase 3 studies in subjects with treatment-naïve AML who are ineligible for intensive chemotherapy. Methods: A population pharmacokinetic (PK) model for VEN was characterized using data from 771 AML subjects across 5 Phase 1 - 3 studies including subjects with relapsed/refractory AML and subjects with treatment-naïve AML who were ineligible for intensive chemotherapy. PK parameters from this model were used to calculate the exposure metric, the area under the plasma concentration-time curve at steady-state (AUCss), for exposure-efficacy and exposure-safety analyses. Logistic regression and Cox proportional-hazards models were used to characterize the exposure-response relationships for overall survival, event-free survival, and conversion to post-baseline transfusion independence for red blood cells or platelets as well as key safety endpoints of treatment-emergent Grade ≥ 3 neutropenia, thrombocytopenia, and infections. Additionally, best overall response of complete remission (CR), CR + CR with incomplete blood count recovery (CRi), and CR + CR with partial hematological recovery (CRh) were also characterized in the exposure-response analyses. Separate analyses were performed for VEN + HMA and VEN + LDAC, including subjects taking placebo (PBO) + HMA or PBO + LDAC, respectively, to inform the intercepts. A total of 575 subjects with treatment-naïve AML were included in the exposure-response analyses for VEN + HMA and 279 subjects with treatment-naïve AML were included in the exposure-response analyses for VEN + LDAC. Results: VEN + HMA: For all efficacy endpoints studied, there was a clear trend for higher efficacy in subjects treated with VEN + HMA as compared to PBO in combination with azacitidine (AZA). When PBO patients were included, significant exposure-response relationships between VEN exposure and overall survival and event-free survival were identified, and a maximal effect (Emax) model best described the statistically significant positive relationships between VEN exposure and best overall response of CR + CRi and CR + CRh. However, there were no apparent relationships between VEN exposure and any efficacy endpoint without the inclusion of PBO subjects, suggesting that the beneficial effect of VEN is already maximized in the dose range studied (400 to 1200 mg daily [QD]). No exposure-response relationship was identified between VEN exposure and treatment-emergent Grade ≥ 3 thrombocytopenia or infections. An Emax model best described the statistically significant relationship between VEN exposure and treatment-emergent Grade ≥ 3 neutropenia, consistent with the clinical finding that subjects in the VEN + HMA treatment arms had higher rates of reported neutropenia than those in the PBO + AZA arm. VEN + LDAC: For all efficacy endpoints studied, there was a clear trend for higher efficacy in subjects treated with VEN + LDAC as compared to PBO + LDAC. With PBO subjects included, an Emax model best described the statistically significant relationships between VEN exposure and best overall response of CR, CR + CRi, and CR + CRh, with probability of response plateauing at exposures corresponding to 600 mg QD of VEN. There were no apparent relationships between VEN exposure and any efficacy endpoint when the PBO subjects were excluded from analysis, indicating that the beneficial effect of VEN is already maximized at 600 mg QD. Although reported rates of treatment-emergent Grade ≥ 3 neutropenia were higher in the VEN + LDAC treatment arms as compared to PBO + LDAC, no significant exposure-response relationships were found between VEN exposure and treatment-emergent Grade ≥ 3 neutropenia, thrombocytopenia, or infections. Conclusion: The VEN exposure-efficacy and exposure-safety analyses confirm the benefit of adding VEN to either HMA or LDAC and support the dose regimens of VEN 400 mg QD in combination with an HMA and VEN 600 mg QD in combination with LDAC in treatment-naïve AML patients who are ineligible for intensive chemotherapy. Disclosures Eckert: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Brackman:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Menon:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Salem:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Smith:Pfizer: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Jazz Pharmaceuticals: Consultancy; Agios: Consultancy. Wei:AbbVie Inc.: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; MacroGenics: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee and receives a fraction of its royalty stream related to venetoclax; Pfizer: Honoraria; Genentech: Honoraria; Astra Zeneca: Honoraria, Research Funding. Hayslip:Abbvie Inc: Current Employment, Other: may hold stock or other options. Miles:Genentech Inc.: Current Employment, Current equity holder in publicly-traded company. Mensing:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Gopalakrishnan:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Zha:AbbVie Inc.: Current Employment, Other: may hold stock or other options.

Aims To report long-term safety/efficacy of VEN+LDAC. Methods Patients ≥ 60 yrs with previously untreated AML ineligible for standard induction chemotherapy (ECOG performance status: 0–2 [≥75 yrs]; 0–3 [60–74 yrs]) were enrolled. Before dose ramp-up of VEN in cycle 1, patients received prophylaxis to mitigate risk of tumor lysis syndrome (TLS). Patients were treated at recommended phase 2 dose (RP2D): VEN 600 mg per day (QD) orally in 28-day (d) cycles, with subcutaneous LDAC 20 mg/m2 QD on d1–10. Key objectives at RP2D were to assess response rates, duration of response (DOR), overall survival (OS), and safety/tolerability. Results Eighty-two patients received RP2D and ≥1 dose of VEN. Median age was 74 yrs; secondary AML: 49%, prior treatment with a hypomethylating agent (HMA): 29%, poor-risk cytogenetics: 32%. In patients evaluable for molecular analyses, baseline mutations in TP53, FLT3, IDH1/2, and NPM1 were detected in 14%, 21%, 26%, and 13%, respectively. Median treatment duration was 4.2 mo (range 0.2–41.8); 26% received >12.0 mo of treatment. The complete remission (CR)/CR with incomplete blood count recovery (CRi) rate was 54% (CR: 26%; CRi: 28%); median time to first response, 1.4 mo (range 0.8–14.9). Median with 95% confidence interval (CI) DOR (CR/CRi) was 9.8 mo (5.3, 14.9), and median OS was 9.7 mo (5.7, 14.0). Among patients with de novo AML (n=42), CR/CRi rate was 71% (CR: 45%; CRi: 26%); median DOR: 10.8 mo (5.5, 32.8), median OS: 15.7 mo (9.7, 22.4). Patients with prior HMA exposure (n=24), CR/CRi was achieved in 33% (CR: 4%; CRi: 29%); median DOR: 5.3 mo (2.3, 10.2), median OS: 4.1 mo (2.9, 10.1). Longer median OS showed in patients with mutations in NPM1 or IDH1/2 (not reached and 15.9 mo, respectively), intermediate-risk cytogenetic features (14.2 mo), or no prior treatment with HMA (11.7 mo). Common grade 3 or 4 treatment-emergent adverse events (≥30%) were febrile neutropenia (43%), thrombocytopenia (39%), and decreased white blood cell count (34%); 2 patients reported grade ≥3 laboratory TLS event. Conclusion At median 3.5-yr follow-up, VEN+LDAC resulted in median OS of 10 mo. At 2 yrs, 22% of study population remained alive; 32%, 36%, and 64% were alive with IDH1/2, de novo, or NPM1 mutant AML, respectively. Further analyses identifying baseline features predictive of response with prolonged duration are ongoing. Abstract was previously published at EHA25.

7511 Background: VIALE-C was designed to compare the safety and efficacy of the BCL-2 inhibitor venetoclax (VEN) or placebo (PBO) plus low-dose cytarabine (LDAC) in previously untreated patient (pts) with acute myeloid leukemia (AML; ≥75 yr or ≥18 yr with comorbidities precluding intensive chemotherapy). The primary overall survival (OS) analysis showed a clinically meaningful improvement with VEN+LDAC, although the primary endpoint was not met. Herein, we present a 6-mo update after primary analysis, with a focus on OS. Methods: This double-blind, PBO-controlled phase 3 study (NCT03069352) randomized pts 2:1 to VEN (600 mg orally QD, days [d]1–28) with 4-d ramp-up in first cycle or PBO in 28-d cycles, plus LDAC (20 mg/m2 subcutaneously QD, d1–10). The primary endpoint was OS; secondary endpoints included response, transfusion independence (TI; red blood cells [RBC] or platelets), and event-free survival (EFS). OS and EFS were analyzed by the Kaplan-Meier method and compared between arms using the log-rank test stratified by AML status (de novo vs secondary) and age (18 to < 74 vs ≥75). The planned sample size was 210 pts (n = 140, VEN; n = 70, PBO) to detect a hazard ratio (HR) of 0.545 in OS with 2-sided alpha of 5% and power of 90%. Results: As of 15 Aug 2019, 211 pts were randomized (n = 143, VEN; n = 68, PBO); median age: 76 yr in both arms (range: 36–93); secondary AML: 38% (88% post-MDS/CMML); prior hypomethylating agent: 20%. With a median follow-up of 17.5 mo (range: 0.1–23.5), median OS was 8.4 mo vs 4.1 mo in the VEN+LDAC and PBO+LDAC arms (HR 0.70; 95% CI 0.50–0.99; P= .04), representing a 30% reduction in the risk of death. Complete remission (CR)/CRi and CR/CRh (CR with partial hematologic recovery) rates were both 48% for the VEN+LDAC arm, and 13% and 15%, respectively, for PBO+LDAC. RBC/platelets TI rates were 43%/49% vs 19%/32% for VEN+LDAC and PBO+LDAC. Median EFS was 4.9 mo vs 2.1 mo in the VEN+LDAC and PBO+LDAC arms (HR 0.61; 95% CI 0.44–0.84; P= .003). Grade ≥3 adverse events (AEs [ > 30%]; VEN+LDAC/PBO+LDAC) included neutropenia (49%/18%), thrombocytopenia (45%/38%), and febrile neutropenia (32%/29%); serious AEs ( > 10%) were febrile neutropenia (17%/18%) and pneumonia (14%/10%); tumor lysis syndrome occurred in 5.6%/0%. Conclusions: VEN+LDAC demonstrates a clinically meaningful improvement in OS compared with PBO+LDAC, with a tolerable and manageable safety profile. These data support VEN+LDAC as a frontline treatment option for older pts with AML, as well as those considered unfit for intensive chemotherapy. Clinical trial information: NCT03069352 .

Purpose: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL. Patients and Methods: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue. Results: Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n = 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non–germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). Conclusions: The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

Background\ud \ud Patients with relapsed or refractory lymphoma or chronic lymphocytic leukaemia have a poor prognosis. Therapies targeting more than one isoform of PI3K, as well as mTOR, might increase antitumour activity. We aimed to investigate the efficacy and safety of voxtalisib (also known as XL765 or SAR245409), a pan-PI3K/mTOR inhibitor, in patients with relapsed or refractory lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma.\ud Methods\ud \ud We did a non-randomised, open-label, phase 2 trial at 30 oncology clinics in the USA, Belgium, Germany, France, the Netherlands, and Australia. Patients aged 18 years or older with Eastern Cooperative Oncology Group (EGOG) performance status score of 2 or lower and relapsed or refractory mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma were enrolled and treated with voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity. The primary endpoint was the proportion of patients in each disease-specific cohort who achieved an overall response, defined as a complete response or partial response. All patients who received more than 4 weeks of treatment and who completed a baseline and at least one post-baseline tumour assessment were analysed for efficacy and all patients were analysed for safety. This study is registered with ClinicalTrials.gov, number NCT01403636, and has been completed.\ud Findings\ud \ud Between Oct 19, 2011, and July 24, 2013, 167 patients were enrolled (42 with mantle cell lymphoma, 47 with follicular lymphoma, 42 with diffuse large B-cell lymphoma, and 36 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The median number of previous anticancer regimens was three (IQR 2–4) for patients with lymphoma and four (2–5) for patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma. Of 164 patients evaluable for efficacy, 30 (18·3%) achieved an overall response (partial, n=22; complete, n=8); 19 (41·3%) of 46 with follicular lymphoma, five (11·9%) of 42 with mantle cell lymphoma, two (4·9%) of 41 with diffuse large B-cell lymphoma, and four (11·4%) of 35 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The safety profile was consistent with that of previous studies of voxtalisib. The most frequently reported adverse events were diarrhoea (in 59 [35%] of 167 patients), fatigue (in 53 [32%]), nausea (in 45 [27%]), pyrexia (in 44 [26%,]), cough (in 40 [24%]), and decreased appetite (in 35 [21%]). The most frequently reported grade 3 or worse adverse events were anaemia (in 20 [12%] of 167 patients), pneumonia (in 14 [8%]), and thrombocytopenia (in 13 [8%]). Serious adverse events occurred in 97 (58·1%) of 167 patients.\ud Interpretation\ud \ud Voxtalisib 50 mg given orally twice daily had an acceptable safety profile, with promising efficacy in patients with follicular lymphoma but limited efficacy in patients with mantle cell lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma.

Tipifarnib, a farnesyltransferase inhibitor (FTI), was initially designed to disrupt RAS farnesylation and membrane localization necessary for RAS function. However, alternative geranylgeranylation has been postulated as an escape mechanism by which RAS bypasses the effect of FTI treatment. In this study, we demonstrate that simvastatin, an HMG-CoA reductase inhibitor, augments the cytotoxic effect of tipifarnib by blocking the alternative geranylgeranylation of RAS. Notably, this effect was accompanied by disruption of RAS membrane localization and ERK downregulation. In addition, the apoptotic effect of this combination was associated with downregulation of the antiapoptotic Mcl-1 protein and activation of the caspase cascade. These findings demonstrate that combining tipifarnib and simvastatin was successful in targeting RAS/ERK signaling and inducing apoptosis in leukemia cells. Both simvastatin and tipifarnib were used at clinically achievable doses, which make the combination promising for future clinical studies.

BACKGROUND: Allogenic hematopoietic stem cell transplant (SCT) is a potentially curative option for patients with acute myeloid leukemia (AML). However, patients who are older, are ineligible for intensive chemotherapy due to significant comorbidities, or have biologically aggressive and refractory disease are not often considered as viable SCT candidates. Venetoclax, a highly selective, potent BCL-2 inhibitor that induces apoptosis in AML cells, has resulted in high rates of durable remission when combined with hypomethylating agents (HMAs) or low dose cytarabine (LDAC), in older patients traditionally considered high risk and ineligible for standard induction chemotherapy. Here, patients who received SCT after venetoclax-based treatments were analyzed to determine the impact of SCT on patient outcomes. METHODS: This study includes patients from the global, open-label phase 1b (NCT02203773) and phase 1/2 (NCT02287233) clinical trials studying the safety and efficacy of venetoclax in combination with the HMAs decitabine or azacitidine, and LDAC, respectively. Patients had newly diagnosed AML and were ineligible for intensive chemotherapy due to comorbidities or age. Patients in the venetoclax plus HMA trial (n=212) were treated with venetoclax (400, 800, or 1200 mg) coadministered with either 20 mg/m2 of intravenous decitabine on days 1-5 or 75 mg/m2 of intravenous or subcutaneous azacitidine on days 1-7 within each 28-day cycle. Patients in the venetoclax plus LDAC trial (n=92) were treated with venetoclax (600 or 800 mg), and with LDAC (20 mg/m2 daily) subcutaneously administered on days 1-10 of each cycle. Patients proceeding to SCT were evaluated for efficacy endpoints including best response (complete remission [CR] or CR with partial hematologic recovery [CRh]), time to best response, time from last dose of venetoclax until SCT, and 12-month post-SCT survival. RESULTS: Of 304 patients treated with venetoclax-based therapy, 31 (10%) proceeded to have allogenic SCT, all of whom were treated in the US. Key demographics for those who received SCT are shown in the Table. The median age was 69 (range: 63-76), 29% had secondary AML, and 39% had adverse cytogenetic risk. The median time on study drug was 3.7 months (range: 0.9-20), and the median time from last dose of venetoclax to SCT was 1.2 months (range: 0.4-10). Twenty-two (71%) patients achieved CR or CRh, with a median time to best response of 2.3 months (range: 0.9-7.1). The median survival time for those that achieved CR (n=16) and CRh (n=6) was 28 months (range: 5.6-54) and 32 months (range: 14-41), respectively. Of 22 patients that achieved CR or CRh, 13 (59%) remained in remission for at least 12 months posttransplant. Across all patients, 55% (17/31) remained in remission for at least one year after SCT, with 12 such patients having remained in remission for ≥2 years. Overall, 68% (21/31) of patients remained alive at 12 months posttransplant. CONCLUSIONS: Venetoclax in combination with either HMAs or LDAC has led to high rates of early, deep and durable responses in untreated AML patients ineligible for standard induction chemotherapy. In this combined study of over 300 such patients, 10% went on to receive stem cell transplant, a majority of whom remained alive and in remission for at least 12 months thereafter. Nearly 40% of SCT patients had durable remissions (≥2 years), suggesting that venetoclax-based regimens prior to SCT, even in patients deemed unfit for standard induction chemotherapy, may provide a path to curative therapy. Disclosures Pratz: Astellas: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium/Takeda: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding. DiNardo:abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria. Arellano:Gilead: Consultancy. Letai:Zeno Pharmaceuticals, Vivid Bioscience, Flash Therapeutics, Dialectic Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Cofounder or Advisory Board member; AbbVie, AstraZeneca, Novartis: Consultancy, Research Funding. Thirman:Merck: Research Funding; Roche/Genentech: Consultancy; Gilead: Research Funding; TG Therapeutics: Research Funding; Up to Date: Honoraria; AbbVie: Consultancy, Research Funding; Astra Zeneca: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy; Janssen: Consultancy. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: 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; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: 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; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Becker:The France Foundation: Honoraria; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy. Hong:Roche: Equity Ownership; Genentech Inc.: Employment, Equity Ownership. Jiang:AbbVie, Inc.: Employment, Other: stock or options. Hayslip:AbbVie, Inc.: Employment, Other: stock or options. Potluri:AbbVie, Inc.: Employment, Other: Stock/stock options. Pollyea:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: 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, Research Funding; Diachii Sankyo: 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.

Background Acute myeloid leukemia (AML) is a highly heterogeneous disease with multiple prognostic indicators of outcomes to conventional treatments; including age, cytogenetic risk, and presence of genomic abnormalities (NPM1, TP53, FLT3 and IDH1/2). Additionally, overexpression of BCL-2 is a predictor for poor response to chemotherapy and can lead to therapeutic resistance in AML (Campos et. al. Blood, 1993). Venetoclax (Ven), an oral selective BCL-2 inhibitor, in combination with hypomethylating agents (HMA) or low dose cytarabine (LDAC), was recently approved for treatment naive patients (pts) with AML who were not fit for standard induction therapy on the basis of two phase 1b/2 studies (DiNardo et.al, Lancet Onclogy, 2018; Wei et.al., J Clin. Oncol., 2019). Here, we present clinical outcome results from the phase 1b/2 study populations in subgroups defined by molecular markers and correlations with BCL-2 family expression. Methods: The data cut-off dates were 31-Aug-2018 (VEN+HMA study M14-358, NCT02203773) and 22-Aug-2018 (VEN+LDAC study M14-387 NCT02287233). Pt responses were assessed according to the IWG criteria for AML (Cheson et.al., J Clin. Oncol.,2003). The presence of AML associated mutations (NPM1, IDH1, IDH2, TP53 and FLT3) were determined centrally in bone marrow aspirates (BMA) at baseline. BCL-2 (BCL2) gene expression was defined centrally by quantitative polymerase chain reaction (qPCR) using the deltaCt (ΔCt) method. BCL2 expression normalized to a reference gene (2-ΔCt) was evaluated for pts with > 50% AML blasts in baseline BMA (median 75%; range 50-99%). The composite complete remission (CR) and CR with incomplete marrow recovery (CRi) rate, overall survival (OS), time to first response (TTR), and duration of response (DOR), and BCL-2 gene expression were correlated with presence of baseline molecular markers. Results: Data from 209 pts who received Ven 400 mg or 600 mg in combination with either HMA or LDAC are reported here. The median age was 74 years (range: 61-90 years) and 61% (n=127) were male (Table 1). Of the 167 pts with centrally assessed molecular markers, IDH1 or IDH2 mutations were detected in 25.7%, NPM1 mutations in 15.6%, TP53 mutations in 22.2%, and FLT3 mutations in 18.0% pts. Pts may have more than one of these mutations (i.e co-mutations of NPM1 and IDH1or IDH2, NPM1 with FLT3, or NPM1 with TP53) identified in baseline BMA. The CR/CRi rates were 83.7% for pts with IDH1/IDH2 mutations, 84.6% for pts with NPM1 mutations, 59.5% for pts with TP53 mutations, and 53.3% for pts with FLT3 mutations (Table 2). The median OS was not reached (NR) for pts with IDH1, IDH2 or NPM1 mutations, while the median OS for pts with detectable TP53 mutations or FLT3 mutations was 8.9 mos and 12.4 mos respectively. The remissions (CR or CRi) were rapid (median TTR between 1.1 mos to 1.8 mos) for each group (Table 2) and durable responses were observed for pts with IDH1, IDH2, NPM1, or FLT3 mutations (median DOR was either NR for IDH and NPM1 and 19.9 mos for FLT3). Pts with TP53 mutations are known to have poor prognosis and the DOR in this cohort was 5.6 mos. The median time on study was 11.6 mos (range: 0.3-44 mos). The range of BCL2 mRNA expression (2-ΔCt) in bone marrow blasts was 0.03 to 2.93, with a median of 0.86. The Cox hazard ratio for OS was 1.06, p=0.8565 based on BCL2 above the median (> 0.86 2-ΔCt). The multivariate analysis included age, cytogenetic risk, AML type (primary vs secondary) and trial (M14-387 vs M14-358). Albeit not statistically significant and small sample sets, pts with either IDH1 or IDH2 mutations (N = 21) tended to have higher BCL2 expression (median 2-ΔCt 1.1 ; range 0.19 -2.93) while pts with TP53 mutations (N = 7) had lower levels of BCL2 expression (median 2-ΔCt 0.55; range 0.03 - 1.27). Determination of baseline expression of other family members (BCL2L1, MCL1, BCL2A1, BCLw, NOXA, etc) is ongoing and additional univariate and multivariate analyses will be presented at the meeting. Conclusions: These analyses demonstrate that VEN + HMA or LDAC has efficacy across multiple molecular markers in AML. This activity is rapid and durable, and is observed across different levels of BCL2 expression in AML blasts. Disclosures Chyla: Abbvie, Inc: Employment, Other: Stock or options. Harb:AbbVie Inc: Employment, Other: Stock/stock options. Mantis:AbbVie Inc: Employment, Other: Stock/stock options. Riehm:AbbVie Inc.: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options. Sun:AbbVie: Employment, Other: Stock/stock options. Huang:AbbVie Inc: Employment, Other: Stock/stock options. Jiang:AbbVie Inc.: Employment, Other: Stock/stock options. Dail:Genentech: Employment, Equity Ownership. Peale:Genentech Inc.: Employment, Other: Stock/stock options. Potluri:AbbVie, Inc.: Employment, Other: Stock/stock options. Hayslip:AbbVie Inc: Employment, Other: Stock/stock options. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment in acute myeloid leukemia, which is not an approved indication.

Introduction Over-expression of the anti-apoptotic protein BCL-2 in MDS has been implicated in progression and drug resistance in MDS. Venetoclax (Ven), a selective, potent, orally bioavailable BCL-2 inhibitor, was recently approved in combination with HMAs or low dose cytarabine for the frontline management of older unfit pts with AML. In this study, we sought to evaluate the safety and efficacy of Ven in pts with R/R MDS. Methods This is an ongoing phase 1b, open-label, multicenter study in R/R MDS (NCT02966782). Key eligibility criteria include age ≥18 years, failure of HMA after receiving at least 4 cycles of Aza or 4 cycles of decitabine within the previous 5 years, marrow blasts The primary objectives were to evaluate the safety profiles and the recommended Phase 2 dose (RP2D) of Ven monotherapy and Ven+Aza. Key secondary objectives included a preliminary assessment of overall response rate (ORR, defined as complete remission [CR]+marrow complete remission [mCR]+partial response [PR]) , time to first response (TTR), progression-free survival (PFS), and overall survival (OS). We used the modified International Working Group 2006 criteria for response assessment (Cheson et. al., Blood, 2006). Results As of April 9, 2019, 46 pts [87% male, median age 76 years (range 44-91)] were enrolled. C1 (Ven monotherapy) included 22 pts, C2 (combination therapy) included 24 pts. At baseline, 37 (80%) pts received at least one prior therapy, 2 (15%) pts received 2, and 1 (2%) patient received >3 therapies prior to enrollment in the study. Baseline bone marrow blasts were: ≤5% was observed in 16 (35%) pts, >5% and ≤10% in 23 (50%), and >10% in 7 (15%) pts respectively. Cytogenetics risk was evaluated in 27/46 pts and were as follows: Good 12 (44%), Intermediate 9 (33%), and Poor 6 (22%). Overall, 9 pts discontinued study therapy (8 deaths, 1 withdrew consent). The most frequent treatment-emergent adverse events (TEAEs) included neutropenia, thrombocytopenia, nausea, and diarrhea (Table ). Infectious TEAEs included febrile neutropenia and pneumonia. Predominant Grade 3 and 4 TEAEs were hematological and included neutropenia (41%), thrombocytopenia (30%), leukopenia (24%), and anemia (15%). Serious TEAEs occurring in ≥2 pts were febrile neutropenia (n=8), pneumonia (n=6), thrombocytopenia (n=2), and epistaxis (n=2). Death on study occurred in 8 (17%) pts, of whom 6 died of progressive disease. Other causes of death were septic shock (n=1) and pneumonia (n=1). Forty of 46 pts were response evaluable. Median follow-up time was 4.7 mos (range: 3.7-6.3 mos). In C1, ORR was 7% (1/16). Stable disease was observed in 75% (12/16) pts. Median TTR was 1.6 mos (range: 1.6-1.6 mos). Median PFS was 3.4 mos (95% CI: 1.9-5.2 mos) and 6-mos estimate for OS was 57% (95% CI: 22%, 81%). In C2, ORR was 50% (12/24 pts). Of those, 13% (3/24) had CR and 38% (9/24) had mCR. Stable disease was observed in 31% (10/24) pts. Median PFS, and OS were not reached. The 6-mos estimate for PFS was 76% (95% CI: 50%, 89%) and estimated OS at 9-mos was 83% (95% CI: 55%, 95%). Finally, 4 pts came off study to receive allogeneic stem cell transplantation. Conclusion Ven monotherapy and combination Ven+Aza were well tolerated in pts with R/R MDS and most AEs were manageable. Although the study is still ongoing, the 6-mos OS estimate of 57% in monotherapy pts compares favorably to historical controls. In addition, the ORR observed with combination therapy, and the observed 9-mos OS rate of 83% also compare favorably with historical data. Updated data on safety and efficacy, including data on RP2D, will be presented at the meeting. Disclosures Zeidan: Ariad: Honoraria; Agios: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding. Pollyea:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: 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; Forty-Seven: 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. Garcia:Abbvie: Research Funding; Genentech: Research Funding. Brunner:Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Roncolato:St. George Hospital: Employment. Borate:Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Odenike:Astra Zeneca: Research Funding; Astex Pharmaceuticals: Research Funding; Agios: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI/Baxalta: Research Funding; NS Pharma: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Research Funding; Oncotherapy: Research Funding. Bajel:Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria. Watson:Amgen: Other: Travel grant; Roche: Other: Travel grant. Götze:AbbVie: Membership on an entity's Board of Directors or advisory committees. Nolte:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Tan:AbbVie Inc: Other: Investigator in AbbVie funded trial. Hong:Roche: Equity Ownership; Genentech Inc.: Employment, Equity Ownership. Dunbar:AbbVie Inc: Employment, Other: Stock/stock options. Zhou:AbbVie Inc: Employment, Other: Stock/stock options. Gressick:AbbVie Inc: Employment, Other: Stock/stock options. Ainsworth:AbbVie Inc: Employment, Other: Stock/stock options. Harb:AbbVie Inc: Employment, Other: Stock/stock options. Salem:AbbVie: Employment, Other: Stock/stock options. Hayslip:AbbVie Inc: Employment, Other: Stock/stock options. Swords:AbbVie Inc: Employment, Other: Stock/stock options. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment in myelodysplastic syndromes, which is not an approved indication.

Although poor nutritional status and weight loss in cancer patients is known to affect outcomes, little is known about malnutrition differences based on geographic location. We investigated nutritional and inflammatory status of 220 newly diagnosed adults with solid tumors at the University of Kentucky's Markey Cancer Center during December 2008 through October 2011. Chi-square tests were used to determine any associations between suboptimal nutritional levels and rural-urban areas of residence. Out of the 13 lab values collected, the only significant difference between rural and urban participants was found for vitamin D resulting in more rural subjects (67.4%) having a suboptimal vitamin D status as compared to those residing in urban areas (53.3%, P = 0.04). Controlling for baseline demographics including age, race, sex, body mass index, nutritional status, and type of cancer, logistic regression analyses concluded those in rural areas had nearly a twofold increase in the odds of having a suboptimal vitamin D level compared to those in urban areas (odd's ratio = 1.97; 95% confidence interval = 1.04, 3.74). Further investigation into the rural-urban differences in vitamin D needs to be investigated in order to improve outcomes during cancer treatment.

Simvastatin (SIM) is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor widely used in hyperlipidemia therapy. SIM has recently been studied for its anticancer activity at doses higher than those used for the hyperlipidemia therapy. This prompted us to study the pharmacokinetics of high-dose SIM in cancer patients. For this purpose, an LCâMS/MS method was developed to measure SIM and its acid form (SIMA) in plasma and peripheral blood mononuclear cells (PBMCs) obtained from patients. Chromatographic analyte separation was carried out on a reverse-phase column using 75:25 (% v/v) acetonitrile:ammonium acetate (0.1Â M, pH 5.0) mobile phase. Detection was performed on a triple quadrupole mass spectrometer, equipped with a turbo ion spray source and operated in positive ionization mode. The assay was linear over a range 2.5â500Â ng/mL for SIM and 5â500Â ng/mL for SIMA in plasma and 2.5â250Â ng/mL for SIM and 5â250Â ng/mL for SIMA in cell lysate. Recovery was >58% for SIM and >75% for SIMA in both plasma and cell lysate. SIM and SIMA were stable in plasma, cell lysate and the reconstitution solution. This method was successfully applied for the determination of SIM and SIMA in plasma and PBMCs samples collected in the pharmacokinetic study of high-dose SIM in cancer patients. Keywords: Simvastatin, LCâMS/MS, Human plasma, Cell lysate, Pharmacokinetic, High-dose

BACKGROUND: The median age for diagnosis of acute myeloid leukemia (AML) is 68 years. Elderly patients are often ineligible for intensive chemotherapy and have limited treatment options. Venetoclax (Ven), an oral agent that targets the antiapoptotic protein, BCL-2, has demonstrated high rates of remission (>60%) when administered in combination with low-dose cytarabine (LDAC), and could represent a potent therapeutic option for patients ineligible for intensive chemotherapy. METHODS: This open-label, phase 1/2 study (NCT02287233) evaluated the safety and efficacy of venetoclax in combination with LDAC in patients with previously untreated AML who were ineligible for intensive chemotherapy due to comorbidities or age. Patients had an Eastern Cooperative Oncology Group (ECOG) performance score of 0-2, had adequate hepatic and renal function, and were enrolled from December 2014 to May 2017. In the dose escalation portion of the study, 600 mg venetoclax was determined to be the recommended phase 2 dose (RPTD). Venetoclax was initiated at 50 or 100 mg daily and dose escalated over 4-5 days to reach the RPTD. In subsequent 28 day cycles, venetoclax was administered at 600 mg on all days. LDAC (20 mg/m2 daily) was subcutaneously administered on days 1-10 of each cycle. At the beginning of the study, concominant strong and moderate CYP3A inhibitor use was prohibited; however, as additional safety and pharmacokinetic data became available, their use was allowed with appropriate venetoclax dose adjustments. Time to first response, rates of complete remission (CR), CR with incomplete blood count recovery (CRi), CR with partial hematologic recovery (CRh), duration of response, achievement of transfusion independence, overall survival (OS) and adverse events (AEs) were evaluated. Minimal residual disease (MRD) was evaluated centrally by multicolor flow cytometry at a cutoff of 10-3 leukemic cells. RESULTS: Data cutoff was November 8, 2017. Of 82 patients treated with 600 mg of venetoclax, 65% were male, 95% white race, 60% had intermediate and 32% had poor cytogenetic risk, and 49% had secondary AML (of whom 60% had prior HMA exposure). Transfusion dependence for red blood cells (RBC) and platelets within 8 weeks prior to venetoclax treatment was 65% (53/82) and 28% (23/82) of patients, respectively. Most common grade ≥3 AEs across all patients were febrile neutropenia (43%), thrombocytopenia (38%), neutropenia (27%), and anemia (27%). Laboratory evidence of grade 3 tumor-lysis syndrome (TLS) was observed in two patients; both patients achieved the target dose of venetoclax. Forty seven percent of patients received moderate (40%) or strong (7%) CYP3A inhibitors for at least 7 days (predominantly azole antifungals); no relevant differences in serious adverse event rates were observed. Key efficacy results are shown in the Table. Median time to first response was 1.4 months, and 54% and 46% of patients achieved CR/CRi and CR/CRh, respectively. The rates of CR/CRi for patients with secondary and de novo AML were 35% and 71%, respectively; median DOR for those with secondary and de novo AML was 8.1 and 11.6 months, respectively. Patients with selected genetic mutations achieved the following rates of CR/CRi: TP53, 30%; IDH1/2, 72%; FLT3, 44%; NPM1, 89%. MRD response below 10-3 cutoff was achieved by 32% of patients with CR/CRi; median OS has not yet been reached for these patients. Among patients that were RBC or platelet transfusion dependent at baseline, 49% (26/53) and 65% (15/23), respectively, achieved transfusion independence while on venetoclax therapy. CONCLUSIONS: Venetoclax in combination with LDAC led to rapid, deep, and durable responses in patients with AML who were ineligible for intensive chemotherapy. Venetoclax plus LDAC demonstrated an improved CR rate (26% vs. 8%), CR/CRi rate (54% vs. 11%) and median overall survival (10 months vs. 5 months) compared to the historical rates with LDAC alone. Furthermore, a majority of patients achieved transfusion independence during venetoclax therapy. Strong and moderate CYP3A inhibitors, including azole antifungals, were safely coadministered with appropriate venetoclax dose adjustments. These results demonstrate that venetoclax, in combination with LDAC, represents an effective therapeutic option for patients with AML who are not suitable for standard induction therapy. Disclosures Wei: Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Strickland:Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Consultancy; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis Pharmaceuticals: Consultancy, Research Funding. Fiedler:Amgen: Consultancy, Other: Meeting attendance, Patents & Royalties, Research Funding; ARIAD/Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Gilead: Other: Meeting attendance; GSO: Other: Meeting attendance; Teva: Other: Meeting attendance; JAZZ pharma: Other: Meeting attendance; Daiichi Sankyo: Other: Meeting attendance. Lin:Jazz Pharmaceuticals: Honoraria. Walter:Actinium Pharmaceuticals, Inc: Other: Clinical Trial support , Research Funding; Amgen Inc: Other: Clinical Trial Support, Research Funding; Amphivena Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Aptevo Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Covagen AG: Consultancy, Other: Clinical Trial Support, Research Funding; Seattle Genetics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Pfizer, Inc: Consultancy; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy. Hong:Genentech Inc/Roche: Employment, Other: Ownership interests PLC. Chyla:AbbVie, Inc: Employment, Equity Ownership. Popovic:AbbVie Inc: Employment, Equity Ownership. Fakouhi:AbbVie, Inc: Employment, Equity Ownership. Xu:AbbVie, Inc: Employment, Equity Ownership. Hayslip:AbbVie: Employment, Equity Ownership. Roboz:Bayer: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; AbbVie: Consultancy; Orsenix: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Astex Pharmaceuticals: Consultancy; Orsenix: Consultancy; Roche/Genentech: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Sandoz: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Sandoz: Consultancy; Janssen Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; Celltrion: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Eisai: Consultancy.

Introduction: Venetoclax, a selective BCL2 inhibitor, is approved for treatment of chronic lymphocytic leukemia in patients who received at least one prior therapy and is being studied in several other hematological malignancies including acute myeloid leukemia (AML). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships of venetoclax in patients with newly diagnosed AML who are not eligible for standard anthracycline-based induction therapy treated with venetoclax plus a hypomethylating agent (HMA) either azacitidine or decitabine, or low dose cytarabine (LDAC) to inform dose selection. Methods: A population pharmacokinetic model for venetoclax was developed using data from 336 AML subjects. Post hoc pharmacokinetic parameters generated from the model were used to calculate the exposure metric, steady-state area under the plasma concentration-time curve (AUCss), in the exposure-efficacy and exposure-safety analyses. Multivariate cumulative logistic regression analyses were performed using efficacy and safety data. In total, for the venetoclax plus HMA combination, 201 subjects were included in the exposure-efficacy and 212 subjects were included in the exposure-safety analyses. For the venetoclax plus LDAC combination, 83 subjects were included in the exposure-efficacy and 92 subjects were included in the exposure-safety analyses. Predictions based on the exposure-response model parameter estimates were used to explore the exposure- and dose-response relationships and select the optimal venetoclax dose. Results: Venetoclax in Combination with HMAs: Simulations indicated that venetoclax dosage of 400 mg once daily (QD) in combination with HMAs maximizes the probability of a typical subject achieving a response of complete remission (CR).. Venetoclax exposure-response relationship was similar for both azacitidine and decitabine combination (P > 0.05). For exposure-safety analyses, only treatment-emergent Grade ≥ 3 infections showed a statistically significant relationship with venetoclax exposures in combination with HMAs across the tested venetoclax dose range (400 - 1200 mg QD). The probability of occurrence of treatment-emergent Grade ≥ 3 infections at venetoclax dose of 400 mg and 800 mg was 51% (95% CI: [43, 58%]) and 59% (95% CI: [50, 66%]), respectively. Venetoclax in Combination with LDAC: A statistically significant association of best responses was determined with increasing steady-state area under the plasma concentration-time curve (AUCss). Based on the tolerability data, the probability of achieving CR with incomplete count recovery (CRi) or better, and CR was predicted for doses up to 600 mg. The predicted probability of achieving CRi or better was approximately 46% (95% CI: [37, 55%]) and 55% (95% CI: [45 - 66%]) at exposures associated with the 400 mg and 600 mg dosage regimen given once daily, respectively. Conclusions: The venetoclax exposure- efficacy and exposure-safety analyses supported the 400 mg QD dosage regimen of venetoclax in combination with the HMAs and 600 mg QD dosage regimen of venetoclax in combination with LDAC in treatment naïve AML patients who are ineligible for standard induction chemotherapy. Disclosures Agarwal: AbbVie: Employment, Equity Ownership. Gopalakrishnan:AbbVie: Employment, Equity Ownership. Mensing:AbbVie: Employment, Equity Ownership. Potluri:AbbVie: Employment, Equity Ownership. Hayslip:AbbVie: Employment, Equity Ownership. Friedel:AbbVie: Employment, Equity Ownership. Menon:AbbVie: Employment, Equity Ownership. Salem:AbbVie: Employment, Equity Ownership.

Background: Older patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy are unlikely to achieve remission with available therapy and have unacceptably short survival. Venetoclax (VEN) is a small molecule inhibitor of BCL-2 that achieved remission rates of >60% combined with low-dose cytarabine (LDAC). Presented are long-term outcomes, including 1-year overall survival (OS) and biomarker analyses. Methods: This phase 1b/2, open-label study (NCT02287233) evaluates the safety and preliminary efficacy of orally administered VEN combined with LDAC in patients ≥65 years with previously untreated AML (except for hydroxyurea). Patients were ineligible for intensive chemotherapy because of comorbidity or other factors and had an ECOG performance score of 0-2, with adequate hepatic and renal function. Exclusion criteria were acute promyelocytic leukemia, active CNS involvement with AML, concominant use of moderate or strong CYP3A inhibitors, or prior treament with cytarabine for a preexisting myeloid disorder. Prior treatment for myelodysplastic syndrome (MDS) was allowed. In cycle 1, VEN was started at 50 mg/day PO and increased over a 5-day ramp-up to reach the designated cohort dose of 600 or 800 mg/day on day 6, which was continued through day 28. In subsequent cycles, the desingated dose of VEN 600 or 800 mg/day was administered on days 1-28. LDAC 20 mg/m2/day SQ was given on days 1-10 of each cycle. Preliminary efficacy was assessed as the overall response rate (ORR, which included complete remission [CR], CR with incomplete blood count recovery [CRi], and partial remission [PR]). Adverse events (AEs) and laboratory values were monitored. Exploratory analysis of biomarkers (eg, cytogenetics, molecular markers) was performed to identify potential predictors of clinical outcomes. Results: Data cutoff was May 30, 2017. All 71 patients were enrolled ≥1 year prior (46 [65%] male; median age, 74 years [range, 66-87 years]): 10 received VEN 800 mg and 61 received VEN 600 mg, the recommended phase 2 dose. Thirty-three patients (47%) had a history of antecedent hematologic disorder (AHD), most commonly MDS. Among 61 patients given VEN 600 mg, median time on VEN treatment was 6 months (range, Conclusions: The safety profile of VEN 600 mg/day plus LDAC was acceptable for elderly patients with treatment-naive AML who were ineligible for intensive chemotherapy. After ≥1 year of follow-up, the observed median OS was 11.4 months. This cohort included 44% (27/61) of patients with AHDs. Corelations of specified AML mutations with response and duration should be confirmed in later trials. Due to the observced CR/CRi rate of 62%, extended duration of response, and encouraging OS in a cohort of patients with particularly poor-risk features, the 600-mg dose of VEN combined with LDAC is being tested in an ongoing phase 3 study. Figure Figure. Disclosures Wei: AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria; AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity's Board of Directors or advisory committees. Strickland: Boehringer-Ingelheim: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy; Tolero: Consultancy; Astellas: Consultancy; CTI BioPharma: Consultancy; Baxalta: Consultancy. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Hou: Teva Oncology, Seattle Genetics: Speakers Bureau. Fiedler: Amgen, Pfizer: Research Funding; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance; Amgen: Patents & Royalties; Amgen, ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees. Lin: Jazz Pharmaceuticals: Consultancy. Walter: ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding. Chyla: Abbvie: Employment, Equity Ownership. Popovic: AbbVie: Employment, Equity Ownership. Fakouhi: AbbVie: Employment, Equity Ownership. Shah: AbbVie: Employment, Equity Ownership. Dunbar: AbbVie: Employment, Equity Ownership. Xu: AbbVie: Employment, Equity Ownership. Mabry: AbbVie: Employment, Equity Ownership. Hayslip: AbbVie: Employment, Equity Ownership.

The addition of antibiotics to an adhesive haemostat results in an ideal system for the treatment of a localized infectious disease. Fibrin sealant (FS) is a biocompatible, resorbable, adherent haemostat that can deliver antibiotics. Previous use of fibrin to deliver antibiotics resulted in rapid release and limited bioactivity. We have reported previously that poorly soluble antibiotics significantly retard release from FS, resulting in extended delivery in vitro, and overcome antibiotic-resistant infection. We now report that localized antibiotic delivery from FS controls peritoneal infection without measurable systemic antibiotic. Rats and mice were implanted with preformed FS discs containing tetracycline free-base to evaluate control of peritoneal sepsis and to measure serum tetracycline levels. Infection was initiated with Staphylococcus aureus. Morbidity and mortality were evaluated for 14 days. Serum was isolated from jugular vein blood with subsequent evaluation for antimicrobial activity. Mice prophylactically treated with FS-tetracycline (FS-TET) 500 mg/kg 2 days before infection cleared the S. aureus infection, resulting in 100% survival. Mice treated with FS-TET 500 mg/kg 7 days before infection survived. Mice treated with FS-TET 1750 mg/kg 35 days before infection also survived. Rats treated with FS-TET 500 mg/kg had undetectable serum tetracycline levels, whereas in vitro release of tetracycline from FS-TET pellets in rat serum was readily detected. We conclude that fibrin is an excellent vehicle for extended delivery of low solubility tetracycline. Tetracycline delivered from FS is an appropriate chemotherapy for S. aureus peritonitis. FS-TET controls localized infection without a measurable concentration of systemic tetracycline.

We report the results of a phase I study with four dose levels of bortezomib in combination with idarubicin. Eligible patients were newly diagnosed with acute myeloid leukemia (AML) age ≥60 years, or any adult with relapsed AML. Bortezomib was given twice weekly at 0.8, 1.0, or 1.2 mg/m2 with once weekly idarubicin 10 mg/m2 for four weeks. Twenty patients were treated: 13 newly diagnosed (median age 68, range 61–83) and 7 relapsed (median age 58, range 40–77). Prior myelodysplastic syndrome (MDS) was documented in 10/13 (77%) newly diagnosed and 1/7 (14%) relapsed patients; the three newly diagnosed patients without prior MDS had dyspoietic morphology. Two dose-limiting toxicities occurred at the initial dose level (bortezomib 0.8 mg/m2 and idarubicin 10 mg/m2); idarubicin was reduced to 8 mg/m2 without observing subsequent dose-limiting toxicities. The maximum tolerated dose in this study was bortezomib 1.2 mg/m2 and idarubicin 8 mg/m2. Common adverse events included: neutropenic fever, infections, constitutional symptoms, and gastrointestinal symptoms. No subjects experienced neurotoxicity. Most patients demonstrated hematologic response as evidenced by decreased circulating blasts. Four patients (20%) achieved complete remission. There was one treatment-related death. The combination of bortezomib and idarubicin in this mostly poor-risk, older AML group was well tolerated and did not result in high mortality. This trial was registered at www.clinicaltrials.gov as # NCT00382954 .

To evaluate the pharmacokinetics of simvastatin at the maximum tolerated dose (MTD) of 7.5 mg/kg, twice daily, in the context of a pilot trial enrolling patients with recurrent and refractory chronic lymphocytic leukemia. Patients received simvastatin orally at MTD for 7 days during a 21-day cycle for 6 cycles. Blood samples were collected during cycle 1. Simvastatin lactone and carboxylate concentrations were measured in plasma and peripheral blood mononuclear cells (PBMCs) using a validated HPLC–MS/MS assay. Patients accrued to this study showed high variability in their exposure to simvastatin. Exposure was dose proportional (AUC and C max) as compared to those receiving standard hyperlipidemia therapy. Peak plasma concentrations ranged from 0.08 to 2.2 and from 0.03 to 0.6 μM for simvastatin lactone and carboxylate, respectively. Our study shows that when simvastatin is administered at its MTD, only low micro-molar concentrations are achieved in plasma and PBMCs, which is consistent with the results observed in previous studies with lovastatin, but far lower than the concentrations required for anticancer effects in vitro. However, whether simvastatin at its MTD can confer therapeutic benefits to patients still remains to be determined.

Background: Multiple studies have demonstrated the modest efficacy of low-dose cytarabine (LDAC) in older patients (≥65 years) with Acute Myeloid Leukemia(AML) who are unlikely to benefit from an anthracycline and cytarabine intensive induction [CR/CRi rates of 10 - 26%; (CRi = complete remission with incomplete marrow recovery)]. Venetoclax, a selective BCL-2 inhibitor has demonstrated single-agent activity in patients with relapsed and refractory AML [Konopleva et al., ASH 2014]. When administered with LDAC, the recommended phase 2 dose (RP2D) of venetoclax was 600 mg daily [Lin et al., ASCO 2016 (abstract 7007)]. Here we present the safety and efficacy data at RP2D of venetoclax from the dose escalation and expansion phases of the study (NCT02287233). Methods: Patients enrolled as of 15DEC2015 are included in this analysis with a data cut-off date of 31MAR2016. Patients were eligible if considered unfit for intensive chemotherapy, had an ECOG performance status of 0-2 and adequate renal and liver function. Patients treated with cytarabine for a pre-existing myeloid disorder, or those with acute promyelocytic leukemia or active CNS involvement with AML were excluded from the study. Venetoclax 600 mg was administered orally once daily on days 2 - 28 of Cycle 1 and days 1 - 28 of subsequent cycles. A 5-day dose ramp-up schedule was followed to reach the 600 mg dose. LDAC 20 mg/m2 was administered s.c. daily on days 1-10 in 28-day cycles. To mitigate the potential risk of tumor lysis syndrome (TLS), all patients were hospitalized and received prophylaxis commencing 48 hours prior to venetoclax during Cycle 1. Adverse events (AEs) were graded by NCI CTCAE Version 4.0. Results: Twenty patients were enrolled in the study (escalation, n=8; expansion, n=12). The median age was 74 years (range: 66 - 87). 8/20 (40%) patients had an antecedent hematologic disorder. Median time on venetoclax was 147.5 days (range: 8 - 455). Grade 3/4 AEs (≥10% patients) excluding cytopenias were febrile neutropenia (35%), hypertension (20%), hypophosphatemia (20%), decreased appetite, increased blood bilirubin, hyponatremia, hypoxia, hypotension, pneumonia, sepsis, syncope, urinary tract infection, and vomiting (10% each). No events of TLS occurred. Venetoclax exposures on Cycle 1 Day 10 (with LDAC) vs. Cycle 1 Day 18 (venetoclax alone) were comparable. The mean ± SD of maximum observed concentration (Cmax, µg/mL/mg) were 2.04 ± 1.45 vs. 2.92 ± 2.15, respectively. The mean ± SD of area under the curve (AUC24, µg*hr/mL) were 33.3 ± 27.5 vs. 46.1 ± 36.8, respectively. Similarly, co-administration of venetoclax did not markedly affect LDAC exposures. The mean ± SD of Cmax (ng/mL) of LDAC on Cycle 1 Day 1 (LDAC alone) vs. Cycle 1 Day 10 (with venetoclax) were 158.89 ± 79.08 vs 166.49 ± 32.06, respectively. Similarly, the mean ± SD of AUCinf (ng*hr/mL) were 170.64 ± 102.86 vs 246.51 ± 93.41, respectively. 15/20 (75%) patients achieved an objective response (CR+CRi+PR). Of them, 14/20 (70%) patients had a CR+CRi; all 14 patients belonged to a subset of 18 patients with no prior myeloproliferative neoplasm (MPN). 16/19 (84%) patients with available data had their bone marrow blast percentage reduced to below 5%. The 12-month overall survival (OS) estimate for all patients was 74.7% (95% CI=49.4 - 88.6) and that for the responders (n=15) was 86.7% (95% CI=56.4 - 96.5). The overall response rates and 12-month OS estimates for patients with or without prior hypomethylating agent (HMA) and with or without MPN are summarized in Table 1. A Kaplan-Meier curve showing OS for responders vs. non-responders is shown in Figure 1. The median time to best response was 30 days (range: 23 - 169). Only 2/14 patients who achieved CR/CRi have died [disease progression (n=1), acute hepatic failure (n=1)]. Conclusions: Venetoclax (600 mg RP2D) plus LDAC demonstrated an acceptable safety and pharmacokenitic profile in patients aged ≥65 years with treatment-naive AML who are not eligible for an intensive anthracycline-containing induction chemotherapy. Clinical remission was achieved in the majority of patients. The median OS has not been reached. A substantially better survival in responders as compared to non-responders suggests that the improvement is likely due to treatment with venetoclax plus LDAC. Updated responses and survival estimates for all patients, including those in dose expansion phase that were enrolled after the preliminary data cut, will be presented. Disclosures Wei: Novartis: Honoraria, Research Funding. Strickland:Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sanofi: Research Funding; Sunesis Pharmaceuticals: Consultancy, Research Funding; Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding. Fiedler:Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; Kolltan: Research Funding; Novartis: Consultancy; Teva: Other: Travel; Ariad/Incyte: Consultancy; Gilead: Other: Travel; Pfizer: Research Funding; GSO: Other: Travel. Martinelli:MSD: Consultancy; Celgene: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Consultancy; BMS: Speakers Bureau; Novartis: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Fakouhi:AbbVie Inc.: Employment, Other: may own stock. Darden:AbbVie Inc.: Employment, Other: may own stock. Dunbar:AbbVie Inc.: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Agarwal:AbbVie Inc.: Employment, Other: may own stock. Salem:AbbVie Inc.: Employment, Other: Stocks or options. Mabry:AbbVie Inc.: Employment, Other: May own stock. Hayslip:AbbVie Inc.: Employment, Other: May own stock.

7007Background: Treatment options for older patients (pts) with acute myelogenous leukemia (AML) unfit for intensive chemotherapy are limited. Expected complete remission rates for low-dose cytarabine (LDAC) are about 10% in this population. Targeting the pro-survival molecule BCL-2 has demonstrated clinical efficacy as a therapeutic strategy in various hematologic malignancies. Venetoclax (VEN), a selective BCL-2 inhibitor, shows synergy with cytarabine in several AML cell lines and primary samples. Methods: This is a non-randomized, open-label phase 1/2 dose-escalation/expansion study of VEN + LDAC, in treatment-naive AML pts ≥ 65 years not eligible for intensive chemotherapy. Pts receive oral VEN once daily (QD) on days 1‒28 and subcutaneous LDAC 20 mg/m2 QD on days 1‒10 of each 28-day cycle. VEN dose escalation follows a 3 + 3 design; dose-limiting toxicities (DLTs: grade 4 toxicity, platelet count < 25,000/μL, or absolute neutrophil count < 500/μL within 14 days of last VEN dose) areassessed during c...

Follicular lymphoma (FL) is an indolent lymphoma that generally responds well to treatment. However, individuals with FL commonly face multiple complex treatment decision-making (TDM) experiences because it frequently follows a relapsing and remitting course. This study explored TDM and distress among individuals with FL (N = 32). Results indicated that most participants reported little decisional conflict or regret and wanted to be actively involved in TDM. However, more than 25% of participants reported clinically-relevant cancer-specific distress, and 60% indicated moderate or higher anxiety symptoms. Research is needed to clarify the cause and course of the psychological distress revealed in this study.

Numerous clinical trials have demonstrated that immunomodulating diets (IMDs) reduce treatment complications such as the risk of acquired infections, length of hospital stay, and wound complications in patients receiving planned surgery. These complications are possibly exacerbated by malnutrition at the time of surgery, resulting in decreased cell-mediated and humoral immune responses, which can be improved with the utilization of IMDs both prior to and following surgery. Although numerous randomized studies have investigated IMDs in the surgical setting, IMDs have not been well studied to evaluate whether their use improves outcomes for other patient groups with high incidence of malnutrition and acquired infections. Patients receiving stem cell transplantation following preparative myeloablative chemotherapy for treatment of a hematologic malignancy would be a prime example of another patient group who would share these characteristics. Given the proposed mechanism of action by which IMDs have aided recovery after surgery, it is reasonable to expect that IMDs may aid recovery after stem cell transplantation, and current preclinical and clinical data support the need for further clinical studies.

Learning Objectives After completing this course, the reader will be able to: Outline the five steps that comprise shared decision making.Identify specific tactics that can be used to engage a patient in a shared decision making process. This article is available for continuing medical education credit at CME.TheOncologist.com Background. There is growing interest by patients, policy makers, and clinicians in shared decision making (SDM) as a means to involve patients in health decisions and translate evidence into clinical practice. However, few clinicians feel optimally trained to implement SDM in practice, and many patients report that they are less involved than they desire to be in their cancer care decisions. SDM might help address the wide practice variation reported for many preference-sensitive decisions by incorporating patient preferences into decision discussions. Methods. This paper provides a perspective on how to incorporate SDM into routine oncology practice to facilitate patient-centered communication and promote effective treatment decisions. Oncology practice is uniquely positioned to lead the adoption of SDM because of the vast number of preference-sensitive decisions in which SDM can enhance the clinical encounter. Results. Clinicians can facilitate cancer decision making by: (a) determining the situations in which SDM is critical; (b) acknowledging the decision to a patient; (c) describing the available options, including the risks, benefits, and uncertainty associated with options; (d) eliciting patients' preferences; and (e) agreeing on a plan for the next steps in the decision-making process. Conclusion. Given recent policy movements toward incorporating SDM and translating evidence into routine clinical practice, oncologists are likely to continue expanding their use of SDM and will have to confront the challenges of incorporating SDM into their clinical workflow. More research is needed to explore ways to overcome these challenges such that both quality evidence and patient preferences are appropriately translated and incorporated into oncology care decisions.

Purpose A recent Intergroup trial showed that receiving adjuvant rituximab after having a second remission from follicular lymphoma (FL) improved progression-free and overall survival (OS). The current study was conducted to determine the incremental cost-effectiveness ratio of this strategy in the United States. Patients and Methods We constructed a transition state model to estimate the incremental cost-effectiveness ratio of extended adjuvant rituximab for 2 years for patients having a second FL remission. Event-free and OS rates were estimated from the recently published Intergroup trial. These were adjusted to reflect the contribution of non-cancer—specific mortality for patients aged 65–70 years, a more commonly affected age group than in the Intergroup trial, which had a median age of 54 years. Previously reported quality of life and cost estimates were obtained from peer-reviewed sources. Results Five years after a second induction with R-CHOP (rituximab with cyclophosphamide/doxorubicin/vincristine/prednisone), disease-free survival is expected to be 47% and 22%, and the OS rates are estimated to be 73% and 61% for extended adjuvant rituximab and observation, respectively, during the second remission. The discounted incremental cost-effectiveness ratio for the addition of adjuvant rituximab is estimated to be $19,522 per quality-adjusted life-years gained. Conclusion Extended adjuvant rituximab offers a clinical benefit to patients aged 65–70 years who have a second remission from FL at a cost generally acceptable to the US healthcare system.

Background COX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-κB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors. Methods Patients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days) or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days), in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily. Results No dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease. Conclusion The combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated. Trial registration number NCT00290680.

Infusion-related reactions during administration of monoclonal antibody therapy are often mild and unlikely to recur with subsequent treatment. If patients experience another severe reaction upon reattempting treatment, future treatments with the same agent are typically not pursued. It is unclear whether different monoclonal antibodies that bind the same tumor cell or antigen are likely to induce similar infusion reactions. Here, we report the case of a patient with repeated severe infusion reactions with rituximab who subsequently safely received treatment with iodine-131 tositumomab and discuss the relevant literature.

Purpose Chemotherapy-induced cognitive impairment (CICI) is a common sequelae of cancer therapy. Recent preclinical observations have suggested that CICI can be mediated by chemotherapy-induced plasma protein oxidation, which triggers TNF-α mediated CNS damage. This study evaluated sodium-2-mercaptoethane sulfonate (Mesna) co-administration with doxorubicin to reduce doxorubicin-induced plasma protein oxidation and resultant cascade of TNF-α, soluble TNF receptor levels and related cytokines. Methods Thirty-two evaluable patients were randomized using a crossover design to receive mesna or saline in either the first or second cycle of doxorubicin in the context of a standard chemotherapy regimen for either non-Hodgkin lymphoma or breast cancer. Mesna (360 mg/m2) or saline administration occurred 15 minutes prior and three hours post doxorubicin. Pre-treatment and post-treatment measurements of oxidative stress, TNF-α and related cytokines were evaluated during the two experimental cycles of chemotherapy. Results Co-administration of mesna with chemotherapy reduced post-treatment levels of TNF-related cytokines and TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (p = 0.05 and p = 0.002, respectively). Patients with the highest pre-treatment levels of each cytokine and its receptors were the most likely to benefit from mesna co-administration. Conclusions The extracellular anti-oxidant mesna, when co-administered during a single cycle of doxorubicin, reduced levels of TNF-α and its receptors after that cycle of therapy, demonstrating for the first time a clinical interaction between mesna and doxorubicin, drugs often coincidentally co-administered in multi-agent regimens. These findings support further investigation to determine whether rationally-timed mesna co-administration with redox active chemotherapy may prevent or reduce the cascade of events that lead to CICI. Trial Registration clinicaltrials.gov NCT01205503.

Rasburicase is currently approved at a dosage of 0.15-0.2 mg/kg once/day for 5 days in pediatric patients with cancer to lower plasma uric acid concentrations and manage tumor lysis syndrome (TLS). Information on rasburicase dosing in adults is limited, with some data on using rasburicase as a single dose instead of multiple daily doses. Therefore, we evaluated the efficacy of a single dose of rasburicase for preventing or managing TLS in adults. We collected retrospective data for 11 adults with hematologic malignancies who received a single 6-mg dose of rasburicase. All patients received intravenous hydration with urinary alkalinization and allopurinol; however, due to adverse reactions, two patients received short courses of allopurinol. Only patients at high risk for TLS (e.g., large tumor burden, increasing uric acid concentration) or those with TLS received rasburicase. The single dose of rasburicase 6 mg resulted in a median 0.0773-mg/kg dose (range 0.0232-0.1361 mg/kg). The single 6-mg dose rapidly lowered uric acid concentrations in 10 of the 11 patients. The median uric acid concentration of 11.7 mg/dl (range 7.4-17.4 mg/dl) declined to 2.0 mg/dl (range 0.5-15.4 mg/dl) within a day after rasburicase administration (p=0.022). In these 10 patients, uric acid concentrations remained low despite subsequent chemotherapy, and none required additional rasburicase doses. The only patient who did not respond to the single 6-mg rasburicase dose was a morbidly obese man (259 kg, body mass index 87 kg/m2) who subsequently responded to an additional dose of rasburicase 12 mg. These results warrant further investigation of a single 6-mg dose of rasburicase in adults with TLS or at high-risk for developing TLS.

Background: In diffuse large B-cell lymphoma (DLBCL), a MYC-rearrangement (MYC-R) is present in approximately 10% of cases and has been associated with an inferior outcome following R-CHOP chemotherapy. In a previous report that retrospectively analyzed the prognostic impact of a MYC-R on survival following DA-EPOCH-R, patients with a MYC-R had a similar outcome to MYC negative cases (4 year EFS of 83% versus 76% respectively: p=0.46 Ann Oncol 2011 (22) Suppl 4 # 71). We set out to prospectively validate these results in a multicenter study. Methods: Patients were newly diagnosed with DLBCL or B-cell lymphoma unclassifiable (BCL-U) with features intermediate between DLBCL and Burkitt lymphoma (BL). Only cases that harbored a MYC translocation by fluorescent in-situ hybridization (FISH) or conventional cytogenetic testing were included in this report. Treatment consisted of 6 cycles of DA-EPOCH-R. R esults: 52 patients were included in this preliminary analysis. Characteristics were median (range) age 61 (29-80) years; male sex 37 (71%); stage III or IV disease 38 (73%); IPI score 0-2 in 35% versus 3-5 in 65%; HIV positive 4 (7%). Histologic diagnosis was DLBCL in 45 (86%) and BCL-U in 7 (14%). All cases had a MYC-rearrangement. BCL2 was rearranged in 14/31 (45%) and overexpressed by IHC in 24/43 (56%) cases tested. There were 3 deaths secondary to infectious complications and otherwise toxicities were similar to previous reports of the regimen. At a median follow-up time of 14 months, progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 79%, 86% and 77% respectively for all patients. PFS was 87% and 64% in cases that were FISH positive (double-hit) and IHC positive for BCL2 respectively. Conclusions: Albeit short follow-up, DA-EPOCH-R in MYC-R DLBCL demonstrates promising activity in a multicenter prospective setting. Further analysis of this data is planned with central pathology review of cases and longer follow-up. The principal arm of this study testing the regimen in BL remains open to accrual (NCT01092182). Figure 1 Figure 1. Disclosures LaCasce: Seattle Genetics, Inc.: Research Funding.

Background Amplification and/or over-expression of the mitotic Aurora A kinase (AAK) have been reported in a variety of tumors. The investigational, selective, AAK inhibitor MLN8237 (alisertib) has shown signs of anti-tumor activity in pts with hematologic malignancies including aggressive non-Hodgkin lymphoma (NHL). Over-expression of AAK leads to resistance to microtubule targeted agents such as vincristine (V) and inhibiting AAK leads to synergy in the presence of these agents (Mahadevan D et al. CCR 2012). The combination of MLN8237 (M) + rituximab (R) ± V has shown synthetic lethality in pre-clinical B-NHL mouse models (ibid) supporting clinical evaluation of this combination; we report the safety and recommended phase 2 dose (RP2D) from the phase 1 clinical data of this MR ± V combination in pts with aggressive B-NHL. Methods Adults with CD20+ B-NHL after 1–4 prior regimens (including ASCT) and ECOG PS 0–2 were eligible. In part 1 (MR), pts received one dose level of M 50 mg BID days 1–7 + R 375 mg/m2 IV day 1 in 21-day cycles (up to 8) in combination, followed by single agent M. In part 2 (MRV), M dose escalation followed a 3+3 design (M starting dose: ∼50% of MR RP2D [30mg BID] days 1–7 + R 375 mg/m2 IV on day 1 + V 1.4 mg/m2 [max, 2 mg] IV on days 1 and 8 of 21-day cycle). The RP2D was determined as the dose level at which Results As of 16 July 2013, 35 pts were enrolled (28 DLBCL, 1 transformed follicular, 1 Burkitt, and 5 mantle cell) with data entered for 32 pts (21 male) at time of data cut-off (part 1, n=13; part 2, n=19 [MLN8237: 30 mg, n=4; 40 mg n=12; 50 mg, n=3]). 1 pt in the MR cohort and 8 pts in the MRV cohorts continue on treatment. Pt demographics, exposure, and safety data are shown in the table. MR was well tolerated with 1 DLT; therefore M 50 mg BID x 7 d + R 375mg/m2 was the recommended regimen for this doublet. For the MRV triplet the RP2D was M 40 mg BID. Common grade (G) ≥3 drug-related AEs across the cohorts included: thrombocytopenia, leukopenia, neutropenia, fatigue and anemia. To date, 26 pts have discontinued treatment (15 progressive disease [PD], 5 AEs [including 2 unrelated deaths, unrelated G4 T7 spinal cord mass and compression, G1 related pulmonary fibrosis, G2 unrelated cough and dysphagia], 3 symptomatic deterioration, 2 other, 1 withdrawal by subject). An additional unrelated, on-study death occurred in a pt who had discontinued treatment due to PD. At the MR RP2D combination, MLN8237 median Tmax was 2 hr and geometric mean steady-state AUC0-12hr was 18,960 nM*hr (n=11, CV: 61.2%), which is consistent with what was achieved in M single agent at 50 mg BID. Assessment of the effect of MLN8237 on vincristine PK is ongoing. 12 pts administered MR were response evaluable; 1 50 y male pt with DLBCL had a complete response (CR), 2 pts had partial response (PR) including one 79 y male pt with DLBCL ongoing at 29 cycles, and 5 pts had stable disease (SD) for up to 13 cycles. 8 MRV pts are currently response evaluable (M 30 mg, n=3; 40 mg, n=5); one 78 y male pt with DLBCL in the 30 mg cohort had CR; at the RP2D (40 mg BID cohort) one 71 y male with non- germinal center B-cell-like DLBCL and having progressed following prior transplant had CR; one 66 y male pt with large B-cell had PR, 5 pts had SD. Response assessments are pending for 5 pts. Enrollment continues to the MRV RP2D to complete the required number of PK-evaluable pts. Conclusions MR ± V is overall well tolerated and has shown preliminary anti-tumor activity in pts with relapsed/refractory B-cell lymphomas. Disclosures: Off Label Use: Use of the investigational agent MLN8237 in combination in patients with aggressive B-cell NHL. Persky:Millennium: The Takeda Oncology Company: Research Funding. Mahadevan:Novartis: Honoraria; Millennium: The Takeda Oncology Company: Honoraria. Miller:Spectrum: Research Funding; Abbott Laboratories: Research Funding. Hayslip:Celgene: Research Funding. Park:TEVA: Research Funding; Seattle Genetics, Inc.: Research Funding. Ruan:Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Rosen:Disney Family Cancer Center: Research Funding. Padmanabhan Iyer:Millennium: The Takeda Oncology Company: Research Funding. Zhang:Takeda Pharmaceutical Company Ltd.: Equity Ownership; Millennium: The Takeda Oncology Company: Employment. Zhou:Millennium: The Takeda Oncology Company: Employment. Dansky Ullmann:Millennium: The Takeda Oncology Company: Employment. Leonard:Millennium: The Takeda Oncology Company: Employment, Equity Ownership.

Background Dysregulation of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway signaling has been implicated in the pathogenesis of lymphoma. SAR245409 is a potent inhibitor of class I PI3K isoforms (α, β, γ and δ) and also inhibits mTORC1 and TORC2. In the phase 1 dose-expansion cohort of study TED11440 (NCT00485719), SAR245409 showed promise in several lymphoma subtypes: 1 complete response (CR) in a transformed lymphoma and 2 partial response (PR) [1 diffuse large B cell lymphoma (DLBCL) and 1 mantle cell lymphoma (MCL)] and 3 patients with stable disease (SD) longer than 3 months [1 follicular lymphoma (FL), 1 MCL and 1 Hodgkin Lymphoma] (Papadopoulos et al. ASH 2011). The Sanofi sponsored study ARD12130 (NCT01403636) is an ongoing multicenter, multinational, open-label, phase 2 study of SAR245409 in patients with lymphoproliferative malignancies enrolling on 4-arms: FL, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), MCL and DLBCL. Preliminary Stage 1 results from FL patients (pts) are reported. Methods Eligible pts for the FL arm had relapsed or refractory FL (Grade 1, 2, or 3a) with no clinical suspicion of transformation to an aggressive subtype and who had received ≥2 but ≤ 6 prior chemotherapy regimens. Pts were treated with SAR245409 at 50 mg twice daily orally until disease progression or withdrawal for other reasons including toxicity. Tumor response was based on modified International Working Group response criteria. A Simon 2-stage design was used to evaluate the primary efficacy endpoint of objective response rate (ORR) in the FL arm; if at least 6 of the first 24 evaluable patients in Stage 1 achieved an objective response (OR), the study would continue to Stage 2 with a total of 45 evaluable patients. If 14 or greater total patients among the 45 total evaluable achieved OR, the null hypothesis would be rejected. Results Twenty-eight FL patients were enrolled to stage 1. Median age was 62 years (range 38-87 years), 60% were males, 78% of pts had stage III/IV disease and 64% had received ≥ 3 prior lines of treatment. At data cutoff (end of March 2013), 15/28 (54%) pts had discontinued treatment: 10 due to disease progression, 2 due to adverse events (AEs) (grade 2 pneumococcal pneumonitis and grade 3 diarrhea), 2 due to consent withdrawal, and 1 due to non-compliance. Median treatment duration was 32 weeks (range 4-72 weeks). Among the first 24 evaluable patients in the per protocol primary efficacy population, the ORR was 50% (2 CR and 10 PR); 14 (58%) had progression free survival (PFS) ≥ 24 weeks and the median PFS has not yet been reached with a median follow-up of 8 mos. Eighty-three percent of pts experienced treatment emergent AEs (TEAEs), with the most common (≥ 10%) TEAEs regardless of relationship including diarrhea, pyrexia, fatigue, cough, decreased weight, vomiting, decreased appetite, nausea, anemia and headache. Fifty-five percent of pts presented with Grade 3/4 TEAES (any relationship) which included lymphopenia (13%) and the following TEAEs in less than 10% of pts: anemia, pneumonia, neutropenia, alanine aminotransferase elevation (ALT), diarrhea, hypokalemia, hyperglycemia, thrombocytopenia, decreased appetite and general physical health deterioration. Fifty-four percent of pts had serious adverse events but only the following events were reported as related to SAR245409: general physical health deterioration, diarrhea, hypophosphatemia, lung infection and cortical cataracts. The pre-specified criteria for the primary endpoint of ORR of at least 25% was achieved in Stage 1 and the FL arm has been expanded to enroll Stage 2. Conclusions Single agent SAR245409 exhibited clinical activity and an acceptable safety profile in patients with relapsed or refractory FL. Disclosures: Brown: Novartis: Consultancy; Avila: Consultancy; Vertex: Consultancy; Sanofi Aventis: Consultancy; Onyx: Consultancy; Emergent: Consultancy; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy; Genzyme: Research Funding. Off Label Use: The abstract shows scientific information on SAR245409 which is an investigational product developed by Sanofi. This investigational product is not approved by any health authority for any indication. Karlin:Celgene: Expert board Other, Honoraria; Janssen: Honoraria. Hayslip:Sanofi: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Celgene: Research Funding. Wagner-Johnston:Celgene: Research Funding. Cartron:Roche: Consultancy, Honoraria, Speakers Bureau; GSK: Honoraria; LFB: Honoraria. Ribrag:Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Bayer: Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; J&J: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Opat:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Tilly:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Takeda: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Research Funding. Janssens:Amgen: Speakers Bureau; Roche: Speakers Bureau; GSK: Speakers Bureau. Offner:Lilly: Membership on an entity’s Board of Directors or advisory committees. Ganguly:Sanofi: Research Funding. Millenson:Sanofi: My spouse was previously employed by Sanofi (within the past 24 months, ending April 2013) Other. Bron:Sanofi: Research Funding. Xu:Sanofi: Employment. Ruiz-Soto:Sanofi: Employment. Kersten:Sanofi: Honoraria, Member of steering committee for this study Other.

Introduction The value of Rituximab with High dose chemotherapy and autologous stem cell transplant (auto-HCT) has been evaluated in some retrospective studies. It is noted that the addition Rituximab to auto-HCT results in significant improvement in overall (OS) and disease free survival (DFS). However, it is unclear that the addition of Rituximab with auto-HCT would result in significant benefit in patients who have received prior Rituximab based therapy. Methods We retrospectively evaluated twenty seven consecutive patients who had B cell non-Hodgkin's lymphoma (NHL) and underwent auto- HCT at Markey cancer center between January 2010 and December 2012. All patients received 375 mg/m2of Rituximab with chemotherapy. Rituximab was not administered with high dose chemotherapy (BEAM: BCNU, Etoposide, Cytarabine and Melphalan) prior to auto-HCT. All patients received GCSF starting day 5 after auto-HCT. Results There were 27 patients who underwent auto-HCT for NHL. Median age of the patients was 60 years (36-72 years). Nineteen patients were male and 8 patients were female. Fifteen patients were in complete remission (CR) and the rest were in partial remission (PR). Patients had: Diffuse large B cell lymphoma (DLBCL=11 patients): Mantle cell lymphoma (MCL=13 patients): follicular lymphoma (3 patients). Median CD 34 count of infused cells was 4.14 x 106 cell/kg (2.26- 9.45). Median time to neutrophil recovery was 11 days (9-14). Median lymphocyte count at day 30 after auto HCT was 1130 x 10 6/l (320- 5180). After a median follow up of 7.9 months (3.0- 32.4) eight patients had relapsed. Five patients who had relapsed had refractory disease before auto-HCT. Non -Relapse mortality (NRM) is shown in figure 1. Median overall survival and disease free survival were not reached. Seventy percent patients had not relapsed. We did not find any factors associated with relapse. Conclusion We performed a retrospective study to evaluate the impact of Rituximab with high dose chemotherapy and in patients with NHL. Review of literature showed that median 2 year and 5 year OS was 80% and 69% in patients who received Rituximab with auto HCT. Median 2 year DFS was 67%. In our study 70% patients were relapse free at a median follow up of 8 months. We would need a longer follow up to determine the efficacy of Rituximab with auto- HCT in patients with NHL who had prior exposure to Rituximab. Disclosures: Off Label Use: The use of Thymoglobulin® for GVHD prevention. Hayslip:Sanofi: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Celgene: Research Funding.