Citations

Abstract Background: Synthetic lethality (SL) is characterized by the chemical inhibition of multiple aberrant genes to differentially kill malignant cells. We investigated small-molecule combinations for SL through in vitro and in vivo screening and optimization studies (as in the granted patents in USA and China) and demonstrated the synergistic potential of best-in-class combinations of targeted agents, drug repositioning, immune modulation and low-dose combinations. We hypothesize that BTK and mTOR inhibition coupled with an IMID will target multiple key signaling pathways, improve differential apoptosis and target acquired drug resistance. DTRM-555, an optimized mechanism-based combination, consists of the clinically differentiated BTK inhibitor DTRMWXHS-12 (or DTRM-12), everolimus (EV) and pomalidomide (POM). In xenograft tumor models, DTRM-555 administered orally has demonstrated superior efficacy over monotherapy at very low dose combinations of the three agents (1/18 of DTRM-12, 1/6 of EV, and 1/6 of POM). DTRM-12 monotherapy has been safe and well tolerated in simultaneous phase Ia trials (US and China) with preliminary efficacy across 50 mg through 400 mg once daily (QD). Here we report the US clinical results of the oral combination therapies DTRM-505 (DTRM-12 plus EV) and DTRM-555 (DTRM-12 plus EV plus POM) for the first time (NCT02900716). Methods: The safety and anti-tumor activity of the oral doublet therapy DTRM-505 and the oral triplet therapy DTRM-555 are evaluated using a "3+3" study design. Enrollment was conducted concurrently with a phase Ia study of DTRM-12 monotherapy; with DTRM-505 opened for accrual when monotherapy DTRM-12 cleared the 200-mg dose level. Eligible patients are at least 18 years old, having ECOG performance status less than 2 with relapsed/refractory chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL) or classical Hodgkin lymphoma (cHL). Study treatment is administered daily for 21 consecutive days over a 28-day cycle. The dose-limiting toxicity (DLT) period was defined during the first cycle of therapy, and treatment was continued until disease progression or unacceptable toxicity. Patients underwent tumor evaluations every 2 months and response was recorded using revised response criteria (IWCLL and Cheson 2014). Results: Between 9/2016 and 7/2018, 19 patients have been treated with DTRM-12 monotherapy in the USA (6 pts, 50-300 mg) and China (13 pts, 50-400 mg). Patients have tolerated up to 23+ cycles of DTRM-12 monotherapy. Seven patients, including DLBCL, CLL, MCL, FL and cHL, have been treated with oral doublet therapy DTRM-505 for 2 to 12 cycles. Three patients (2 DLBCL, 1 FL) have been treated with oral triplet therapy DTRM-555, including one patient transitioned from the doublet DTRM-505 under an exploratory arm. No patient has discontinued due to an adverse event (AE) and no DLT has occurred. Recurring AEs are mostly grade 1 or 2 and responses have been seen with DTRM-505 and DTRM-555 across diverse lymphoma histologies (See Tables). All patients evaluable for response demonstrated partial response to DTRM-505 and DTRM-555, with 2/7 (doublet) and 3/3 (triplet) patients remaining on therapy. Conclusion: The maximum tolerated dose has not been reached for DTRM-12 monotherapy and for the current fixed dose doublet and triplet combinations. Toxicities have been mild and repeated cycles of study treatment have been well tolerated without delays of subsequent treatment cycles. Enrollment continues for refractory lymphoma patients to demonstrate the safety and efficacy for the first-in-class oral triplet therapy DTRM-555. Disclosures Huntington: Janssen: Consultancy; Bayer: Consultancy; Celgene: Consultancy. Schuster:Merck: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Dava Oncology: Consultancy, Honoraria; Physician's Education Source, LLC: Honoraria; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. He:Zhejiang DTRM Biopharma Co. Ltd.: Other: Founder and CEO; Zhejiang DTRM Biopharma LLC: Other: Founder and CEO. Shen:Zhejiang DTRM Biopharma LLC: Other: Clinical Operations Director. Kennard:AbbVie, Gilead, Verastem: Consultancy. Dwivedy Nasta:Incyte: Research Funding; Takeda/Millenium: Research Funding; Debiopharm: Research Funding; Pharmacyclics: Research Funding; Rafael/WF: Research Funding; Aileron: Research Funding; Roche: Research Funding; Merck: Other: DSMC; Celgene: Membership on an entity's Board of Directors or advisory committees. Landsburg:Takeda: Consultancy; Curis: Consultancy, Research Funding. Porter:Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Genentech: Other: Spouse employment; Kite Pharma: Other: Advisory board. Svoboda:Bristol-Myers Squibb: Consultancy, Research Funding; TG Therapeutics: Research Funding; Kyowa: Consultancy; Regeneron: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; KITE: Consultancy. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zhu:Beijing Cancer Hospital: Employment. Brander:Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Ding:Merck: Research Funding. Mato:Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AstraZeneca: Consultancy; Regeneron: Research Funding; Celgene: Consultancy; Acerta: Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Portola: Research Funding; Johnson & Johnson: Consultancy; Prime Oncology: Honoraria; Medscape: Honoraria.

Abstract Age-related clonal hematopoiesis (CH) is a common condition that is associated with an increased risk of hematologic malignancies (HM) and cardiovascular disease (CVD). The majority of candidate driver mutations occur in epigenetic regulatory genes such as ASXL1, DNMT3A, and TET2 genes. However, a significant proportion of older people harbor clonal hematopoiesis without candidate driver mutations. In older women, clonal hematopoiesis can also be detected by the human androgen receptor A gene (HUMARA) assay regardless of the presence or absence of candidate driver mutation(s). The HUMARA assay evaluates non-random X-inactivation (NRX-I) as a marker for clonal hematopoiesis. The purpose of this study is to evaluate the association between NRX-I and cardiovascular risk factors and other health correlates. We screened for NRX-I in 904 women ages 65 and older participating in an ongoing, prospective cohort study in Oregon (Women Engaged in Advancing Health Research [WEAR] study). This approach was used to enhance the investigation of changes in CH that occur over time that may prove to be impactful for health outcomes. We examined the HUMARA results and any association with previous health history using a cross-sectional study design. Analysis of variance and logistic regression analyses were used to examine the relationship between HUMARA assay results and baseline CVD risk, controlling for age and race. HUMARA assay results were quantified and 3 groups were established: random X-inactivation, NRX-I, and extremely skewed NRX-I. No significant differences were detected between groups with respect to age, race, education, reproductive health indices or body mass index. With respect to cardiovascular risk factors, women with extreme NRX-I were more likely to be lifetime non-smokers compared to women without NRX-I and those with NRX-I with less skewing (P: 0.049), though no difference was seen in the proportion of current smokers (P: 0.213) and the total pack years smoked by those with a smoking history (P: 0.846).The proportion of subjects reporting statin or other cholesterol lowering medication did significantly differ between groups, with 24.3% women without NRX-I reporting statin use, versus 30.4% in women with NRX-I, and 36.7% in women with NRX-I extreme skewing (P: 0.005). Post-hoc pairwise tests showed significant differences between women with no NRX-I and women with NRX-I extreme skewing (P: 0.004). Cardiovascular event history differed significantly between the three groups of interest. 5.6% of women without NRX-I reported a history of transient ischemic attack (TIA), cerebral vascular accident (CVA), or myocardial infarction (MI) versus 7.0% in the NRX-I group and 11.0% in the NRX-I with extreme skewing group (P: 0.05). Post-hoc pairwise tests showed significant differences between women with no NRX-I and women with NRX-I extreme skewing (P: 0.043). The adjusted odds of TIA, CVA, or MI more than doubled (OR: 2.15, 95%CI: 1.14-3.42) among women with extremely skewed HUMARA results compared to women with NRX-I, controlling for age, high cholesterol, smoking history, hypertension, and type II diabetes. Cholesterol was also found to be independently associated with TIA, CVA, and MI. Women with hypercholesterolemia were 1.84 times as likely to report a history of TIA, CVA, or MI compared to women without hypercholesterolemia (95% CI: 1.06, 3.20). In summary, prediction of major adverse cardiac events is based on the presence of traditional risk factors including high blood pressure, high cholesterol, uncontrolled diabetes, smoking, and family history. Yet there is significant residual risk; many will still die from CVD without these risk factors. NRX-I, in addition to enriching for mutations known to confer CVD and HM risk; may be a marker for additional and unique health risks. An association between NRX-I, high cholesterol, and history of TIA, CVA, and MI, supports the current biological hypothesis that clonal hematopoiesis, perhaps irrespective of the cause or underlying driver mutation, is a driver for CVD. Disclosures Druker: Celgene: Consultancy; Fred Hutchinson Cancer Research Center: Research Funding; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Beta Cat: Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; McGraw Hill: Patents & Royalties; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Monojul: Consultancy; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Henry Stewart Talks: Patents & Royalties; Millipore: Patents & Royalties; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding. Dao:Incyte: Consultancy.

Abstract Abstract 2836 Monoclonal antibodies (mAb) are an effective but non-curative treatment of CLL. Although the mechanisms of action of mAb in vivo are not fully defined, complement dependent cytotoxicity (CDC) appears to play an important role. We have previously shown that addition of ofatumumab (OFA) significantly increases alemtuzumab (ALM) CDC in vitro and identified a subpopulation of CLL cells that are intrinsically resistant to activated complement. We propose that resistance to CDC could be an important cause of mAb treatment failure in CLL patients. To test the hypothesis that CLL cells treated in vivo with OFA would be resistant to subsequent OFA retreatment in vitro, we studied CLL cells and serum from 10 previously untreated patients with progressive CLL treated with pentostatin, cyclophosphamide, and ofatumumab (PCO). Methods. Patients received 300 mg of OFA followed by 2 mg/m2 of pentostatin and 600 mg/m2 of cyclophosphamide on day 1 of therapy. Samples were taken prior to treatment (S1), immediately after the OFA infusion and prior to chemotherapy (S2), and post-chemotherapy before the second dose of OFA on day 2 (S3). Mononuclear blood cells isolated from EDTA anticoagulated blood by Ficoll-Paque centrifugation were purified to achieve a concentration of > 90% CLL. CDC was assayed at a concentration of 2 × 106/ml CLL cells with 10 mg/ml of ALM (Genzyme), OFA (G.S.K.) or rituximab (RTX)(Genentech) in AIM V medium (Invitrogen, CA) and 10% normal human serum (10%NHS)(Sigma, MO) as a source of complement for 1 hour at 37°C. Absolute viable cell counts were measured by flow cytometry using counting beads (Trucount, BD, CA) and propidium iodide staining (Sigma, MO) with a FACSCalibur (BD, CA) and CellQuest Pro software (BD, CA). Percent CDC was calculated relative to counts for CLL cells treated with only 10%NHS. Binding of mAb and C3b to CLL cells was measured by flow cytometry with mouse anti-human Fc antibody FITC-HB43 and anti-C3b antibody FITC-7C12. C5 deficient serum (C5-serum)(Sigma, MO) was used to examine mAb and C3b binding without CDC. Results were expressed as delta mean fluorescent intensity (dMFI) relative to cells treated without mAb in 10%NHS or C5-serum as appropriate. Complement (CH50) was measured based on lysis of opsonized sheep red cells using standard methods. OFA concentrations in serum samples were determined by measuring the level of binding to Daudi cells compared to standards as previously described. Results: S1 CLL cells were significantly more susceptible to in vitro OFA CDC (median 30%) than S2 and S3 cells (both 0%, p=0.002)(Fig. 1). In contrast, high levels of CDC (median 86 – 88%) were induced in vitro by ALM in all these samples and prior in vivo exposure to OFA did not affect susceptibility to ALM CDC in vitro (p>0.1). CLL cells from S2&S3 had low levels of OFA binding both prior to and post in vitro exposure to OFA (median dMFI 2 and 3 respectively) which was significantly less than OFA binding for S1 (median dMFI 38 p=0.002) likely reflecting in vivo trogocytosis of bound OFA and CD20, as previously described for RTX. In vitro ALM binding was higher than OFA (median dMFI>150) in all specimens. C3b binding was low in S2&S3 both before and after in vitro OFA exposure (median dMFI 3 and 4 respectively) with significantly higher levels in S1 (median dMFI 94, p=0.002). C3b binding was higher in all CLL cells treated with ALM (median dMFI>358). OFA treatment resulted in marked decreases in serum complement levels in S2 (median 86%, range 65–98%) and S3 (median 78% range 61–88%) compared to S1. The median serum OFA concentration was 18.5 μg/ml (range 7.3–50.4) in S2 and 19.8 μg/ml (range 0–32.3) in S3. Conclusions: Circulating CLL cells from patients treated with OFA are resistant to in vitro OFA CDC primarily because of low levels of expression of CD20. The reduction in complement titers could limit in vivo CDC but we found no evidence that low levels of OFA were important. Cells surviving OFA in vivo do retain sensitivity to ALM CDC. Our data support the previous description of trogocytosis in CLL patients treated with RTX and suggest that lower doses of these mAb, that promote far lower levels of trogocytosis, could be more effective in sustaining CDC. In addition, our study provides pre-clinical data to support a clinical trial of combination therapy with OFA and ALM for CLL. Acknowledgment: This study was supported by funding from GlaxoSmithKline and the University of Iowa/Mayo Clinic Lymphoma SPORE (CA097274). Disclosures: Taylor: Genmab: Consultancy; Glaxo Smith Kline: Research Funding. Zent:GlaxoSmithKline: Research Funding; Genentech: Research Funding; Genzyme: Research Funding.

Abstract Background Distinguishing Clostridioides difficile infection from colonization is challenging in patients with Inflammatory Bowel Disease (IBD). Cycle threshold (Ct), the cutoff for PCR positivity, has been investigated in non-IBD patients. Methods Patients with positive C. difficile PCR (25 IBD, 51 non-IBD) were identified retrospectively. Fifteen-day outcomes were assessed. Results Ct correlated with diarrheal days in non-IBD (P = 0.048), but not IBD patients (P = 0.769). IBD patients had shorter LOS and less severe infection, but more diarrheal days (P < 0.05). Conclusions IBD patients had a milder course but Ct results were not significant. Larger studies are needed to clarify utility of Ct in IBD.

Abstract Abstract 3899 BACKGROUND: Although chemoimmunotherapy (CIT) has substantially improved response rates, treatment free survival, and overall survival in patients with chronic lymphocytic leukemia (CLL), only 40–50% of patients achieve a complete remission and the majority have residual disease when evaluated using sensitive assays for minimal residual disease (MRD). While these facts generated interest in consolidation strategies for patients with residual disease, previous trials of alemtuzumab-based consolidation found excess morbidity/mortality. In 2008 we began a trial of lenalidomide-based consolidation for patients with previously untreated CLL who had received 6 cycles of CIT induction. Preliminary analysis suggested that lenalidomide consolidation may improve the quality of response and prolong time to retreatment (Shanafelt; ASH 2010), although follow-up was short (median 16 months). METHODS: Eligible patients were previously untreated and had CLL in need of treatment according to the NCI-WG criteria (Blood 111:5446). Treatment schema consisted of 6 cycles of pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2) and rituximab (375 mg/m2) given every 21 days (Blood 109:405). All patients completing 6 cycles of PCR induction, underwent complete restaging including evaluation for MRD using sensitive flow cytometry. Patients subsequently received 6 months of lenalidomide consolidation by daily administration with a starting lenalidomide dose of 5 mg/day and escalation to 10 mg/day after the first cycle as tolerated. Patients again underwent complete restaging including MRD evaluation after 6 months of lenalidomide. At the time of restaging, MRD negative patients entered observation. Those with residual disease continued on lenalidomide and underwent repeat MRD assessment every 3 months until an MRD negative state was achieved. RESULTS: 45 patients were enrolled at Mayo Clinic between 3/2008 and 12/2009 of whom 44 were eligible. Median age was 65 (range: 44–78) and 71% of patients were male. 61% of patients had intermediate Rai risk and 39% high Rai risk. On prognostic testing 32% were CD38+, 52% Zap-70+, 52% IGHV unmutated, and 16% had high risk FISH (del 17p13; del 11q22). Of the 38 eligible patients who completed 6 cycles of PCR induction, 34 (89%) initiated lenalidomide consolidation. Thus by intent to treat analysis, 34/44 (77%) patients starting CIT with PCR were able to receive consolidation therapy. Among the 34 patients who initiated consolidation, the median number of cycles of lenalidomide received was 6 (range: 1–29). Nine of 34 (26%) patients had the lenalidomide dose increased to 10 mg daily while 18 (53%) required a reduction to 5 mg every other day. Five patients are still on lenalidomide at the time of this report. No cases of tumor lysis syndrome or tumor flare reaction were observed. Adverse events deemed at least possibly related to lenalidomide consolidation included 23 (68%) patients with grade 3+ hematologic toxicity and 5 (15%) with grade 3+ non-hematologic toxicity. Among the 34 patients who received at least 1 cycle of lendalidomide, 6 patients have improved the quality of their response including 3 patients who converted from having residual disease to a MRD- state. After a median follow-up of 29 months, 39/44 patients are alive and the median duration of response has not been reached. To date 8/44 (18%) patients have progressed to require additional treatment. Finally, since the eligibility criteria were nearly identical to our historic trial of PCR without lenalidomide consolidation, we conducted an intent to treat analysis that compared all 44 patients in the present trial (i.e. regardless of whether they received lenalidomide consolidation) to the 64 patients previously treated on our PCR trial (Blood 109:405). The demographic and prognostic characteristics of patients in the two studies were similar. With the caveat it represents a comparison across phase II trials, the proportion of patients free of retreatment at 30 months was 79% (95% CI:67–93) for PCR followed by lenalidomide consolidation vs 66% (95% CI: 54–80) for PCR alone (Figure 1). CONCLUSION: Lenalidomide-based consolidation for CLL patients receiving first-line CIT induction appears to improve the quality of response and prolong time to retreatment. Randomized clinical testing of lenalidomide-based consolidation appears warranted. Disclosures: Shanafelt: Celgene: Research Funding; Hospira: Research Funding; Genentech: Research Funding. Off Label Use: PCR-Lenalidomide (off label use of pentostatin and lenalidomide). Tun:Celgene: Research Funding. Kay:Biothera: Research Funding; Clegene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Glaxo Smith Kline: Research Funding; Hospira: Research Funding; Novartis: Research Funding; Supergen: Research Funding; Calistoga: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Emergent Biosolutions (Formerly Trubion): Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 283 Background: Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The antibody-drug conjugate (ADC) brentuximab vedotin (SGN-35) delivers the highly potent antimicrotubule agent monomethyl auristatin E (MMAE) to CD30-positive malignant cells by binding specifically to CD30 on the cell surface and releasing MMAE inside the cell via lysosomal degradation. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest, and results in apoptotic death of the CD30-expressing tumor cell. In a previous phase 1 study with brentuximab vedotin dosing every third week, 11 of 12 patients (92%) treated at the maximum tolerated dose of 1.8 mg/kg had tumor reductions and 6 of 12 patients (50%) achieved an objective response (complete remission [CR] + partial remission [PR]). Methods: A pivotal, phase 2, single-arm, multicenter study was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory HL post autologous stem cell transplant (ASCT). Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. The primary endpoint was the overall objective response rate (ORR) as assessed by an independent review facility according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: A total of 102 patients with relapsed or refractory HL were treated at 26 study centers. Median age was 31 years (range 15–77) and approximately half of the patients were female (53%). Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 (41%) or 1 (59%). All patients had previously received an ASCT and the median number of prior chemotherapy regimens was 4 (range 1–13). More than 70% of the patients had primary refractory disease, defined as failure to achieve a CR or progression within 3 months of completing frontline therapy. In addition, 39% of patients had lymphoma that was refractory to the most recent salvage therapy excluding ASCT. The median duration of brentuximab vedotin treatment on this study was 27 weeks (range 3–54) and the median number of cycles was 9 (range 1–16). The most common (>15%) treatment-related adverse events (AEs) of any grade were peripheral sensory neuropathy (43%), fatigue (40%), nausea (35%), neutropenia (19%), diarrhea (18%), and pyrexia (16%); most events were Grade 1 or 2. Grade 3 treatment-related AEs reported in >1 patient were neutropenia (14%), peripheral sensory neuropathy (5%), thrombocytopenia and hyperglycemia (3% each), and fatigue (2%). The only Grade 4 treatment-related events were neutropenia (4%), and thrombocytopenia, abdominal pain, and pulmonary embolism (1% each). No related Grade 5 events were observed. 18 patients discontinued treatment due to an AE. Consistent with findings from the phase 1 study, 97 patients (95%) had a reduction in tumor size per investigator assessment. Of the 35 patients who had B symptoms at baseline, 29 (83%) experienced resolution of these symptoms. The median time to B symptom resolution was 3 weeks (range <1–16 weeks). To date, 5 patients have received an allogeneic stem cell transplant as their first therapy after discontinuing treatment in the study; all of these patients remain in follow up. Per protocol, no interim analyses were planned for the primary endpoint of ORR by independent review. Independent assessment of ORR is being conducted and final efficacy results will be presented at the meeting. Conclusions: Brentuximab vedotin was associated with manageable adverse events and, based on investigator assessment, demonstrated encouraging activity in heavily pretreated patients with relapsed or refractory HL. Tumor shrinkage was observed in 95% of patients and the B symptom resolution rate was 83%. Final results of the independent assessment of ORR, as well as duration of response, progression-free survival, and updated safety data, will be presented at the meeting. Disclosures: Chen: Seattle Genetics, Inc.: Research Funding. Off Label Use: This clinical trial uses the investigational drug, brentuximab vedotin (SGN-35). Gopal:Seattle Genetics, Inc.: Research Funding. Smith:Seattle Genetics, Inc.: Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Klasa:Seattle Genetics, Inc.: Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Engert:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Larsen:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Seattle Genetics, Inc.: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; SBIO: Honoraria, Research Funding.

Abstract Background: Classical Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The standard of care for patients (pts) with relapsed or refractory (R/R) HL is salvage chemotherapy followed by high dose chemotherapy and autologous stem cell transplant (auto-SCT). Approximately 50% of these pts will experience relapse or progression of HL after auto-SCT. For these individuals, outcomes have historically been poor, with median overall survival (OS) from time of relapse ranging from 10.5 to 27.6 mos (Crump, 2008; Fanale, 2013). A pivotal phase 2 study evaluated brentuximab vedotin, a CD30-directed antibody-drug conjugate, in pts with R/R HL after auto-SCT (ClinicalTrials.gov #NCT00848926). Primary results and 3-year follow-up data have been previously reported (Younes, 2012; Gopal, 2015). Here, we summarize final data from the 5-year follow-up period. Methods: Pts received 1.8 mg/kg brentuximab vedotin once every 3 wks as a 30-min outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Assessments of response and durability of response per an independent review facility (IRF) have been previously reported. Following a protocol amendment that removed the requirement for routine CT scanning during the follow-up period, disease status was only assessed per the investigator. Survival and disease status were assessed every 3 mos for 2 yrs and then every 6 mos through Year 5. CT scans were required if progression was suspected clinically. At the time of the amendment, 18 patients were still being assessed for progression; these patients had been in long-term follow-up for a median of over 30 months. Results: The enrolled population of 102 pts (53% female) was heavily pretreated and had a median age of 31 yrs (range, 15-77 yrs). Pts received a median of 9 cycles (range, 1-16) of brentuximab vedotin. Per investigator, the ORR to brentuximab vedotin was 72% and complete remission (CR) rate was 33%. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events of Grade 3 or higher that occurred in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. At study closure, which occurred approximately 5 yrs after the last patient's end-of-treatment visit, the median observation time for all enrolled patients from first dose was 35.1 mos (range, 1.8 to 72.9). The estimated 5-year overall survival rate was 41% (95% CI: 31 %, 51%) and the median OS was 40.5 mos (95% CI: 28.7, 61.9 [range, 1.8 to 72.9+]). Median OS by best clinical response was CR (n=34): median not reached; partial remission (PR, n=39): 39.4 mos; and stable disease (SD, n=28): 18.3 mos. The median PFS was 9.3 months overall, but was not reached in CR pts. Of the 102 enrolled patients, 15 remained in follow-up and in remission at study closure. Among these 15 pts, 6 received consolidative allo-SCT and 9 have received no further therapy since completing brentuximab vedotin. Conclusions: These end-of-study results demonstrate that single agent brentuximab vedotin can induce durable remissions and long-term survival in a subset of heavily pretreated patients with relapsed/refractory HL, particularly in pts that achieve CR. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with AVD (doxorubicin, vinblastine, and dacarbazine) versus ABVD (A, bleomycin, VD) for frontline treatment of advanced HL (ECHELON-1 trial, ClinicalTrials.gov #NCT01712490). Figure 1. Overall Survival Figure 1. Overall Survival Disclosures Chen: Seattle Genetics: Consultancy, Research Funding; Genentech: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Gopal:BMS: Research Funding; Piramal: Research Funding; Emergent/Abbott: Research Funding; Millenium: Honoraria, Research Funding; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; BioMarin: Research Funding; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sanofi-Aventis: Honoraria; Merck: Research Funding. Smith:Seattle Genetics: Research Funding; Celgene: Consultancy, Speakers Bureau. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Rosenblatt:Seattle Genetics: Research Funding. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Engert:Takeda Millenium: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Larsen:Seattle Genetics Inc.: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Fong:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Janssen: Honoraria; Novartis: Research Funding; Incyte: Honoraria; Takeda Millenium: Honoraria; Celgene: Honoraria; Bristol Meyer Squibb: Honoraria; Curis: Research Funding; Bayer: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria; Johnson and Johnson: Research Funding.

Abstract Background: A phase III trial comparing thalidomide plus dexamethasone (Thal/Dex) versus dexamethasone alone (Dex) as first line therapy in newly diagnosed multiple myeloma (MM). The results of an interim analysis on 109 of 207 enrolled patients (pts) were reported earlier (Rajkumar et al, Proc ASCO 2004). This report provides results from 198 of 202 eligible pts entered on this study. Methods: Pts with newly diagnosed, untreated, symptomatic MM were eligible. Pts in the Thal/Dex arm (Arm A) received Thal 200 mg/day PO with Dex 40 mg on days 1–4, 9–12, and 17–20 PO. Pts in the Dex arm (Arm B) received Dex alone, at the same dose as Arm A. Therapy was repeated monthly. The primary endpoint was best response at 4 months on intent to treat basis. At 4 months pts could go off study for stem cell transplant or elect to continue therapy. Response was defined as a decrease in serum and urine monoclonal (M) protein by 50% or higher. If serum M protein was unmeasurable, a 90% or higher decrease in urine M protein was required. Responses had to be verified on 2 consecutive determinations separated by at least 2 weeks. Results: 207 pts were enrolled as planned: 103 randomized to Thal/Dex and 104 to Dex alone. Median age was 65 yrs. 6 pts were ineligble for failing to meet eligibility criteria for study entry and are excluded from response analysis. Response to therapy could be assessed at this time on 198 of 202 eligible pts. Response rate with Thal/Dex was significantly higher than with Dex: 58% versus 42%, respectively, (p=0.0164; one-sided Fisher’s exact test). The corrected response rate allowing for use of serum M protein levels in pts in whom a measurable urine M protein was unavailable at follow-up was 69% with Thal/Dex versus 51% with Dex. Median time to response was rapid, and similar in both arms (1.1 months). 3% of pts in the Thal/Dex arm and 5% in the Dex arm met criteria for disease progression within the first 4 months. Toxicity data are available on 204 pts. Grade 3 or greater non-hematologic toxicities occurred within the first 4 months/cycles in 68% of pts on the Thal/Dex arm and 43% in the Dex arm. Grade 3 or higher cardiac ischemia occurred in 3 (2 prior to 4 months, 1 approx. 1 wk after 4 months) pts in Arm A and 2 pts (both prior to 4 months) in Arm B. As a planned analysis, incidence rates of grade 3 or higher deep vein thrombosis (DVT), rash, bradycardia, and neuropathy and any grade 4–5 toxicity in the first 4 months were compared (see Table). The p-value (one-sided Fisher’s exact test) for increased toxicity (of the specified types) is <0.0001. In this period, 18 pts died, 7 in arm A and 11 in Arm B. Conclusions: Thal/Dex demonstrates superior response rates in newly diagnosed MM compared to Dex, comparable to historical results with VAD. The use of Thal/Dex must be weighed in each pt given the higher toxicities compared to Dex alone. Both regimens have low progression rates as pre-transplant induction therapy, and negate the need for intravenous VAD. Major Grade 3–4 toxicities Toxicity Arm A (n=102) Arm B (n=102) DVT (Grade>=3) 18% 3% Rash (Grade>=3) 4% 0% Sinus Bradycardia (Grade>=3) 1% 0% Neuropathy (Grade>=3) 7% 4% Toxicity of Any Type (Grade>=4) 34% 17% Total 46% 20%

Abstract Abstract 2742 Poster Board II-718 Background: The BCR-ABL inhibitor imatinib has revolutionized the treatment of CML, and improves the efficacy of chemotherapy in Ph+ ALL. Acquired imatinib resistance (IR) is an emerging problem. Patients who develop IR have a dismal prognosis and novel therapeutic strategies are needed. Mechanisms of resistance include mutations and overexpression of BCR/ABL. In addition, BCR/ABL-independent pathways may contribute to resistance. Mounting evidence suggests that aberrant histone deacetylase (HDAC) expression plays a key role in acquired IR. HDAC inhibition has been shown to downregulate BCR/ABL expression via multiple mechanisms. The functional effects of HDAC inhibition include cell cycle arrest and induction of mitochondrial damage and caspase-dependent apoptosis, both in cells that are imatinib sensitive (IS) and IR. We hypothesized that HDAC inhibition will demonstrate synergistic activity in combination with imatinib in IR cells. To test this hypothesis, we employed entinostat (SNDX-275), a novel, class I HDAC isoform selective inhibitor currently being tested in multiple phase 2 clinical trials. We explored the use of SNDX-275 alone and in combination with imatinib and dasatinib in IR and IS p210BCR/ABL expressing cell lines. Methods: K562 (p210BCR/ABL expressing CML cell line), IR K562 cells (Weisberg E, et al. Blood. 2000;95:3498), Ba/F3 cells, Ba/F3 cells transfected with p210BCR/ABL and Ba/F3 cells transfected with the T315I mutant form of BCR/ABL were treated with increasing concentrations of SNDX-275 (0.2 to 1.6μM), imatinib (0.1 to 1.6 μM), and dasatinib (0.3 to 250 nM) for 72 hours. The cells were also treated with combinations of SNDX-275 plus imatinib and SNDX-275 plus dasatinib at the same range of concentrations for 72 hours. All experiments were done in triplicate. Drug-related effects on cell viability were determined by MTT cytotoxicity assays. CalcuSyn software was used to calculate the IC50 for each drug in each cell line and to calculate the combination index (CI) for cell lines treated with combinations of imatinib or dasatinib plus SNDX-275. A CI from 0.9 to 1.1 indicates that the two drugs have an additive effect, below 0.9 indicates synergy between the two drugs and above 1.1 indicates antagonism. Results: In the Ba/F3 p210BCR/ABL and Ba/F3 T315I cells, SNDX-275 alone had minimal activity up to 1 μM. In K562 and IR K562 cells SNDX-275 alone led to significant cytotoxicity with an IC50 of 0.662 μM and 0.495 μM respectively. In the IR cell lines, cotreatment with SNDX-275 enhanced the activity of both imatinib and dasatinib. For the IR K562 cells, imatinib plus SNDX275 was potently synergistic with a CI of 0.6234. Dasatinib plus SNDX275 treatment of IR K562 cells was additive with a CI of 1.1015 (figure 1). Similarly, in the Ba/F3 T315I cells imatinib plus SNDX275 resulted in synergistic activity (CI = 0.87) and additive activity when treated with dasatinib plus SNDX275 (CI = 0.97). On the contrary, cotreatment of non-IR cell lines with dasatinib or imatinib plus SNDX-275 did not result in synergistic activity and revealed evidence of antagonism. In the K562 cells, the combination of imatinib plus SNDX-275 was antagonistic with a CI of 1.308 (figure 1A). In the Ba/F3 p210BCR/ABL cells, the combination of dasatinib plus SNDX-275 was strikingly antagonistic with a CI of 2.9. Conclusions: BCR/ABL-independent mechanisms of resistance, including aberrant acetylation of histone and non-histone proteins secondary to the deregulation of HDACs, contribute to IR in patients with CML and Ph+ ALL. Our data support this hypothesis, as the HDAC inhibitor SNDX-275 enhances the activity of imatinib and, to a lesser extent, dasatinib in IR p210BCR/ABL expressing cell lines. Therefore, SNDX-275 may represent a novel therapeutic approach to patients with IR CML and Ph+ ALL, and a phase I clinical study is planned. In contrast, SNDX-275 may antagonize the activity of the tyrosine kinase inhibitors in nonresistant CML and Ph+ ALL. To our knowledge, this is the first report of antagonism between a HDAC inhibitor and tyrosine kinase inhibitors in CML. Further investigation is necessary to define the mechanism and clinical significance of this antagonism. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Hypomethylating agents (HMA) such as 5-Azacitidine (Aza) have overall responses rate of ~35-50% in acute myeloid Leukemia (AML) and higher risk myelodysplastic syndrome (MDS) patients (pts). However, eventually all pts develop resistance on therapy. To improve upfront response rates and to address HMA failure, we performed genome-scale RNAi screens targeting genes on chromosomes 5 and 7, recurrent cytogenetic abnormalities in AML/MDS. These screens identified Hedgehog pathway (Hh) genes as potentially targetable vulnerabilities with Aza. Combination experiments with smoothened (SMO) inhibitors (SMO is a central activating gene within the Hh pathway) showed pre-clinical synergy. These and additional published data support the Hh pathway as a targetable vulnerability in AML, and provide a rational for a trial. Methods: A phase I/Ib protocol of the oral SMO inhibitor LDE225 (Sonidegib) in combination with Aza in untreated and relapsed/refractory (rel/ref) AML, chronic myelomonocytic leukemia (CMML), MDS, or MDS/myeloproliferative neoplasm overlap pts. Objectives of the phase I part are to determine safety, toxicity and MTD and for the phase Ib part to assess the preliminary overall efficacy. Sonidegib was started at dose level (DL) 0 at 400mg oral daily continuously and Aza at the approved doses (75mg/m2 x 7 days or days 5-2-2) with dose adjustment per label. A classical 3+3 design was used and DLT (CTCAE v4.0) defined as > grade 3 CPK elevation or hepatic or non-hematologic adverse events (AEs) lasting > 7 days or any grade 4 event, except for hematologic toxicities. DLT was assessed after 42 days when steady-state concentrations of Sonidegib were reached. Pharmacokinetic assessments were not performed for this study. Results: Patients and Dose Levels : Between 5/22/2014 and the data cut-off date (7/20/2015), 36 pts were enrolled. Median age was 72 y (range 52-85 y) and 64% were male. Most AML pts (23 of 24) had intermediate or unfavorable cytogenetics and most MDS/CMML pts were in the int.- to high-/very high-risk group (IPSS-R). Six pts were treated at DL-0 of Sonidegib 400mg/day and one DLT of CPK elevation was observed. Another patient had grade 4 neutropenia (which at the time was included in the DLT definition, later removed). Due to overall tolerance of the combination at DL 0 and investigator assessment, despite only 1/6 pts having a formal DLT, DL -1 at Sonidegib 200mg was explored at which 0/3 pts (1 pt non-evaluable) had DLT and the phase Ib portion was opened at DL -1. To date a total of 24 AML (13 newly dx, 11 rel/ref), 11 MDS/CMML (5 newly dx, 6 rel/ref ) and 1 myelofibrosis pt have been enrolled. Safety and Tolerability: An initial safety and efficacy assessment for 25 of the 29 pts treated on the phase Ib (n=26) + the MTD cohort of 200 mg (n=3) and for who at least 2 cycles of treatment follow up was available, showed that all pts experienced at least one grade-3 or 4 hematologic AE with a lower rate in the untreated vs. treated cohort. Other, non-hematologic grade-3 and 4 AEs respectively were seen in 24 and 28% of patients-most commonly hyponatremia and fatigue, known AEs for this drug class. Treatment delays occurred in 28% of pts and Aza or Sonidegib dose reductions in 16%. 23 (79%) pts are alive and 6 have died (21%), with one death while pt was actively treated but was deemed unrelated; 11 pts remain on study, with the remainder showing disease progression (n=3) or taken-off study for other reasons (n=3 each for AEs and did not want further treatment; n=4 other). Efficacy : As of 7/20/15 with a median treatment duration of 2 cycles, 2/5 untreated MDS/CMML pts achieved CR/CRi; 1 HMA rel/ref AML had CR; 1 untreated AML pt each had PR and MLFS. 90% of pts have not progressed. Updated results will be presented at the ASH 2015 meeting; by then all 29 pts will have completed a minimum of 4-6 cycles on study and full efficacy and AE result on all pts will be reported. To date the OS at 6 mo is 77% (95% CI: 44-97%) with a median PFS of 4 mo (range: 2-NR). Many pts in the untreated cohorts have just enrolled. Conclusion: Hh pathway inhibition with the clinically well tolerated SMO inhibitor Sonidegib in combination with Aza in MDS and AML pts is well tolerated with mostly hematologic AEs as expected with early signs of clinical activity in untreated and HMA-failure pts. Full efficacy results of 29 pts and updated safety data will be reported for this first combination trial of a SMO inhibitor in combination with a HMA in MDS and AML pts. Disclosures Mesa: Gilead: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; CTI Biopharma: Research Funding. Al-Kali:Novartis: Research Funding.