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Incorporating human values and behavior into natural resource management has been linked to more sustainable and efficient outcomes. Estimating these values often requires survey-based data collect...

Inhibitors of Bruton’s tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenström macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients with WM who were either treatment-naïve (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per International Workshop on Waldenström Macroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n = 50) or 320 mg once daily (n = 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0 months for patients with R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24 months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with single-agent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

By conducting a field experiment, we investigate whether consumers value expert opinion labels on wine as a form of reducing asymmetric information about product quality. We use two types of data. First, we use a macro-level monthly-product-store dataset,collected before and after our field experiment, which involves treating a random subset of wine products by displaying expert scores in one store, and comparing sales with wine sales in similar, non-treated stores. Secondly, we use a micro-level panel dataset from the treated store that provides information on products purchased and household characteristics. We combine these data with additional information on products, such as, varietal, region of production, price point relative to other wines, and expert scores. Using the macro-level data for treated and control stores, we estimate a structural random coefficient demand model for wine. With the household micro dataset, we estimate a random coefficient mixed logit demand specification, allowing for consumer heterogeneity in demand for wine. In order to capture the demand for wine, the products are defined as bundles of attributes, including the expert score that is experimentally introduced into the market. We find robust results in terms of consumer valuations for expert scores, using both datasets. In particular, we obtain an implied average willingness to pay (WTP) between 2 (using the macro level dataset for treated and control stores) and 3.2 dollars (using the micro level dataset for the treated store) for an average score of 83. Although not all of the consumer demographics help explain the heterogeneity in the value of expert scores, the wine ratings matter significantly less to consumers that have higher incomes, or are more likely to own a home. Finally, using counterfactual simulations we estimate the changes in consumer surplus resulting from available quality information in the form of expert opinion scores. Using the micro level dataset we find that removing scores leads to significant welfare losses especially for lower income consumers and for men. Overall, using the macro level dataset for treated and control stores, we estimate there to be a significant welfare loss eliminating scores of roughly one percent of total wine revenue in the treated store.

Background: BCL2, a key regulator of apoptosis, is aberrantly expressed in many hematologic malignancies, which can lead to pathologic cancer cell survival. BCL2 inhibitors have been shown to be safe and effective, resulting in their approval for the treatment of pts with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and acute myeloid leukemia. Treatment with the currently approved BCL2 inhibitor, venetoclax, can be limited by common gastrointestinal toxicities, neutropenia, and the emergence of specific BCL2 mutations around the BH3-binding groove causing resistance. BGB-11417 was developed as a potent and highly selective inhibitor of BCL2. It has shown antitumor activity superior to venetoclax in human acute lymphoblastic leukemia, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) xenograft models (Hu, AACR 3077). BGB-11417 also has a favorable pharmacokinetic profile with excellent bioavailability and selectivity for BCL2 at concentration The combination of a BCL2 inhibitor and a BTK inhibitor is tolerable with synergistic activity in CLL and MCL pts (Hillmen, J Clin Oncol 2019;37(30):2722-9; Jain, N Engl J Med 2019;30;380(22):2095-103; Siddiqi, ASH 2020 S158; Tam, N Engl J Med 2018; 378:1211-23). Zanubrutinib is a next-generation BTK inhibitor that has shown excellent activity and favorable toxicity in pts with CLL/SLL (Hillmen, EHA 2021 LB1900) and MCL (Tam, Blood Adv 2021;5(12):2577-85); with approval for treatment in MCL. Here we report preliminary results of the BGB-11417-101 trial (NCT04277637) in pts with non-Hodgkin lymphoma (NHL) or CLL/SLL treated with BGB-11417 monotherapy or in combination with zanubrutinib. Methods: BGB-11417-101 is a phase 1, open label, multicenter, dose-escalation and expansion study. Pts with NHL or CLL/SLL are treated with BGB-11417 as monotherapy or in combination with zanubrutinib. For dose escalation, pts with R/R B-cell malignancies are enrolled in 1 of 5 potential dose levels of BGB-11417 (40, 80, 160, 320, or 640 mg once daily). All pts utilize a ramp-up to intended target dose that varies by disease type. Pts in the combination therapy arm receive zanubrutinib 320 mg daily beginning 8-12 weeks before BGB-11417 is introduced. Adverse events (AEs) are reported per Common Terminology Criteria for AEs v5.0. Dose-limiting toxicity (DLT; assessed from ramp-up through day 21 at intended daily dose), evaluated by Bayesian logistic regression model, will be used to determine the maximum tolerated dose (MTD). Results: As of 24 May 2021 (data cutoff) 19 pts had been treated; 14 pts with monotherapy (NHL: n=11; CLL/SLL: n=3) and 5 pts with combination (all CLL; 3 pts were still on zanubrutinib pretreatment; 2 had started combination treatment). Median age was 72 y (range, 50-86); median follow-up was 1.9 mo (range, 0.7-12.4); all pts were R/R with a median of 2 prior regimens (range, 1-4). No DLTs were observed in pts with NHL receiving BGB-11417 monotherapy (n=11) up to the 160 mg dose level. AEs across all dose levels occurring in ≥2 pts (monotherapy) or ≥1 pt (combination) are listed in Table 1. A total of 5 pts discontinued treatment (all NHL) due to disease progression (n=4; 2 at 40 mg, 2 at 80 mg) or lack of efficacy (n=1 at 40 mg). No pt discontinued due to AEs. Laboratory tumor lysis syndrome was observed in 1 pt with CLL and high tumor burden (resolved with no sequelae). Initial efficacy after 3-month restaging in pts with CLL/SLL demonstrated 1 partial response (monotherapy arm) at the first dose level tested. All pts with CLL/SLL who have completed ramp-up (n=2, both monotherapy) normalized absolute lymphocyte count (ALC). Marked decreases in ALC were observed in pts with CLL at doses as low as 1 mg (Figure 1). Conclusion: Preliminary results suggest that BGB-11417 monotherapy is tolerable in pts with R/R NHL at the tested dose levels. Further assessment of safety and efficacy of BGB-11417 +/- zanubrutinib in CLL/SLL and NHL will be presented at the meeting, and evaluation in patients with treatment naïve CLL/SLL, R/R MCL, and R/R WM is planned. Figure 1 Figure 1. Disclosures Tam: AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Loxo: Consultancy; Novartis: Honoraria; Pharmacyclics: Honoraria. Verner: Janssen-Cilag Pty Ltd: Research Funding. Lasica: Celgene: Other: Travel, Accommodations, Expenses; Janssen: Other: Education. Arbelaez: Amgen: Other: Travel, Accommodations, Expenses. Browett: AbbVie: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Soumerai: BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy; GlaxoSmithKline: Research Funding; BostonGene: Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy, Research Funding. Hilger: BeiGene: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Fang: BeiGene (Shanghai) Co, Ltd.: Current Employment, Current equity holder in publicly-traded company. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Simpson: Janssen: Research Funding; GSK: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; MSD: Research Funding; Roche: Research Funding; Celgene: Research Funding; Amgen: Research Funding; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; BeiGene: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Opat: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GIlead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Monash Health: Current Employment; BeiGene: Research Funding; Sandoz: Research Funding. Cheah: Ascentage Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not been approved for NHL or CLL/SLL in the US

Influenza vaccination rates in the United States remain low. Many emergency department (ED) patients may not routinely seek care elsewhere. In a survey of ED visitors, 36.8% of unvaccinated respondents were willing to consider influenza vaccination during their visit. Participants at high risk for influenza complications were more likely to have been previously vaccinated, but unvaccinated participants at high risk were not significantly more likely to consider ED-based vaccination compared with other participants. ED-based influenza vaccination may be an effective method to expand vaccine coverage.

Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. Inhibition of BTK has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. Increased specificity may minimize toxicities reported with ibrutinib potentially due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue (Coutre et al. Blood Advances 2019). In non-clinical studies, zanubrutinib has been shown to be highly potent, selective, bioavailable, and irreversible, with potentially advantageous pharmacokinetic (PK) and pharmacodynamic properties. Complete and sustained BTK occupancy has been observed with zanubrutinib treatment in both peripheral blood mononuclear cells and in lymph nodes (Tam et al. Blood 2019). Based on drug-drug interaction studies and population PK analyses (internal data), zanubrutinib may also be co-administered with strong or moderate CYP3A inhibitors at a reduced dose, proton pump inhibitors, vitamin K antagonists, as well as direct oral anticoagulants. Zanubrutinib does not prolong the QT interval. Pooled clinical data from 6 zanubrutinib monotherapy trials including 682 patients (pts) with either non-Hodgkin lymphoma, Waldenström macroglobulinemia, or CLL/SLL suggests that zanubrutinib has been generally well tolerated amongst pts with B-cell malignancies (Tam et al. EHA 2019). This data further showed that some toxicities often associated with BTK inhibitors were infrequent with zanubrutinib, including 1.9% atrial fibrillation/flutter (0.6% grade ≥3), 2.5% major hemorrhage (2.1% grade ≥3), 10.9% fatigue (0.7% grade ≥3), 18.0% rash (0.1% grade ≥3), 18.3% thrombocytopenia (6.6% grade ≥3), and 19.4% diarrhea (0.9% grade ≥3). Early clinical data in pts with treatment-naïve (TN; n=22) or relapsed/refractory (R/R; n=56) CLL/SLL showed that zanubrutinib was highly active: 96.2% overall response rate (ORR), including 4.5% and 1.8% with complete response in TN and R/R CLL/SLL, respectively (Tam et al. Blood 2019). Study Design and Methods: This ongoing phase 3, randomized, global study (ALPINE; NCT03734016) is designed to compare the efficacy of zanubrutinib to ibrutinib based on ORR in pts with R/R CLL/SLL (Figure). This open-label study randomizes approximately 400 pts 1:1 to each arm, stratified by age (< 65 vs ≥ 65 years), refractory status (yes vs no), geographic region (China vs other), and del(17p)/TP53 mutation status (present vs absent). The study population includes adult pts who have had prior treatment for their CLL/SLL and were either refractory to or relapsed from prior CLL/SLL treatment. Major inclusion criteria include R/R CLL/SLL requiring treatment per International Workshop on CLL (iwCLL) criteria, disease measurable by computed tomography/magnetic resonance imaging, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematologic function. Major exclusion criteria include prior treatment with a BTK inhibitor, current or past history of Richter transformation, clinically significant cardiovascular disease, or history of severe bleeding disorder. Zanubrutinib is dosed at 160 mg twice daily, and ibrutinib is dosed per label at 420 mg daily; treatment in both arms may continue until progression. The primary endpoint is ORR as determined by an independent review committee according to iwCLL guidelines, with modification for treatment-related lymphocytosis for pts with CLL and per 2014 Lugano Classification for pts with SLL. The study is powered to test the non-inferiority, and subsequently the superiority, of the ORR for zanubrutinib vs ibrutinib. Secondary endpoints include progression-free survival, ORR as determined by investigator, safety, duration of response, overall survival, and pt-reported outcomes. Exploratory endpoints include the correlation between clinical outcomes and prognostic and predictive biomarkers. Recruitment began in November 2018 and is ongoing in 14 countries. Disclosures Hillmen: Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Brown:AbbVie: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Juno/Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy. Byrd:Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S. Eichhorst:BeiGene: Research Funding; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lamanna:Celgene: Consultancy; Oncternal: Research Funding; TG Therapeutics: Research Funding; Ming: Research Funding; Infinity/ Verastem: Research Funding. O'Brien:GlaxoSmithKline: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Regeneron: Research Funding; Eisai: Consultancy; Celgene: Consultancy; Aptose Biosciences, Inc: Consultancy; TG Therapeutics: Consultancy, Research Funding; Amgen: Consultancy; Kite: Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Verastem: Consultancy; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; Vaniam Group LLC: Consultancy. Salmi:BeiGene: Employment. Hilger:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie company: Honoraria; Novartis: Honoraria; BeiGene: Honoraria; Roche: Honoraria. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US

TPS7572 Background: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib, an investigational inhibitor of BTK, was specifically engineered to optimize selectivity, half-life and solubility in an effort to decrease toxicities and better penetrate tumor tissue. Early clinical data suggested that zanubrutinib treatment in patients with treatment-naïve (TN; n = 16) or R/R (n = 50) CLL/SLL induced deep responses: 94% overall response rate (ORR), including 6% and 2% complete response rates in TN and R/R CLL/SLL, respectively (ICML 2017). This study is designed to evaluate whether zanubrutinib monotherapy exhibits non-inferior and potentially superior efficacy based on the ORR vs ibrutinib monotherapy in patients with R/R CLL/SLL. Methods: This ongoing phase 3, randomized, open-label, global study (NCT03734016, BGB-3111-305) is comparing the efficacy and safety of zanubrutinib vs ibrutinib in adult patients with R/R CLL/SLL. Approximately 400 patients will be randomized, 1:1 to each arm and stratified by age (< 65 vs ≥ 65 years), refractory status (yes vs no), geographic region, and del(17p)/ TP53 mutation status (present vs absent). Key inclusion criteria include R/R CLL/SLL requiring treatment per iwCLL criteria, ECOG PS 0-2, and adequate hematologic function. The primary endpoint is ORR as determined by an independent review committee according to iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL and per 2014 Lugano Classification for patients with SLL. The study is powered to test the non-inferiority and superiority of the ORR for zanubrutinib vs ibrutinib. Secondary endpoints include progression-free survival, safety, duration of response, and overall survival. Recruitment is ongoing. Clinical trial information: NCT03734016.

Background: The Bruton tyrosine kinase (BTK) inhibitor zanubrutinib,has demonstrated greater selectivity for BTK versus other TEC- and EGFR-family kinases in biochemical assays and favorable pharmacokinetic/pharmacodynamic properties in preclinical studies. In a phase 1 clinical trial, zanubrutinib showed complete and sustained 24-hour BTK occupancy in both blood and lymph node biopsies from patients treated at 160 mg twice daily (bid; Tam et al. Blood 2016;128:642), and was associated with durable responses in patients with non-Hodgkin lymphoma (Tam et al. Blood 2017;130:152). Here, we present initial safety and efficacy data from a phase 2 trial of zanubrutinib in patients with relapsed or refractory mantle cell lymphoma (R/R MCL). Methods: Conducted in China, BGB-3111-206 (clinicaltrials.gov NCT03206970) is a pivotal, single-arm, open-label, multicenter phase 2 study. Patients with R/R MCL aged 18-75 years and with 1-4 prior treatment regimens received zanubrutinib 160 mg bid until disease progression (PD) or unacceptable toxicity. The primary objective is to evaluate the efficacy of zanubrutinib as measured by overall response rate (ORR) assessed by an Independent Review Committee (IRC). Response was assessed with PET-CT scans (in subjects with FDG-avid disease) and CT or MRI scans (in subjects with FDG non-avid disease) at each response assessment and for confirmation of complete response (CR) per the International Conference on Malignant Lymphoma (Lugano) criteria (Cheson, 2014). Key secondary endpoints included progression free survival (PFS), time to response (TTR), duration of response (DOR) and safety. Treatment-emergent adverse events (TEAEs) were assessed according to NCI CTCAE v4.03. Results: As of 27 March 2018, 86 patients with R/R MCL were enrolled and treated. Patient characteristics are summarized in the Table. Over one-half (52.3%) of patients were refractory to their last prior therapy. Median follow-up was 36 weeks (range,1-56) at the data cut. Twenty-one patients discontinued zanubrutinib (13 for PD; 6 for TEAEs; 1 withdrew consent; and 1 per investigator's discretion). One patient was not evaluable for response due to a lack of central pathologic confirmation of MCL. Of the 85 evaluable patients, ORR per the IRC was 84% (n=71; Table), with CR reported in 59% of patients (n=50). The estimated event-free rate for responders was 90% at 24 weeks after response. In total, 12 patients have progressed; the estimated PFS rate was 82% at 24 weeks. The most frequent (≥15%) TEAEs due to any cause included decreased neutrophil count (31.4%), upper respiratory tract infection (29.1%), rash (29.1%), decreased platelet count (22.1%), and decreased white blood cell (WBC) count (17.4%). Grade ≥3 TEAEs due to any cause reported in >2 patients included decreased neutrophil count (11.6%), lung infection (5.8%), anemia (4.7%), and decreased WBC count (3.5%). Petechia/purpura/contusion and hematuria were each reported in 4 patients (4.7%, all grade 1/2); major hemorrhage (serious or grade ≥3 bleeding or central nervous system bleeding of any grade)was reported in 1 patient (1.2%); no cases of atrial fibrillation/flutter or tumor lysis syndrome were reported. Six patients died within 30 days of last study treatment, 1 from PD, 4 due to Grade 5 TEAEs and 1 due to a Grade 5 event that was not treatment emergent. TEAEs leading to discontinuation of zanubrutinib included (n=1 each): infection, pneumonia, lung infection, interstitial lung disease, and twoGrade 5 TEAEs (cerebral hemorrhage and road traffic accident). Conclusions: Zanubrutinib was shown to be highly active in patients with R/R MCL, as demonstrated by a high rate of CR documented by PET-based imaging. Zanubrutinib was generally well-tolerated, consistent with previous reports of zanubrutinib treatment in patients with various B-cell malignancies. Disclosures Song: Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zhou:Affiliated Cancer Hospital of Zhengzhou University: Employment; Health and Family Planning Commission of Henan Province: Patents & Royalties: Scientific and technological innovative talents "51282" Project leaders; Henan Cancer Hospital: Consultancy, Employment; Natural Science Foundation of China: Research Funding. Jin:College of Medicine, Zhejiang University: Employment; The National Natural Science Foundation of China: Research Funding. Guo:BeiGene (Shanghai) Co., LTD: Employment. Wang:BeiGene (Shanghai) Co., LTD: Employment. Hilger:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Huang:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Novotny:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Osman:BeiGene USA: Employment, Equity Ownership. Zhu:Beijing Cancer Hospital: Employment.

Background: Investigational Bruton tyrosine kinase (BTK) inhibitor zanubrutinib has demonstrated greater selectivity vs other TEC and EGFR family kinases in biochemical assays and favorable pharmacokinetic/pharmacodynamic properties in preclinical studies. In phase 1 testing, high plasma concentrations were achieved, resulting in complete and sustained 24-hour BTK inhibition in blood and lymph nodes in patients treated at 160 mg twice daily (bid; Tam et al. Blood 2016;128:642). A recent update of clinical data suggested that complete and sustained 24-hour BTK occupancy is associated with durable responses in patients with non-Hodgkin lymphomas (Tam et al. Blood 2017;130:152). Here, we present updated safety and efficacy data from patients with mantle cell lymphoma (MCL). Methods: Study AU-003 is a global, open-label, multicenter, phase 1b trial investigating zanubrutinib in patients with B-cell malignancies. After dose escalation, the expansion phase enrolled disease specific cohorts at the recommended phase 2 dose of zanubrutinib (320 mg/day once daily or 160 mg bid). Treatment emergent adverse events (TEAEs) were summarized according to NCI CTCAE v4.03 and response was assessed per International Conference on Malignant Lymphoma criteria (Cheson et al. J Clin Oncol 2014;32:3059). Positron-emission tomographic (PET) scan was not required for response assessment. Results: As of 28 Feb 2018, 43 patients were enrolled: 38 relapsed/refractory and 5 treatment-naïve (Table). Median follow-up was 10.3 months (range, 0.1-39.2). Twenty patients have discontinued treatment (12 due to progressive disease; 8 due to TEAEs). Most common TEAEs of any cause (≥15% of patients) included diarrhea (30.2%), petechiae/purpura/contusion (30.2%), upper respiratory tract infection (27.9%), constipation (18.6%), fatigue (18.6%), and rash (16.3%). Two cases of atrial fibrillation/flutter (4.7%) and 3 cases of major hemorrhage (7.0%; renal hematoma, gastrointestinal hemorrhage, and tumor hemorrhage, all grade 3) were reported. Most common grade ≥3 TEAEs of any cause (≥2 patients) included anemia (7.0%), cellulitis (7.0%), pneumonia (7.0%), myalgia (7.0%), neutropenia (4.7%), back pain (4.7%), peripheral edema (4.7%), hypertension (4.7%), and acute kidney injury (4.7%). Fourteen patients experienced ≥1 serious TEAE (SAE) of any cause; SAEs occurring in >1 patient included pneumonia (7.0%) and cellulitis (4.7%). Nine TEAEs led to discontinuation of zanubrutinib in 8 patients: pneumonia, cognitive disorder, antineutrophil cytoplasmic antibody-positive vasculitis and acute kidney injury (same patient), joint effusion, and myelodysplastic syndrome; 3 of the 9 were fatal TEAEs designated by the investigator as unrelated to zanubrutinib including pneumonia, congestive cardiac failure, and cerebral infarction. Three patients who had not yet reached their first response assessment were not evaluable for response. As shown in the Table, overall response rate was 90.0% (n=36/40) including 20.0% (n=8) with complete response. Response was based on computed tomography (CT) scan alone for the majority of patients as PET was not required. The 4 non-responders included 1 with progressive disease, 1 with stable disease, and 2 patients who discontinued because of TEAEs (pneumonia, congestive cardiac failure) before the first response assessment. Median progression-free survival was 18.0 months (Table, Figure). Conclusions: Zanubrutinib monotherapy was demonstrated to be highly active in patients with relapsed/refractory MCL, with a safety profile consistent with that of previous reports of zanubrutinib. Disclosures Tam: Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding. Wang:MoreHealth: Consultancy; Novartis: Research Funding; Dava Oncology: Honoraria; Kite Pharma: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Research Funding; Acerta Pharma: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Simpson:Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Research Funding; BeiGene: Research Funding; Merck: Honoraria, Research Funding; Acerta: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria. Opat:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Support, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Support, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Support, Research Funding; Amgen: Research Funding; Mundipharma: Honoraria; Beigene: Other: Clinical Trial Support; Epizyme: Other: Clinical Trial Support; Merck & Co., Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support and travel expenses; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Support, Research Funding. Cull:Takeda Australia: Other: Travel Expenses; Amgen Australia: Other: Travel Expenses; AbbVie (Australia): Membership on an entity's Board of Directors or advisory committees. Munoz:Alexion: Consultancy; Kite: Consultancy, Honoraria, Speakers Bureau; Gilead: Speakers Bureau; Juno: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy, Honoraria; Bayer: Consultancy, Speakers Bureau; Genentech: Consultancy, Honoraria. Phillips:Gilead: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding; Genentech: Consultancy. Kim:Novartis: Research Funding; Roche: Research Funding; Celltrion: Research Funding; Takeda: Research Funding; Kyowa-Kirin: Research Funding; Mundipharma: Research Funding; J&J: Research Funding. Hilger:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Huang:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Novotny:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Trotman:PCYC: Research Funding; Janssen: Other: Unremunerated member of Ad Board, Research Funding; Celgene: Other: Unremunerated member of Ad Board, Research Funding; Takeda: Other: Unremunerated member of Ad Board; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding.

Estimation of consistent parameter estimates for recreational demand models faces challenges arising from the choice-based nature of the data collected primarily for resource management purposes. As an alternative to randomized respondent-based sampling, choice-based onsite sampling can provide information on actual choices made by a subset of the population where participation has a low incidence. While the literature has shown that under specific restrictions the estimation of choice models from onsite sampling data yields unbiased fixed parameter estimates for the conditional logit model, this result does not carry over to estimation of the random parameter logit model. We propose an estimator for the unbiased estimation of the random parameter model using choice-based data; our estimator uses weights based on information about the level of sampling effort. An empirical application of the standard and weighted discrete choice RUM models to onsite sample data on recreational fishing illustrates the advantages of the proposed estimator. The estimation results indicate the compensating variation associated with an decrease, or increase, of 50 % in expected catch rates for a recreational shoreline sportfishing trip to a man-made structure in southern California is $$-{\$}2.80$$ or $${\$}3.54$$ per trip, respectively.

We investigate whether consumers are willing to pay for sustainability in seafood. To do this, we estimate a logit random utility model (RUM) of seafood purchases using a product-level scanner dataset from a quasi-experimental setting that includes data both before and after the implementation of a seafood advisory and sustainability label. Each seafood product is defined as a bundle of attributes, including price, species, and sustainability rating. The sustainability rating is communicated to consumers through the use of a color-based traffic light label system, where a color rating is assigned to each seafood stock-keeping unit. Combining a structural demand model with a difference-in-differences approach allows us to take advantage of the implementation of the labeling treatment in a subset of stores in the local retail chain to estimate consumers’ willingness to pay (WTP) for green, yellow, and red sustainability labels. We find that the addition of a yellow sustainability label negatively impacts consumer’s WTP for seafood products, however this simple average effect does not fully capture many independent underlying mechanisms, such as consumer preferences for wild-caught versus farmed products, and the color-distribution of available labeled products within a species, which are empirically explored. Additional results from a second stage generalized least squares regression of RUM product fixed effects on product characteristics indicate that consumers prefer selective harvest methods, wild caught seafood, and U.S. caught seafood.

In this paper, we extend the latent segmentation approach to the Kuhn–Tucker (KT) model. The proposed approach models heterogeneity in preferences for recreational behavior, using a utility theoretical framework to simultaneously model participation and site selection decisions. Estimation of the latent segmentation KT model with standard maximum likelihood techniques is numerically difficult because of the large number of parameters in the segment membership functions and the utility function for each latent segment. To address this problem, we propose the expectation-maximization (EM) algorithm to estimate the model. In the empirical section, we implement the EM latent segmentation KT approach to analyze a Southern California beach recreation data set. Our empirical analysis suggests that three groups exist in the sample. Using the model to analyze two hypothetical beach management policy scenarios illustrates different welfare impacts across groups.

This study develops a utility theoretic demand model for an arbitrary number of goods that handles correlation between goods and over time. The bivariate compound Poisson estimator is applied to a semi-logarithmic incomplete demand system to estimate the demand for wilderness recreation and the associated welfare measures both prior to and post a 40,000 acre wilderness fire in Washington. Forest fires can simultaneously affect the environmental qualities of many recreational sites; this highlights the need for a utility theoretic demand system approach for modeling consumer behavior that handles the dynamic behavioral and statistical interdependencies over goods and time. Results suggest an increase in consumer welfare per trip post fire, after an initial period of low values, relative to before the fire.

Introduction: The anti-apoptotic protein BCL2 is overexpressed in a number of hematological malignancies, including chronic lymphocytic leukemia (CLL). Venetoclax (VEN) is a selective, oral BCL2 inhibitor with demonstrated activity and an acceptable safety profile both as monotherapy and in combination regimens in relapsed/refractory (R/R) CLL patients (pts). VEN has demonstrated preclinical activity with bendamustine/rituximab (BR), a standard treatment in this population, as well as clinical efficacy with R. The anti-CD20 mAb obinutuzumab (G) has demonstrated improved efficacy in combination with chlorambucil compared with R. Here we present an interim analysis of an ongoing phase 1b study (GO28440) evaluating the maximum tolerated dose (MTD) of both VEN+BR and VEN+BG, plus safety, tolerability, efficacy and optimal order of administration in both R/R or 1L CLL pts (NCT01671904). Methods: Pts with ECOG PS ≤1, 0-3 prior chemotherapy lines, and adequate marrow, hepatic, renal and coagulation function are being enrolled in dose finding cohorts (VEN 100-400mg/day +BR or +BG in a 3+3 dose escalation design) and subsequent safety expansion cohorts (400mg). Dose finding occurs in one of two dosing schedules: Schedule A (VEN introduced before BR or BG) or Schedule B (BR or BG introduced before VEN), with one chosen for expansion per unique population/drug grouping. Both schedules include a gradual VEN dose ramp-up and other prophylactic measures based on risk stratification to reduce the risk of tumor lysis syndrome (TLS). Following completion of 6 months of combination therapy, pts continue single-agent VEN until unacceptable toxicity, disease progression, or (for 1L pts only) up to 1 year total VEN. Dose-limiting toxicity (DLT) data are reviewed after all pts in a cohort have completed 21 days of combination treatment at the target VEN dose and focus on TLS and cytopenias. Efficacy is assessed by iwCLL guidelines; Hallek et al. 2008. Results: At data cutoff (May 2, 2016), 55 pts (baseline characteristics and disposition in Table 1) have been treated; 47 pts received VEN+BR: 30 R/R (12 on Schedule A at doses 100-400mg, 18 on Schedule B all at 400mg) and 17 1L (all at 400mg: 6 on Schedule A, 11 on Schedule B). Eight pts received VEN+BG: all on Schedule B at 400mg. Safety is summarized for VEN+BR (R/R and 1L) and VEN+BG (1L) in Table 2. The most common AEs across all groups were neutropenia, thrombocytopenia, and nausea. Most G3-4 AEs across all groups were hematological toxicities; common non-hematological AEs included diarrhea and fatigue. Platelet transfusions occurred in 4 (13%) R/R VEN+BR and 1 (13%) 1L VEN+BG pts. There were serious AEs in 21 pts (43% R/R VEN+BR, 35% 1L VEN+BR, 25% 1L VEN+BG) including febrile neutropenia, nausea, vomiting, erythema, and infection. No deaths were reported. No TLS events (laboratory or clinical) were observed. Dose interruptions or modifications for VEN and/or BR/BG occurred in 35 (75%) of VEN+BR pts (22 R/R, 13 1L) and 7 (88%) VEN+BG pts, mainly due to neutropenia. Early VEN discontinuations for toxicity: 7 pts VEN+BR (R/R), 2 pts VEN+BR (1L), 1 pt VEN+BG. Early B and/or R/G discontinuations for toxicity: 10 pts VEN+BR (R/R), 4 pts VEN+BR (1L), 2 pts VEN+BG. Common reasons for discontinuations (≥1 pt) included neutropenia and thrombocytopenia. Across all pts, a median of 4 cycles of B were completed. Best overall response and minimal residual disease (MRD) status for evaluated pts are presented in Table 3. All but one R/R pt (off study early for disease transformation) responded across all groups. Conclusion: This study is the first to evaluate both VEN+BR and VEN+BG in pts with CLL. VEN 400mg daily can be combined with BR or BG in patients with either R/R or 1L CLL; neutropenia and thrombocytopenia are manageable with an otherwise acceptable safety profile. Administration schedules (VEN or BR first) appear to have similar toxicity profiles, with no DLT or lab/clinical TLS reported for either during dose finding. As expected, due to the known safety profile of VEN and B, hematologic toxicity was observed with VEN+BR; early VEN+BG safety data appears similar. Events appeared manageable, although early discontinuations contributed to a median of 4 completed cycles of B across all pts. Even with median of Disclosures Stilgenbauer: Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding. Morschhauser:Gilead Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Wendtner:Novartis: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Glaxo-SmithKline: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Cartron:Roche: Consultancy, Honoraria; Celgene: Honoraria; Gilead: Honoraria; Jansen: Honoraria. Hallek:Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Eichhorst:Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Kozloff:AbbVie: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Lozanski:Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding. Punnoose:Genetech, Inc.: Employment. Wang:Genetech, Inc.: Employment. Hilger:Genetech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Salles:Celgene: Consultancy, Honoraria; Janssen: Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy.

Introduction Despite improved response and survival for patients (pts) with follicular lymphoma (FL) receiving rituximab (R) plus chemotherapy, new options are needed. FL is typically characterized by the presence of chromosomal translocation t(14;18), which results in overexpression of the anti-apoptotic protein BCL-2. BCL-2 may also contribute to resistance to chemoimmunotherapy such as bendamustine+R (BR), a regimen commonly used in FL. Venetoclax (VEN), a selective, potent oral BCL-2 inhibitor, is in development for the treatment of B-cell malignancies. Preclinical and early clinical data suggest VEN+R or VEN+BR may improve response over R or chemotherapy alone and is feasible. This open-label study will assess efficacy and toxicity of VEN+R as well as VEN+BR vs BR alone, in pts with relapsed/refractory (R/R) FL (NCT02187861). Methods R/R pts (age ≥18 yrs, confirmed Gr 1-3a FL, ECOG PS 0-2, adequate hematologic function) were assigned (at investigators' discretion) to chemotherapy-free (chemo-free) or randomized to chemotherapy-containing (chemo) arms. Those in the chemo-free Arm (Arm A) received VEN 800mg daily for 1 yr + R (cycles [C] 1, 4, 6, 8, 10 and 12). After a safety run-in (9 pts at 600mg VEN daily + 6 cycles BR), those in the chemo Arm were randomized 1:1 to Arm B (VEN 800mg + 6 cycles BR) or C (BR only). The primary endpoint was complete response (CR) rate by PET-CT. Secondary endpoints include CR rate by CT and overall response rate. Response assessment was per Lugano non-Hodgkin lymphoma assessment (Cheson et al. 2014) 6-8 wks after D1 of C6 (or the cycle non-VEN agents were permanently discontinued: whichever came first). Results One hundred sixty-four pts were enrolled as of May 13, 2016 (Table 1); 53 chemo-free (Arm A) and 111 chemo (9 run-in; 51 Arm B; 51 Arm C). 61% were refractory to prior treatment: 79% Arm A; 56% safety run-in; 43% Arm B; 62% Arm C. One hundred fifty-three of 160 safety evaluable pts (94%) experienced any AE (Table 2). Common AEs (all grades): diarrhea (37%), neutropenia (29%), nausea (25%), fatigue (25%), and IRR (25%). Common AEs for Arm B vs Arm C: nausea (61% vs 38%), neutropenia (51% vs 26%), diarrhea (41% vs 12%), thrombocytopenia (39% vs 20%) and fatigue (37% vs 24%). Neutropenia and thrombocytopenia were the most common Gr 3-4 AEs among all groups. 40 pts had serious AE (SAEs): 14 (27%) Arm A; 4 (44%) run-in; 15 (31%) Arm B; 7 (14%) Arm C. SAEs in >1 pt in any arm: febrile neutropenia (2 run-in; 5 Arm B; 1 Arm C), pneumonia (2 Arm A; 1 Arm B), and LDH increase (2 Arm A). Laboratory tumor lysis syndrome (TLS) events occurred in 2 pts (1 Arm A; 1 Arm B): both manageable and resolved with no clinical complications. Five deaths occurred on study: 3 Arm A (colitis, pulmonary hemorrhage, PD), 1 Arm B (pneumonia), 1 Arm C (PD). Pts with AEs leading to dose interruptions or modification: 28 (54%) Arm A; 7 (78%) run-in; 37 (76%) Arm B; 12 (24%) Arm C. Pts with early drug discontinuations of VEN: 29 (56%) Arm A; 5 (56%) run-in; 11 (22%) Arm B. Early R discontinuations: 28 (54%) Arm A; 3 (33%) run-in; 7 (14%) Arm B; 5 (10%) Arm C. Early B discontinuations: 3 (33%) run-in; 7 (14%) Arm B; 4 (8%) Arm C. Efficacy by PET+CT for safety evaluable patients who reached an assessment event is shown in Table 3. Arm A had 17 (33%) responders with 14% CR. Arm A was predominantly refractory to last treatment (79%): among non-refractory pts (21%), ORR was 64% with 27% CR. There was 68% ORR in Arm B with 50% CR compared with 64% ORR with 41% CR in Arm C. 55 (51%) of chemo pts have yet to reach a response-relevant event. Correlation with expression of BCL-2 family members is pending. Conclusion Early results from the first study evaluating VEN+R and VEN+BR in pts with FL show that daily VEN 800mg has an acceptable benefit/risk ratio. As expected with the known VEN safety profile, both VEN+R and VEN+BR are associated with hematologic and GI toxicity, which appears manageable. Laboratory TLS was rare ( Disclosures Zinzani: Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees. Topp:Amgen: Consultancy, Honoraria, Other: travel, Speakers Bureau; Roche: Honoraria, Other: travel; Pfizer: Consultancy, Other: Travel; Boehringer: Consultancy, Other: Travel, Research Funding; Jazz: Consultancy. Rusconi:Janssen: Consultancy, Other: Congress attendance; Takeda: Consultancy; Teva: Consultancy, Other: Congress attendance. Fleury:Novartis: Consultancy, Speakers Bureau; Lundbeck: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau. Pro:Celegene: Honoraria; Seattle Genetics: Honoraria; Takeda: Honoraria. Hsu:Genetech, Inc.: Employment. Punnoose:Genetech, Inc.: Employment. Hilger:Genetech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Hiddermann:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding.

Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373–379, 2011). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1–16) and two prior bortezomib-containing regimens (range, 0–9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination.

Introduction BCL2 is an anti-apoptotic protein overexpressed in CLL and critical in the pathogenesis of the disease; venetoclax (VEN) is an orally available, selective BCL2 inhibitor. Bendamustine (B) and rituximab (R) combination has demonstrated efficacy in relapsed/refractory (R/R) and previously untreated (frontline, 1L) patients (pts) with CLL. Preclinical data suggest that VEN+BR may provide synergistic activity in pts with CLL. Clinical data from VEN, both as a single-agent and in combination with R, support VEN+BR combination in CLL. We report an ongoing phase 1b study (NCT01671904) that is evaluating as primary objectives the maximum tolerated dose (MTD) of VEN when combined with BR, plus safety, tolerability, and order of administration to reduce toxicities of this combination in R/R or 1L CLL pts. Methods Pts with ECOG PS ≤1, 0-3 prior chemotherapy lines, and adequate marrow, hepatic, renal and coagulation function are being enrolled in dose finding cohorts and subsequent safety expansion cohorts, ranging from VEN 100 to 400 mg/day (3+3 dose escalation design). Pts are assigned to one of two dosing schedules (Fig 1) with VEN (Schedule A) or BR (Schedule B) introduced first; both include a gradual VEN dose ramp-up and other prophylactic measures to reduce the risk of tumor lysis syndrome (TLS) and risk stratification for TLS (high, intermediate and low). On completing combination therapy, pts continue single-agent VEN until disease progression (R/R CLL) or up to 18 months (1L CLL). Dose-limiting toxicity (DLT) data are reviewed after all pts in a cohort have completed 21 days of combination treatment at the target VEN dose and focus on TLS and cytopenias. Efficacy is assessed by investigators (iwCLL guidelines; Hallek et al. 2008). Results At data cutoff (April 30, 2015), 30 pts have been treated; 20 R/R pts, 12 on Schedule A (3 at 100 mg, 3 at 200 mg, and 6 at 400 mg) and 8 on Schedule B (all at 400 mg), and 10 1L pts, 6 on Schedule A and 4 on Schedule B (all at 400 mg). Baseline characteristics are shown in Fig 2. Of 10 pts with reported cytogenetics, 2 have del(17p). Median time on study is 5.5 (range, 0.03-15.2) months. No safety difference between Schedules A and B was seen in the DLT observation period for R/R CLL pts; neither schedule exhibited any toxicities precluding choice of the highest administered dose of 400 mg daily VEN. Schedule B was chosen for R/R safety expansion due to potential for tumor debulking prior to VEN. Dose finding in 1L Schedule A also selected 400 mg; dose finding for Schedule B is ongoing. Of 30 safety-evaluable, 27 (90%) pts experienced any adverse event (AEs; Fig 3). Most common AEs were neutropenia and nausea. Most G3 AEs were hematological toxicities; common non-hematological included diarrhea and hypertension. No TLS events (laboratory or clinical) were observed. There were 13 serious AEs in 10 (33.3%) pts, 8 (26.7%) due to study treatment. No deaths were reported. Of all 30 pts, 25 received VEN, with 5 still completing the BR only portion of Schedule B. Dose interruptions were seen in 13 pts mainly due to neutropenia for both VEN and BR; 8 pts had a VEN dose reduction. Early drug discontinuations (any reason): VEN, 2pts (gastroenteritis norovirus, progressive disease); BR together, 3 pts; B, 7 pts (commonly for neutropenia or physician decision); R, 1 pt. Across cohorts, 17/20 R/R CLL pts had response assessments; 100% responded, with 3 CRi. Response evaluation for 1L pts is early and evaluation across all cohorts and patients is ongoing. Full MRD data will be presented at the meeting, but early analysis shows pts exhibiting MRD negativity in peripheral blood, many as early as Cycle 4. Conclusion These early results report the first study evaluating the VEN+BR combination in pts with CLL. Daily VEN 400 mg can be safely combined with BR in patients with R/R CLL using both administration schedules (VEN or BR first), with 400 mg also established as safe for 1L pts with CLL under Schedule A. No TLS was observed with either administration schedule, despite many pts at medium (53%) or high (33%) TLS risk. VEN+BR is, as expected, associated with frequent hematologic toxicity, which appears manageable in most pts being treated, although 10 pts discontinued either B or BR prior to completing 6 cycles of administration. Early response and MRD data are promising. Disclosures Salles: Celgene Corporation; Roche: Speakers Bureau; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication. Boyd:Genentech, Inc.: Research Funding; Celgene: Speakers Bureau; US Oncology: Research Funding. Morschhauser:Genentech Inc./Roche: Other: Advisory boards. Wendtner:Roche: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Hallek:Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding. Eichhorst:AbbVie: Consultancy; Mundipharma: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau. Kozloff:Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy. Cartron:Gilead: Honoraria; GSK: Honoraria; Celgene: Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Li:Genentech, Inc.: Employment. Hilger:Genentech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Stilgenbauer:Roche: Honoraria, Research Funding.

The effect of expert opinion on demand for experience goods is difficult to quantify, as the relationship between purchases and reviews may be driven by product quality. Further, it is unclear whether a review-based demand effect is due to providing quality or existence information. Using a retail field experiment to overcome these obstacles, we find a significant positive average consumer response to expert opinion labels for wine. Demand decreases for low-scoring wines and increases for wines scoring average or higher. Results indicate that expert opinion labels transmit quality information as opposed to solely shelf visibility. © 2011 The President and Fellows of Harvard College and the Massachusetts Institute of Technology.

Introduction New therapies are needed for patients (pts) with chronic lymphocytic leukemia (CLL). BCL2 is an anti-apoptotic protein that is overexpressed in CLL and may be associated with resistance to available therapies; GDC-0199 is an orally available, selective BCL2 inhibitor. The combination of bendamustine (B) and rituximab (R) has demonstrated efficacy in relapsed/refractory (R/R) and previously untreated pts with CLL and is often used in these pts. Preclinical data suggest that GDC-0199 combined with BR may show synergistic activity in CLL. Moreover, clinical data from single-agent studies of GDC-0199, and in combination with rituximab in pts with CLL, support combining GDC-0199 with BR in this population. Data presented here are from an ongoing phase 1b study that is evaluating the maximum tolerated dose of GDC-0199 when given in combination with BR, as well as the safety, tolerability, and order of administration of this combination in R/R or previously untreated pts with CLL. Methods Pts with an ECOG PS ≤1, adequate marrow, hepatic, renal and coagulation function are being enrolled in dose finding cohorts ranging from 100 to 600 mg/day of GDC-0199 using a 3+3 dose escalation design. Pts are assigned to one of two dosing schedules (Figure 1) with GDC-0199 (Schedule A) or BR (Schedule B) introduced first, both incorporating a gradual dose ramp-up of GDC-0199 to reduce the risk of tumor lysis syndrome (TLS). Prophylaxis measures to mitigate TLS include IV hydration, treatment to prevent hyperuricemia and hospitalization. After completing combination therapy, R/R pts will continue single-agent GDC-0199 until disease progression. Previously untreated pts will continue single-agent GDC-0199 for up to 18 months. Dose-limiting toxicity (DLT) data are identified after all pts in a cohort have completed ³21 days of combination treatment at the target dose of GDC-0199 and focus on treatment emergent TLS and cytopenias. Figure 1 Figure 1. Results As of May 2014, 6 pts with R/R CLL have been enrolled in the dose finding stage of the study with a median time on study of 67 (range 43-113) days. All 6 pts were enrolled on Schedule A; 3 pts were enrolled in the 100 mg GDC-0199 cohort and 3 pts were enrolled in the 200 mg cohort. Baseline characteristics of the 6 pts are as follows: median age 67 (range 52-71) years, 3 male pts, median of 2 prior CLL therapies (range 1-3, including 4 pts with previous exposure to fludarabine, cyclophosphamide and rituximab [FCR] and 1 with previous exposure to FCR and B), beta-2 microglobulin ≥3.5 mg/L in 2 pts, and unmutated IGHV in 5 pts. Prior to starting therapy, the median lymphocyte count was 40.85 x 109 cells/L (range 2.11-169 x 109 cells/L), hemoglobin level was 101.5 g/L (range 99-134 g/L), neutrophil count was 2.54 cells/μL (range 1.81-3.8 cells/μL), and platelet count was 83.5 x 109/L (range 49-250 x 109/L). Pts were assigned to 1 of 3 TLS risk groups based on screening ALC and tumor bulk: low risk 1 pt, medium risk 4 pts, and high risk 1 pt. Cytogenetic data are available for 3 pts: 1 pt had del17p, 2 pts had del 11q, and 3 pts had del 13q. No DLTs were observed. All 6 pts have experienced adverse events (AEs, Figure 2). The most common AE was anemia with most Grade ³3 AEs being hematological toxicities (Figure 2). One serious AE of bronchitis was observed in a pt enrolled in the 100 mg GDC-0199 cohort and resolved after treatment. Two pts in the 100 mg GDC-0199 cohort discontinued BR after the 21-day DLT window secondary to treatment emergent cytopenia: 1 with neutropenia after completing 1 cycle of BR (previous treatment FCR without baseline cytopenia) and the second with thrombocytopenia after completing 3 cycles of BR (previous treatment FCR and chlorambucil with thrombocytopenia at screening). Both pts remain on single-agent GDC-0199. No TLS events (laboratory or clinical) were observed and no deaths reported. Figure 2 Figure 2. Conclusion This is the first study to evaluate the combination of GDC-0199 and BR in pts with CLL. Despite 5 pts being identified as medium or high risk for TLS, no pts developed TLS as a result of the ramp-up dosing of GDC-199 and prophylactic measures. The most frequent AEs were hematological toxicities and generally manageable; however, 2 pts had to discontinue BR (after 1 and 3 cycles) but were able to remain on GDC-0199. Dose escalation in R/R pts is continuing in order to evaluate the optimal dose/schedule with a plan to enroll previously untreated pts in the near future. Disclosures Boyd: Genentech: Research Funding; US Oncology/McKesson: Research Funding; Celgene: Consultancy. Morschhauser:Genentech: Travel grant Other; Gilead, Mundipharma, Bayer, Spectrum, Celgene: Honoraria. Wendtner:AbbVie, Genentech, Hoffman-La Roche, Mundipharma: Consultancy, Research Funding. Lymp:Genentech: Employment. Hilger:Genentech: Employment. Vosganian:Genentech: Employment. Huang:Genentech: Employment. Stilgenbauer:Genentech, Hoffman La Roche: Honoraria, Research Funding.

Background Thalidomide and its immunomodulatory drug (IMiD) derivatives such as lenalidomide (LEN) have shown great promise as treatment options for multiple myeloma (MM) patients (pts). Pomalidomide (POM) is a newer IMiD with high in vitro anti-MM potency that has shown promise as an effective treatment option for relapsed/refractory (R/R) MM pts. Recent data has shown POM to be effective in combination with dexamethasone (DEX), even for patients who are refractory to bortezomib and lenalidomide (Richardson et al, 2012). It has been demonstrated that the addition of pegylated liposomal doxorubicin (PLD) to lenalidomide and thalidomide is effective for both R/R and frontline MM pts (Offidani et al, 2006; 2007). Our recent trial evaluating lenalidomide in combination with dexamethasone, PLD, and bortezomib (DVD-R) showed that both efficacy and tolerability may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). These results imply that the combination of POM, DEX and PLD may be an effective regimen for treating R/R MM pts. We conducted a phase 1/2 trial investigating the safety and efficacy of POM in combination with IV DEX and PLD using our modified dose, schedule, and longer 28-day cycle for pts with R/R MM. Methods For enrollment into the phase 1 portion of the study, eligible pts had to show progressive MM at the time of enrollment. For participation in the phase 2 portion, pts had to be refractory to LEN (singe-agent or in combination) demonstrated by progressive disease while receiving this IMiD or relapsed within 8 weeks of their last dose. Pts who received previous POM treatment were ineligible. During the phase 1 part of the trial, POM was administered orally at 2, 3, or 4 mg daily in 3 successive cohorts of 3 pts each on days 1-21 of each 28-day cycle. DEX (40 mg intravenously over 30 min) and PLD (5 mg/m2infused over 30-90 min) both were given on days 1, 4, 8, and 11 of each cycle. POM doses were escalated per cohort until maximum tolerated dose (MTD) was reached. Phase 2 patients were all enrolled at what was established as the MTD. Results As of July 9, 2013, 33 pts were registered: 11 and 22 enrolled in the phase 1 and 2 portions, respectively. Fifteen patients have discontinued treatment thus far and 18 remain active. Pts had received a median of 5 prior treatments (range, 1-18) with a median of 1 prior PLD regimen (range, 0-2) and 1 prior IMiD regimen (range, 0-4). Pts have completed a median of 4 cycles (range: 0-8) with a median of 3.2 months of follow up (range: 0-9.7). During the phase 1 portion, no dose-limiting toxicities were identified, so the highest administered dose of 4 mg was initially established as the MTD. However, neutropenia ≥ G3 was observed in 10/17 phase 2 pts (58.8%) at this dose; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all phase 2 pts beyond the 29thpt (n = 4). Thirty-two pts have received study drug. Twenty-nine pts were evaluable for response at data cutoff as 3 were active but had not yet had any post-baseline disease assessments. Of the 29 considered evaluable, overall response rate and clinical benefit rates were 34.5% and 48.3%, respectively, Six pts (20.7%) showed stable disease while 8 (27.6%) pts exhibited progressive disease. There was ≥ grade 3 (G3) neutropenia in 12 (37.5%) pts. Two pts experienced this toxicity during the phase 1 portion (3 mg and 4 mg doses- 1 each) whereas the other 10 pts experienced this side effect at the 4 mg dose during phase 2 enrollment. Following the lowering of the MTD to 3 mg due to this issue, neutropenia (≥ G3) has not been observed to date. Other treatment-emergent AEs ≥ G3 occurring in more than 1 pt were leukopenia in 12 (37.5%), lymphopenia in 8 (25%), anemia in 3 (9.4%), hyponatremia in 3 (9.4%), thrombocytopenia in 2 (6.3%), and duodenal ulcers in 1 (3.4%) pts. One pt died during treatment due to sepsis. Conclusions Results from this phase 1/2 trial demonstrate that the combination of pomalidomide with dexamethasone and PLD using a 28-day cycle shows efficacy for MM pts with progressive disease who are refractory to lenalidomide. Notably, less neutropenia has been observed at the 3 mg dose of pomalidomide, with 4 mg POM dosing associated with a high incidence of ≥ G3 neutropenia when used in this three-drug combination. Disclosures: Berenson: Celgene: Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vescio:Celgene: Speakers Bureau.

8599 Background: Recent data has shown that single-agent CFZ can produce responses among MM pts refractory to previous treatment regimens including those containing BTZ. We conducted an intrapatient phase I/II trial investigating the safety and efficacy of CFZ as a replacement for BTZ in BTZEcontaining regimens to which pts have progressed. Methods: Eligible pts progressed while receiving their most recent BTZEcontaining regimen after at least 4 doses of BTZ at ≥1.0 mg/m² in ≤4 weeks per cycle. CFZ replaced BTZ in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each cycle. Treatment continued using the same dose(s) and schedule(s) of each drug administered in the BTZEcontaining regimen. CFZ doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m² or until a maximum tolerated dose (MTD) was reached for that regimen. Results: Of 37 enrolled pts, 33 were evaluable for efficacy and 37 for safety. Pts received a median of 4 prior treatments (range, 1-23) and 2 different BTZ-containing regimens (range, 1-13). Pts were treated with CFZ and a variety of different combinations of agents, including: bendamustine, clarithromycin, cyclophosphamide, dexamethasone, melphalan, methylprednisolone, pegylated liposomal doxorubicin, thalidomide, lenalidomide, and ascorbic acid. Pts have completed a median of 3 cycles with 12 pts going on to maintenance. One of 14 combinations, CFZ + ascorbic acid + cyclophosphamide, has reached a MTD at 45 mg/m2. Clinical benefit was seen in 23 (70%) evaluable pts (complete response = 6%; very good partial response = 18%; partial response = 21%; minor response = 24%) with another 18% showing stable disease. The median time to progression is 8.8 mo. (95% CI: 6.4-11.1 mo.) with 21 pts progressing overall and 9 progressing on study treatment. The most common ≥ G3 adverse events were lymphopenia (35% of pts), thrombocytopenia (19%), neutropenia (11%), and anemia (8%). Conclusions: These results suggest that replacement of BTZ with CFZ in a BTZ-containing combination regimen to which a MM patient is failing often leads to responses and is well-tolerated. Clinical trial information: NCT01365559.

8598 Background: POM is a newer IMiD immunomodulatory compound with high in vitro potency that has shown promise in combination with DEX as an effective treatment option for R/R MM patients (pts), even those refractory to bortezomib and lenalidomide (LEN). We conducted a phase I/II trial investigating the safety and efficacy of POM in combination with IV DEX and PLD using a modified dose and longer 28-day schedule in R/R MM pts. Methods: Phase I pts had progressive MM at the time of enrollment that was R/R to at least one anti-MM regimen. Phase II pts had to be refractory to LEN (singe-agent or in combination) demonstrated by progressive disease while receiving LEN or relapse within 8 weeks of its last dose. During phase I, POM was administered orally at 2, 3, or 4 mg daily in 3 successive cohorts of 3 pts each on days 1-21 of each 28-day cycle. DEX was administered IV at 40 mg over 30 min and PLD was administered at 5 mg/m2as an IV infusion over 30-90 min on days 1, 4, 8, and 11 of each cycle. POM doses were escalated until maximum tolerated dose (MTD) was reached. Once MTD was reached, all subsequent pts were enrolled at that dose. Results: To date, 27 pts have been enrolled, with 18 evaluable for efficacy and 19 for safety. Pts received a median of 5 prior treatments (range, 1-18) with a median of 1 prior PLD regimens (range, 0-2). Pts have completed a median of 1 cycle (range: 0-8) with a median of 1.4 months of follow up (range: 0-7.1). No DLTs were seen during phase I, which established the MTD at 4 mg. Phase II has enrolled 16 pts at 4 mg so far. Clinical benefit was seen in 7 (39%) of evaluable pts (partial response = 22%; minor response = 17%) with another 44% showing stable disease. Common ≥ G3 adverse events included leukopenia (32% of pts), neutropenia (32%), lymphopenia (26%), and hyponatremia (16%). Neutropenia at ≥ G3 occurred in more than half of patients on the phase II trial (4 mg POM). Conclusions: The combination of pomalidomide with dexamethasone and PLD on a 28-day cycle shows efficacy for R/R MM pts. However, because of excessive ≥ G3 neutropenia, POM is being reduced to 3 mg for newly enrolled patients. Clinical trial information: NCT01541332.

Abstract 4063 Background: Carfilzomib has shown promise in treating both newly diagnosed and relapsed/refractory MM patients. Recent data has suggested that single agent carfilzomib can produce a response for MM pts refractory to previous treatment regimens, including prior bortezomib-containing regimens. We conducted an intrapatient Phase 1/2 trial investigating the safety and efficacy of carfilzomib as a replacement for bortezomib in bortezomib-containing regimens to which pts have progressed. Methods: Eligible pts had to have progressed while receiving their most recent bortezomib-containing regimen after at least 4 doses of bortezomib at ≥ 1.0 mg/m2 in ≤ 4 weeks per cycle. Patients treated with bortezomib-containing combination regimens, including alkylating agents, anthracyclines, glucocorticosteroids, and/or immunomodulatory agents were eligible. Carfilzomib replaced bortezomib in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each 28 day cycle. For each pt, carfilzomib doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m2 or until maximum tolerated dose (MTD) was reached for that regimen. Aside from carfilzomib replacing bortezomib, regimens utilized the same dose(s) and schedule(s) of each drug administered in the most recent bortezomib-containing regimen to which the patient was refractory. Results: The trial has currently enrolled 32 of 45 planned patients. Pts received a median of 6 prior treatments (range, 1–18) and 2 different bortezomib-containing regimens (range, 1–13). Pts were treated with carfilzomib and 13 different combination regimens at varying doses and schedules. Agents in these combination regimens varied per patient, potentially including any of the following: ascorbic acid, bendamustine, clarithromycin, cyclophosphamide, dexamethasone, lenalidomide, melphalan, methylprednisolone, pegylated liposomal doxorubicin, and/or thalidomide. Six patients received a regimen containing IMiDs (thalidomide or lenalidomide). Pts have completed a median of 3 cycles (range: 0–12) with a median of 5.9 months of follow up (range: 0.4–14.1). To date, 1 regimen, carfilzomib + ascorbic acid + cyclophosphamide, has reached MTD with the maximum dose of carfilzomib (45 mg/m2) without any DLTs. Efficacy data stems from 24 of 32 enrolled pts who have completed at least 1 cycle of treatment. Clinical benefit was seen in 18 (75%) pts (complete response = 8.3%; very good partial response = 16.7%; partial response = 29.2%; minor response = 20.8%) with another 16.7% showing stable disease. Notably, response was achieved for each type of agent included in the trial across a variety of specific treatment combinations. Only 3 pts have progressed while on study, one with progressive disease after an initial response. Kaplan-Meier analysis reveals the median progression-free survival (PFS) at this point in the study to be 10 months (95% confidence interval: 8.6–11.2). The median time to progression (TTP) and duration of response (DOR) have not yet been reached. Safety data stems from all 32 enrolled pts. The most common grade 3/4 hematologic adverse events include: thrombocytopenia, occurring in 16 pts (G3: 5; G4: 2); lymphopenia occurring in 12 pts (G3: 6; G4: 1) and fever occurring in 2 pts (G3). The most common grade 3/4 non-hematologic adverse events include: fever, occurring in 8 pts (G3: 2); urinary tract infection, occurring in 3 pts (G3: 1); sepsis occurring in 1 pt (G4); pneumonia occurring in 2 pts (G3: 1); tumor lysis syndrome occurring in 1 pt (G3). Ten pts experienced a serious adverse event on study. Conclusions: These early results suggest that carfilzomib is an effective and tolerable replacement for bortezomib among pts who are refractory to bortezomib-containing combination regimens. These results appear to be applicable to a variety of combination regimens consisting of a wide array of therapeutic agents. Disclosures: Berenson: Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau.