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Venetoclax, a potent B-cell lymphoma-2 (BCL-2) inhibitor, has demonstrated clinical efficacy in chronic lymphocytic leukemia (CLL). VENICE II is an open-label, single-arm, phase 3b study (NCT02980731) evaluating the impact of venetoclax monotherapy (400 mg once daily) for ≤2 years on health-related quality of life (HRQoL) of patients with relapsed/refractory CLL. The primary endpoint was mean change in the global health status (GHS)/quality of life (QoL) subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) from baseline to Week 48. Overall, 210 patients received ≥1 dose of venetoclax; median treatment duration was 67.4 weeks. The primary endpoint was met with mean improvement of +9.3 points (n = 156, 95% confidence interval 6.1-12.5; p=.004) in GHS/QoL. At Week 48, clinically meaningful improvements were observed for role functioning, fatigue, and insomnia domains of EORTC QLQ-C30, suggesting venetoclax monotherapy has a positive impact on HRQoL. No new safety signals were reported.

Purpose: We previously reported a 44% overall response rate (ORR) with the oral BCL-2 inhibitor venetoclax in a phase I study of relapsed/refractory non–Hodgkin lymphoma (NHL). Complete response (CR) was observed in patients with mantle cell lymphoma [(MCL), 21%, n = 6/28] and follicular lymphoma [(FL), 17%, n = 5/29], and partial response (PR) noted in several patients with Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL). Here, we report the long-term outcomes of these four cohorts. Patients and Methods: All patients (n = 106) received venetoclax monotherapy in dose cohorts of 200 to 1,200 mg daily until disease progression or unacceptable toxicity. ORR, progression-free survival (PFS), duration of response (DoR), and adverse events (AEs) were evaluated. Results: At a median follow-up of 38.5 months (range, 30.0–46.5), the median PFS for all 106 patients was 5.4 [95% confidence interval (CI), 3.5–8.4] months (FL, 10.8; MCL, 11.3; MZL, 21.2; and WM, 30.4). The median DoR was 14.9 (95% CI, 9.7–27.6) months (FL, 26.6; MCL, 15.7; MZL, 20.1; and WM, 25.3). Achievement of CR versus PR predicted longer DoR in both MCL (31.5 vs. 10.1 months) and FL (37.6 vs. 9.7 months). All grade hematologic AEs were infrequent: neutropenia (19%), anemia (19%), and thrombocytopenia (17%), with no new cytopenias after 2 years on therapy. Nonhematologic AEs included nausea (49%), diarrhea (46%), fatigue (44%), with decreased incidence after 1 year. Conclusions: Venetoclax monotherapy has a manageable safety profile and achieves durable responses in a subset of patients with FL, MCL, WM, and MZL, particularly in those who achieve CR. Further research is warranted on combination strategies to enhance the durability of response to venetoclax.

We report long-term follow-up of the phase 1b study of venetoclax and rituximab (VenR) in patients with relapsed chronic lymphocytic leukemia (CLL), including outcomes with continuous or limited-duration therapy. Patients received venetoclax daily (200-600 mg) and rituximab over 6 months and then received venetoclax monotherapy. Patients achieving complete response (CR), CR with incomplete marrow recovery (CRi), or undetectable minimal residual disease (uMRD) assessed by flow cytometry (2 years off venetoclax (range, 2.1-6.4). Four patients were retreated with VenR, with partial responses observed in the 3 evaluable to date. VenR induced deep responses that were highly durable with either continuous or limited-duration therapy. Retreatment with VenR induced responses in patients with CLL progression after discontinuing therapy. Continuous exposure to venetoclax in deep responders does not appear to provide incremental benefit.

International audience; Venetoclax (Ven) is a selective small-molecule inhibitor of BCL-2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open-label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21-day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL-2) and BCL2L1 (BCL-XL ) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow-up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF-kB. VenDex demonstrated efficacy and manageable safety in heavily-pre-treated patients with t(11;14) R/R MM.

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.

Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-XL/BCL2 inhibitor, may allow targeting of both BCL2 and BCL-XL without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose-escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients Significance: In this phase I study, venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Responses were observed in patients across histologic and genomic subtypes and in those who failed available therapies including stem cell transplant. See related commentary by Larkin and Byrd, p. 1324. This article is highlighted in the In This Issue feature, p. 1307

Background: The combination of venetoclax (Ven), a selective oral B-cell lymphoma-2 inhibitor, and obinutuzumab (Obi), a type II anti-CD20 monoclonal antibody, is approved as a 12-cycle fixed duration treatment for adult patients (pts) with previously untreated chronic lymphocytic leukemia (CLL). In the CLL14 study, pts with CLL and coexisting conditions treated with Ven-Obi achieved high rates of undetectable minimal residual disease (uMRD), translating into a 4-year progression free survival (PFS) of 74%. Despite these favorable results, disease relapse may occur after cessation of the fixed duration therapy, particularly for those with higher risk genetics, such as TP53 aberrancy and unmutated IgHV. A key unanswered question in the field is, for pts who initially had a clinical response after first-line (1L) Ven-Obi treatment, how much clinical benefit would they receive from retreatment with Ven-Obi after developing progressive disease (PD)? Retreatment with Ven-Obi would provide a line of treatment in addition to other regimens such as BTK inhibitors. In patients with relapsed/refractory (R/R) CLL, one of the current standard therapies is the combination of Ven and rituximab (R). Updated results from the phase 3 MURANO trial of 24-cycle fixed duration Ven-R demonstrated that patients with disease progression after treatment completion and clinical response had a best overall response rate (ORR) of 72.2% upon Ven-R retreatment. The results of the MURANO study and the favorable safety profile of Ven-Obi suggest that retreatment with Ven-Obi after initial therapy with Ven-Obi may be effective in pts with relapsed CLL. The present study is the first prospective clinical trial to evaluate the efficacy and safety of retreatment with Ven-Obi at the time of PD in pts who had initially responded to 1L Ven-Obi for at least 12 months (mo) after completing therapy. Study Design and Methods: Pts are eligible for this multicenter, open-label, non-randomized, phase 2 study (NCT04895436) if they have a diagnosis of CLL according to iwCLL criteria, were treated with Ven-Obi fixed duration therapy, and achieved a best response of either complete remission (CR), CR with incomplete marrow recovery (CRi), nodular partial remission (nPR), or partial remission (PR). Pts must also have had at least 12 mo of remission between the last dose of Ven and PD. Pts will be divided into two cohorts: PD more than 2 years after completing 1L treatment (Co-1), and pts with PD between 1-2 years post 1L therapy (Co-2). Pts receive Obi (100 mg intravenously [IV] on Day [D] 1 and additional 900mg on either D1 or D2, then 1000mg on D8 and D15 of Cycle [C] 1 and subsequently on D1C2-6). Ven is administered orally once daily (QD) beginning on C1D22, including a 5-week ramp-up period (weekly dose increases from 20, 50, 100, 200, to 400mg QD), followed by 400mg QD thereafter on 28-day cycles, for a total of 12 or 24 cycles in Co-1 and Co-2, respectively. Pts in Co-2 with detectable MRD (≥10 -4) after 15 months of therapy may continue Ven monotherapy beyond mo 24 at the investigator's discretion. The primary objective is to assess the efficacy of Ven-Obi in Co-1 as measured by ORR, defined as a proportion of pts achieving a best response of PR/nPR or CR/CRi at the end of combination therapy (EOCT) assessment (EOCT + 3 mo). Key secondary objectives are CR/CRi at EOCT, CR/CRi rate at end of therapy (EOT), ORR at EOT, time to response (TTR), duration of response (DOR), PFS, overall survival (OS), time to next treatment (TTNT), and uMRD (10 -4)rate at EOCT and EOT. Safety endpoints include the type, frequency, and severity of treatment-emergent adverse events (AEs), and serious AEs. Prespecified exploratory biomarker endpoints include MRD kinetics up to 12 mo post-treatment, and correlations of baseline characteristics of IgHV, TP53 mutation, and del (17p) status with outcomes. Point and interval estimates will be used to characterize the efficacy of Ven-Obi retreatment; exact binomial (Clopper-Pearson) 95% confidence intervals will be provided alongside the corresponding point estimates for the response rates of interest (ORR, CR rate, and uMRD rate), while Kaplan-Meier methodology will be used to summarize the time-to-event endpoints (DOR, PFS, OS, and TTNT). Finally, descriptive statistical summaries will be reported for several patient-reported outcome (PRO) measures, including the EORTC QLQ-CLL-17, EQ-5D-5L, and FACIT-F. Figure 1 Figure 1. Disclosures Davids: Takeda: Consultancy; Novartis: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Merck: Consultancy; MEI Pharma: Consultancy; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Research Funding; Research to Practice: Consultancy; Ascentage Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Surface Oncology: Research Funding; Astra-Zeneca: Consultancy, Research Funding; Eli Lilly and Company: Consultancy; Genentech: Consultancy, Research Funding; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Porro Lurà: F. Hoffmann - La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Sinai: AbbVie Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Sail: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Pesko: AbbVie: Current Employment, Current equity holder in publicly-traded company. Pai: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Komlosi: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Hallek: Roche: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Mundipharma: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau. Brown: Beigene: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Eli Lilly and Company: Consultancy; Nextcea: Consultancy; Genentech/Roche: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Novartis: Consultancy; Morphosys AG: Consultancy; MEI Pharma: Consultancy; Acerta/Astra-Zeneca: Consultancy; Abbvie: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; TG Therapeutics: Research Funding; Sun: Research Funding; SecuraBio: Research Funding; Loxo/Lilly: Research Funding; Gilead: Research Funding; Rigel: Consultancy; Catapult: Consultancy. Al-Sawaf: AbbVie: Honoraria, Research Funding; Adaptive: Honoraria; AstraZeneca: Honoraria; Beigene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding. OffLabel Disclosure: Venetoclax is a B-cell lymphoma 2 inhibitor approved in combination with Obinutuzumab, a type II anti-CD20 monoclonal antibody, for first-line therapy for chronic lymphocytic leukemia.

Background: Venetoclax (VEN), an oral B-cell lymphoma 2 inhibitor, is approved for use in adult patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). As a targeted and highly active antitumor agent, VEN induces rapid and profound tumor reduction. Inpatient monitoring for initial doses of VEN is recommended by US Prescribing Information for pts with medium tumor burden and reduced renal function or high tumor burden. Administration of debulking agents, such as obinutuzumab (G), help reduce tumor burden and, consequently, facilitate subsequent administration of VEN in the outpatient setting. However, tumor reduction data are needed to definitively establish the utility of a debulking strategy. This study performed disease restaging after every 2 cycles of debulking to evaluate the safety and efficacy of G ± bendamustine (B) as a debulking regimen before VEN treatment in the outpatient community setting. The safety and efficacy of subsequent VEN+G treatment after debulking was also evaluated. Methods: This open-label, Phase 3b study (NCT03406156) enrolled adult pts with previously untreated CLL/SLL (except those with 17p deletion) who had medium (any lymph node [LN] 5 to Results: Of 120 pts treated, 81 received G for debulking and 39 received G+B. As of 13 May 2021, 2 pts remained on study treatment, 108 were in posttreatment follow-up, and 10 had discontinued the study for reasons including death (n=7), withdrawn consent (n=2), and COVID-19 infection (n=1). At baseline, 82.5% of pts had ALC ≥25x10 9/L, 33.3% had LN ≥5 cm, and 24.2%/75.0%/0.8% had high/medium/low tumor burden, respectively. Low tumor burden was achieved in 91.6% (109/119) of evaluable pts receiving G±B debulking. In the all-treated population (N=120), the objective response rate (ORR) was 90.0% and the CR/CRi rate was 35.8%. Among pts receiving VEN with disease assessment at EoT (N=76), the ORR was 98.7% and the CR/CRi rate was 44.7% (Table). The best uMRD4 rates in peripheral blood were 89.2% (107/120) for all-treated and 98.2% (107/109) for evaluable pts. Among evaluable pts, the uMRD4 rates were 100% (100/100) and 97.1% (68/70) at EoCT and EoT, respectively. Among pts with MRD assessments at both timepoints (N=67), 19.4% had a deepening of their MRD response from EoCT to EoT, and 67.2% maintained the same MRD level (Figure). At a median follow-up of 24.0 mo, 7 deaths (6 related to COVID-19 infection and 1 from cardiac complication after pancreatic mass resection) and no incidences of disease progression were reported; the estimated 18-mo PFS was 94.1%. In pts treated with G vs G+B debulking, respectively, the incidences of Grade ≥3 TEAEs were 71.6% vs 84.6% (most common was neutropenia at 28.4% vs 41.0%) and serious AEs were 23.5% vs 17.9% (most common were pneumonia and COVID-19 pneumonia, each at 3.7% vs 2.6%). Conclusion: In this study, most (91.6%) pts achieved low tumor burden after debulking. The uMRD4 rate was 98.2% among MRD-evaluable pts (89.2% among all pts), with 100% and 97.1% uMRD4 rates at EoCT and EoT, respectively. Overall, these results highlight the utility of G±B as an effective debulking strategy that can facilitate VEN treatment initiation in the outpatient setting. The efficacy and safety results are consistent with other VEN+G trials. Preventive measures for COVID-19 should be continuously emphasized for pts with CLL. Figure 1 Figure 1. Disclosures Flinn: AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Andorsky: AbbVie: Research Funding; Celgene/Bristol Myers Squibb: Consultancy; Celgene/Bristol Myers Squibb: Research Funding; Epizyme: Research Funding; AstraZeneca: Other: served on steering committees; AbbVie: Consultancy. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Yimer: GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Burke: Kura: Consultancy; Epizyme: Consultancy; Kymera: Consultancy; Adaptive Biotechnologies: Consultancy; Roche/Genentech: Consultancy; Beigene: Consultancy, Speakers Bureau; MorphoSys: Consultancy; Verastem: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy; X4 Pharmaceuticals: Consultancy; SeaGen: Consultancy, Speakers Bureau. Fanning: BMS: Speakers Bureau; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genmab: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Speakers Bureau; Takeda: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees. Islas-Ohlmayer: OHC/USON: Current Employment; AbbVie: Honoraria; Rigel: Honoraria, Speakers Bureau. Vizkelety: AbbVie: Current Employment, Current equity holder in publicly-traded company. Pesko: AbbVie: Current Employment, Current equity holder in publicly-traded company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Jiang: AbbVie: Current Employment, Current equity holder in publicly-traded company. Sharman: Pharmacyclics LLC, an AbbVie Company: Consultancy; BMS: Consultancy; Lilly: Consultancy; BeiGene: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy.

This article explores relationship between parametric bootstrap (PB) and objective Bayesian (OB) approaches to test equality of the factor level means (overall mean test) of heteroscedastic one-way analysis of variance (ANOVA) problem. We compared overall mean tests based on PB, OB, and OB using posterior predictive distribution approaches by simulation studies. We also proved that the PB and OB overall mean tests for one-way heteroscedastic ANOVA are asymptotically equivalent.

Background: Improved therapeutic strategies for patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) remain an unmet need. Venetoclax (Ven), a potent, highly selective, oral B-cell lymphoma 2 (BCL-2) inhibitor, and navitoclax (Nav), an oral BCL-2, BCL-XL, and BCL-W inhibitor, directly bind their BCL-2 family member targets to promote apoptosis. Ven and Nav have shown synergistic antileukemic effects in ALL preclinical models, suggesting dependence on BCL-2 family members. The addition of Ven to low-dose Nav may potentiate efficacy without the dose-limiting thrombocytopenia associated with Nav monotherapy (J Clin Oncol. 2012;30:488). Ven in combination with Nav and chemotherapy are under investigation in a Phase 1, multicenter, open-label, dose-escalation study in patients with R/R ALL and LL (NCT03181126). The results of a previous report on the overall study population (adult and pediatric patients) showed the triplet combination was well tolerated, with promising response rates observed (Jabbour, et al. EHA 2020. Abstract 2389). For the first time, reported here are safety, tolerability, pharmacokinetics, and antitumor activity of Ven with Nav and chemotherapy among the pediatric patients treated in that Phase 1 study. Methods: Eligible pediatric patients (aged ≥4- Results: As of June 23, 2020, 18 pediatric patients (pts) have enrolled (12 in dose-escalation; 6 in safety expansion); 13, 3, and 2 pts had B-ALL, T-ALL, and LL, respectively. Among pts in the dose-escalation phase, 6 received 25 mg Nav and 6 received 50 mg. Median age was 10 years (range, 6-16 years), 56% of pts were male, and the median number of prior therapies was 2 (range, 1-6). Median time on study was 10.4 months. All pediatric pts experienced treatment-emergent adverse events (TEAEs), and the most common were febrile neutropenia (50%), vomiting (44%), hyperglycemia (39%), and hypokalemia (39%). Grade 3/4 TEAEs occurred in 89% of pediatric pts, and the most common were febrile neutropenia (50%), neutropenia (33%), thrombocytopenia (33%), and anemia (28%). The only Grade 3/4 nonhematologic TEAEs related to Ven or Nav that occurred in >1 pediatric pt were alanine aminotransferase increased (n=2) and vomiting (n=2). Of 8 dose-limiting toxicities (DLTs), 2 occurred in pediatric pts. The 2 DLTs included delayed count recovery (25 mg Nav) and sepsis (50 mg Nav, occurred after database lock). No pediatric pts experienced tumor lysis syndrome. No Grade 5 TEAEs occurred in pediatric pts; 8 pediatric pts (44%) died from disease progression. Ten pediatric pts (56%) achieved complete response (CR)/CR incomplete recovery (CRi)/CR without platelet recovery (CRp); 7 pts (39%) achieved undetectable MRD. Median overall survival was 11.4 months (95% CI, 2.9 months-not estimable). Eight pts (44%) proceeded to transplantation (n=5) or CAR T-cell therapy (n=3; cells harvested before start of study; Figure). Weight-based dosing of Ven and Nav achieved comparable exposures in pediatric pts. Exploratory correlative biomarker analyses, including BH3 profiling and genomic analyses, are underway and will be presented. Conclusion: In this Phase 1 study, Ven with Nav and chemotherapy was well tolerated and had promising efficacy in heavily pretreated pediatric patients with ALL and LL. Given that there were four DLTs with 100 mg Nav without evidence of increased efficacy, the recommended Phase 2 dose for adult and pediatric patients is 400 mg Ven with 50 mg Nav for patients weighing ≥45 kg and 25 mg Nav for patients weighing Figure Disclosures Rubnitz: AbbVie Inc.: Research Funding. Alexander:Abbvie, Inc.: Other: Travel Support. Laetsch:Bayer: Consultancy, Research Funding; Cellectis: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Khaw:Amgen: Other: Travel Support, Research Funding; Novartis: Other: Travel Support; AbbVie, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Jazz Pharmaceuticals: Research Funding; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: recipient of a share in royalty payments . Pullarkat:Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Opferman:St. Jude Children's Research Hospital: Current Employment; AbbVie, Inc.: Research Funding; National Institutes of Health: Research Funding. Rosenwinkel:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Tong:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Pesko:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Badawi:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Vishwamitra:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Kim:AbbVie, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: may hold stock or other options. Mullighan:Illumina: Consultancy, Honoraria, Speakers Bureau; AbbVie, Inc.: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau. OffLabel Disclosure: Yes, venetoclax is a BCL-2 inhibitor that is FDA approved for some indications. Venetoclax for treatment of acute lymphoblastic leukemia is not an approved indication.

Background: Venetoclax (VEN), a B-cell lymphoma 2 inhibitor, is an oral agent with demonstrated efficacy in patients (pts) with chronic lymphocytic leukemia (CLL). VEN treatment induces rapid tumor reduction, posing a risk for tumor lysis syndrome (TLS), particularly in pts with high tumor burden, and may require inpatient monitoring at the initiation of therapy. Agents such as obinutuzumab (G), ibrutinib, and bendamustine (B) have been used in clinical studies to debulk tumors prior to treatment with VEN. However, the benefits of these debulking regimens could not be established conclusively, as disease restaging was rarely performed. In the present study, disease restaging was performed every 2 cycles to evaluate the efficacy and safety of G, with or without B, as a debulking therapy in untreated pts with CLL, prior to VEN treatment in an outpatient community setting. Methods: This open-label, phase 3b trial (NCT03406156) enrolled adult pts with previously untreated CLL/small lymphocytic lymphoma (excluding those with 17p deletion) who had Eastern Cooperative Oncology Group performance status of ≤1 and medium (any lymph node [LN] 5 to 10 cm or with del(11q) and LN >5 cm. Restaging data were obtained after every 2 cycles of debulking therapy. When low tumor burden was achieved, VEN was administered (5-week ramp-up schedule) as combination therapy with G (VEN+G) for 5 months, and then as monotherapy (VEN mono) for a total of 1 year. Response assessments were scheduled at week 38 and week 65 post-VEN initiation. Adverse events (AEs) were monitored throughout the study. Primary endpoints were the reduction in tumor burden after debulking therapy and the complete remission (CR)/CR with incomplete marrow recovery (CRi) rates of pts subsequently treated with VEN. We report the results of a planned interim analysis when 50 pts had completed their week 38 disease assessment. Results: As of 3 Feb 2020, 117 pts were treated with study drug(s): 80 (68%) received G and 37 (32%) received G+B for debulking; 113 pts were active in study (7 in the debulking phase; 106 completed debulking therapy and initiated VEN, including 26 in posttreatment follow-up). Four pts discontinued study due to withdrawal by pt (n=2; 1 at debulking and 1 at VEN treatment phase) and physician decision (n=1; at VEN treatment phase) and other (n=1; at debulking). At baseline, 85% of pts had ALC ≥25 × 109/L, 9% had LN ≥10 cm, 23% had LN 5-10 cm; 74%/26% had medium/high TLS risk, respectively, per investigator assessment (1 pt with low TLS risk was enrolled and subsequently discontinued). After 2 cycles of debulking therapy, low tumor burden was achieved in 85% (89/105) of evaluable pts: 86% (63/73) with G and 81% (26/32) with G+B. Reductions by pt subgroups and genetic features are presented in Figure. For pts debulked with G, similar debulking efficacy was observed among the subgroups being explored (Figure). Of the 50 pts with a week 38 disease assessment, 17 pts had an initial response of partial remission and await confirmation per IWCLL criteria. Objective response rate was 96% (48/50) overall, with 95% (37/39) for those debulked with G and 100% (11/11) for those debulked with G+B. The rate of CR or CRi was 52% (26/50) overall, with 54% (21/39) achieving CR/CRi for those debulked with G and 45% (5/11) for those debulked with G+B (Figure). More grade ≥3 AEs were observed in pts receiving G+B than those receiving G: debulking, 62% vs 40%; VEN+G, 43% vs 34%; VEN mono, 41% vs 28%. Conclusions: Most pts (85%) achieved low tumor burden after 2 cycles of G±B. Similar debulking efficacy was observed across subgroups in pts debulked with G. In this early efficacy analysis, CR/CRi at week 38 was observed in 52% of pts treated with VEN after the debulking phase. Preliminary efficacy results from this study are consistent with other VEN studies in treatment-naive pts. Current study highlights the efficacy of the debulking strategy prior to treatment with VEN; this may allow more pts to have VEN ramp-up in outpatient setting. Figure Disclosures Flinn: Calithera Biosciences: Research Funding; Forma Therapeutics: Research Funding; F. Hoffmann-La Roche: Research Funding; Celgene: Research Funding; Merck: Research Funding; Curio Science: Consultancy; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Novartis: Research Funding; MorphoSys: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Constellation Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Teva: Research Funding; BeiGene: Consultancy, Research Funding; Curis: Research Funding; Nurix Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Forty Seven: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Takeda: Consultancy, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; Agios: Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; IGM Biosciences: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Great Point Partners: Consultancy; Loxo: Research Funding; Genentech, Inc.: Research Funding. Andorsky:AstraZeneca: Research Funding; Celgene: Research Funding; AbbVie: Honoraria. Melear:Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Manda:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Anz:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Kolibaba:Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Verastem: Honoraria; Cell Therapeutics: Research Funding; Celgene: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Atara Biotech: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Acerta: Research Funding; Compass Oncology: Ended employment in the past 24 months; McKesson Life Sciences: Consultancy; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: travel, accommodations, expenses, . Yimer:Sanofi: Speakers Bureau; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; TG Therapeutics: Consultancy; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Texas Oncology: Current Employment; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Burke:Adaptive: Consultancy; Kura: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau; Roche: Consultancy; Bristol Myers Squibb: Consultancy; Verastem: Consultancy; Astra Zeneca: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy. Fanning:TG Therapeautics: Consultancy; Abbvie: Consultancy; Prisma Health: Current Employment; Sanofi Aventis: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Courtright:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Islas-Ohlmayer:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Kambhampati:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Jiang:AbbVie: Current Employment, Other: may hold stock or options. Pesko:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Vizkelety:AbbVie: Current Employment, Other: may hold stock or stock options.. Sharmokh:AbbVie: Current Employment, Current equity holder in publicly-traded company. Sharman:AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding.

Background/Aims Bcl-2 inhibitor venetoclax (VEN) has demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL). As VEN induces rapid cell death, patients with medium- to high tumor burden (TB) are at greater risk for tumor lysis syndrome (TLS). We explore tumor debulking prior to outpatient VEN initiation. Methods This phase 3b trial enrolled untreated adults with CLL/SLL without 17p deletion, having medium-to high TB. Patients received at least 2 cycles (C), or a maximum of 6 cycles of debulking therapy (Obinutuzumab [G] ± bendamustine [B]). Once achieved low TB, VEN was started with VEN+G initially, then VEN monotherapy. Primary endpoints were reduction in TB after every 2 C of debulking, and IWCLL response rates. Results As of 12/2/2019, 110 patients were included; 76 received G and 34 G+B for debulking. Majority were Conclusions Most patients achieved low TB at C2 of debulking with G±B prior to VEN ramp-up. AE of TLS was reported in 1 patient during VEN phase. Similar Gr ≥3 AEs were observed during VEN phases regardless of debulking agents. Debulking reduced TB and may facilitate outpatient VEN initiation. Abstract was previously published at EHA25.

Background: Novel and more effective therapies for multiple myeloma (MM) have led to increasing overall survival, but most patients (pts) will eventually relapse or become refractory (RR). The proteasome inhibitor (PI) bortezomib (V), the anti-CD38 antibody daratumumab (D), and dexamethasone (d) are key agents for combination therapy in first-line and RR settings. Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in BCL-2-dependent MM cells in vitro. Encouraging clinical efficacy has been observed with Ven monotherapy in t(11;14) pts, and with VenV in pts irrespective of disease genetic background. In view of MM intraclonal heterogeneity, the addition of D to Ven +/- PI is postulated to further enhance antitumor activity of Ven-based regimens in RRMM. Methods: M15-654 (NCT03314181) is an ongoing Phase 1/2, nonrandomized, multicenter study of combination therapy consisting of VenDd +/- V in pts with RRMM. The primary objective is to evaluate the safety, tolerability, and preliminary efficacy of VenDd +/- V. In Part 1, VenDd was evaluated in t(11;14) MM pts who received ≥1 prior line of therapy that included a PI and an immunomodulatory drug (IMiD). In Part 2, VenDVd was evaluated in MM pts irrespective of t(11;14) status who were non-refractory to PIs and received 1 - 3 prior lines of therapy. Each regimen was evaluated in a dose escalation and expansion phase. In each part, Ven dose escalation was initiated at 400 mg daily (QD) and escalated to 800 mg QD if acceptable safety and tolerability were observed. Escalation cohorts had ≥3 pts, and escalation decisions were based on a Bayesian optimal interval design and the number of pts with a dose limiting toxicity (DLT). In Part 1, cycles (C) were 28-day: Ven QD + D 16 mg/kg intravenous (IV) (C1, 2: Days 1, 8, 15, 22; C3 - 6: Days 1, 15; C7+: Day 1) + d 40 mg total weekly. In Part 2, C1 - 8 were 21-day, C9+ were 28-day: Ven QD + D 16 mg/kg IV (C1 - 3: Days 1, 8, 15; C4+: Day 1) + V 1.3 mg/m2 subcutaneous (C1 - 8, Days 1, 4, 8, 11) + d 20 mg (C1 - 3: Days 1, 2, 4, 5, 8, 9, 11, 12, 15; C4 - 8, Days 1, 2, 4, 5, 8, 9, 11, 12) and 40 mg weekly for C9+. Results: As of 13 May 2019, 48 pts were enrolled. Of 24 t(11;14) pts treated in Part 1 with VenDd, median age was 63 (range, 51 - 76), median prior lines of therapy was 2.5 (range, 1 - 8), 14 (58%) had ISS II/III disease, and 24 (100%) received both prior PI and IMiD (46% refractory to PI, 71% refractory to IMiD, 42% double refractory). Of 24 pts treated in Part 2 with VenDVd, median age was 64 (range, 41 - 80), median prior lines of therapy was 1 (range, 1 - 3), 14 (58%) had ISS II/III disease, and 6 (25%) were t(11;14). Twenty-two (92%) pts received prior PI, 17 (71%) received prior IMiD (33% refractory), and 15 (63%) received prior PI + IMiD. The most common adverse events (AEs; VenDd/VenDVd) were fatigue (54%/21%), diarrhea (50%/42%), nausea (33%/38%), insomnia (29%/42%), cough (21%/8%), headache (21%/4%), upper respiratory tract infection (21%/17%), constipation (8%/33%), infusion related reaction (8%/33%), peripheral neuropathy (4%/25%), and dyspepsia (4%/21%). Grade 3/4 AEs were seen in 63%/54% of pts. The most common Grade 3/4 AEs in pts receiving VenDd were neutropenia (13%), fatigue, hyperglycemia, and hypertension (8% each); in pts receiving VenDVd, the most common were insomnia (17%), diarrhea, and thrombocytopenia (8% each). There were 6 pts with infection-related Grade 3/4 AEs (3 VenDd, 3 VenDVd). No AEs of tumor lysis syndrome were observed. Eleven pts had a serious AE (5 VenDd, 6 VenDVd), the most common being pyrexia in 3 pts. One pt treated with VenDd had a DLT of febrile neutropenia, and 1 pt treated with VenDVd died due to progressive disease. No infection-related deaths were seen. Pharmacokinetic analyses demonstrated that addition of D and V did not impact Ven exposure. Median time on study is 3.6 months (m; 8.1 m escalation, 2.8 m expansion) in the VenDd arm and 3.1 m (5.8 m escalation, 2.4 m expansion) in the VenDVd arm. The objective response rate (ORR) was 92% and 88% in pts receiving VenDd and VenDVd, respectively (Table). Conclusions: This first analysis of pts treated with VenDd +/- V demonstrate a tolerable safety profile with encouraging efficacy, notably among t(11;14) pts treated with VenDd who had an ORR of 92%. No new safety signals were observed. Although the study is currently on partial clinical hold, enrolled pts continue to be followed. Analysis will be updated at presentation. Disclosures Bahlis: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Baz:Bristol-Myers Squibb: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Sanofi: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Quach:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Ho:Celgene: Membership on an entity's Board of Directors or advisory committees. Vangsted:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Jansen: Honoraria. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Gibbs:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Salem:AbbVie: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options. Pesko:AbbVie: Employment, Other: Stock/stock options. Westrup:AbbVie: Employment, Other: Stock/stock options. Vue:AbbVie: Employment, Other: Stock/stock options. Maciag:AbbVie: Employment, Other: Stock/stock options. Bueno:AbbVie: Employment, Other: Stock/stock options. Kaufman:Takeda: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Winship Cancer Institute of Emory University: Employment; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Janssen: Honoraria; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment of multiple myeloma, which is not an approved indication.

Background Venetoclax (Ven) is a selective, small molecule inhibitor of anti-apoptosis protein Bcl-2 that has antitumoral activity against multiple myeloma (MM), notably those with translocation t(11;14). Dexamethasone (d) has shown to enhance the expression of BCL-2 and pro-apoptotic protein Bim, shifting its binding towards Bcl-2 and sensitizing MM cells to Ven. This Phase 1/2 open-label trial is evaluating the safety and efficacy of the combination of Ven+d as a therapeutic approach to improve clinical outcomes in patients with t(11;14) Relapsed/Refractory (R/R) MM. Methods This ongoing study (NCT01794520) has 2 distinct phases. Phase 1 (P1) consisted of separate dose escalation, safety expansion, and Ven+d combination cohorts. The phase 2 (P2) portion is an expansion cohort of Ven+d to further evaluate its efficacy. The safety and efficacy of the Ven+d cohorts from P1 and P2 are reported here. Eligible patients (pts) were adults with t(11;14) R/R MM ≥18 years of age. Key eligibility criteria for the Ven+d cohort in P1 included prior treatment with a proteasome inhibitor (PI) and an immunomodulatory drug (IMID), and an ECOG score ≤1. In P2, eligibility included an ECOG score ≤2, disease progression on or within 60 days from the last dose on previous treatment and having received at least two lines of therapy with a PI, IMID, daratumumab, and glucocorticoids. Additional inclusion criteria for both phases included measurable disease and adequate bone marrow function in all pts, and the presence of t(11;14) determined by fluorescence in-situ hybridization. In both phases, pts received oral Ven 800 mg/day + oral d 40 mg (20 mg for pts ≥75 years of age) on days 1, 8, and 15 of each 21-day cycle. In P1, preliminary efficacy was assessed as the overall response rate (ORR), time to progression (TTP), progression free survival (PFS), and duration of response (DOR) of Ven+d based on the 2011 International Uniform Response Criteria for MM. Efficacy in P2 further evaluated ORR, very good partial response (VGPR) or better, PFS, DOR, TTP, and overall survival (OS) using 2016 IMWG response criteria. Results In P1, as of 15thApril, 2019, 20 pts were enrolled (17 [85%] male; median age, 63 years [range, 46-77]). The median number of prior therapies received was 2.5 (range: 1-7). Nineteen pts (95%) discontinued the study (18 due to progressive disease and 1 underwent transplant). The treatment-emergent adverse events (TEAEs) are summarized in the Table. Most frequent TEAEs were insomnia (45%), hypophosphatemia (40%), hyperglycemia (35%), diarrhea (35%), and thrombocytopenia (30%). Predominant Grade 3 or 4 TEAEs included neutropenia (21%), lymphopenia (29%), and hypophosphatemia (20%). The most common serious TEAE was tumor lysis syndrome (TLS) (10%). No deaths were reported in the treatment-emergent period. ORR was achieved by 13 (65%) and ≥VGPR was achieved by 6 (30%) pts respectively. Partial response (PR) was observed in 7 (35%) pts and stable disease (SD) in 4 (20%) pts. Median time to first response was 1.4 mos (95% CI: 0.7, 2.8). The DOR was 13.1 mos (95% CI: 10.9, 21.9). Median PFS and TTP were both 12.4 mos (95% CI 3.6, 20.9). In P2, as of March 18, 2019, 31 pts were enrolled (18 [58%] male; median age, 65 years [range, 48-80]). The median number of prior therapies received were 5 (range: 1-9). Eight (26%) pts discontinued the study (6 deaths, 1 withdrew consent, 1 due to physician's decision). The most frequent TEAEs reported were diarrhea (32%), nausea (26%) and lymphopenia (32%). The most frequent Grade 3 or 4 TEAEs were lymphopenia (32%), thrombocytopenia (11%), and hypertension (10%). Most common serious TEAE was sepsis (10%). Six (19%) deaths were reported (5 due to progressive disease and 1 due to adverse event). In the intention to treat population, the median TTR was 0.7 mos (range: 0.6-1.5). ORR was achieved by 14 (45%) and >VGPR was observed in 8 (26%) pts. PR was observed in 6 (13%) pts and SD in 8 (26%) pts. Median PFS, DOR, and OS were not reached at the time of data analysis. The 9-mo estimates for PFS, DOR, and OS were 57% (95% CI: 19% 82%), 66% (95% CI: 16%, 91%), and 71% (95% CI: 44%, 87%) respectively. Conclusion In both phases of this study, Ven+d was efficacious and demonstrated tolerable safety in pts with t(11;14) R/R MM. These results support further investigation of Ven combinations in this pt population. This combination is also being investigated in the ongoing Phase 3 trial M13-494 (CANOVA) in t(11;14) positive R/R MM. Disclosures Kaufman: Takeda: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AbbVie: Consultancy; Winship Cancer Institute of Emory University: Employment; Amgen: Consultancy; TG Therapeutics: Consultancy. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Schjesvold:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyliteDX: Honoraria. Moreau:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Boise:Genentech Inc.: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Research Funding. Alzate:AbbVie Inc: Employment, Other: Stock/stock options. Macartney:AbbVie Inc: Employment, Other: Stock/stock options. Pesko:AbbVie: Employment, Other: Stock/stock options. Salem:AbbVie: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options. Hong:Genentech Inc.: Employment, Equity Ownership; Roche: Equity Ownership. Maciag:AbbVie: Employment, Other: Stock/stock options. Pauff:AbbVie Inc: Employment, Other: may own stock or stock options. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, 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 multiple myeloma, which is not an approved indication.

TPS8061Background: Despite the introduction of new compounds to manage relapsed/refractory (R/R) multiple myeloma (MM) over the last decade, none are curative. Trials investigating novel agents or ...

This review is designed to explore the disease, its current treatment, the expanding field of antiangiogenic treatments, and the implications of these advances for the managed care patient.This article is based, in part, on presentations given by the authors in a continuing education symposium presented during the Academy of Managed Care Pharmacy.s 16th Annual Meeting and Showcase, April 1, 2004, in San Francisco.Colorectal cancer (CRC) is the third most common cancer in the United States, and the second-leading non.gender-specific cause of cancer deaths. If the cancer is caught soon enough (before node involvement and metastasis occur), there is a strong chance of survival; however, only slightly more than one third of cases are detected that soon. Emerging treatments that target only the cancer cells are increasing the length of survival for those who are diagnosed at later stages of the disease.