ALBERT

Description: Background: Cirmtuzumab is a first-in-class humanized mAb specific for ROR1, an oncoembryonic antigen found on CLL and cancer stem cells of various cancers, but not on normal post-partum tissues. Work has defined that ROR1 serves as a receptor for Wnt5a, which induces non-canonical Wnt-signaling that promotes planar-cell-polarity, migration, stem-cell renewal, and proliferation. Recent studies demonstrated that Wnt5a binds to ROR1 and induces activation of RhoA and Rac1, promoting leukemia-cell migration and proliferation, respectively. By binding a functional epitope in the extracellular domain of ROR1, cirmtuzumab can block ROR1-dependent, non-canonical Wnt5a-signaling. Methods: We conducted a phase 1 trial of cirmtuzumab in patients (pts) with progressive, relapsed/refractory CLL who were not amenable to approved therapies. The primary aims of the study were to evaluate the safety and tolerability of cirmtuzumab and determine the maximum tolerated dose and/or recommended phase 2 dose. Secondary endpoints included evaluation of antibody pharmacokinetics (PK) and pharmacodynamics (PD). To address these endpoints, pts received only 4 biweekly infusions of antibody at doses ranging from 15 mcg/kg to 16 mg/kg in a standard 3+3 pt-per-cohort schema. Results: As of a planned analysis, 20 pts have received cirmtuzumab. Pts tolerated cirmtuzumab extremely well without any noted drug-related severe adverse events or dose-limiting toxicities. Anemia (7 pts), thrombocytopenia (4 pts), and neutropenia (3 pts) were the most common AEs, were primarily grade 1, and were likely due to late-stage-disease-related cytopenias. We developed an ELISA assay to measure serum levels of cirmtuzumab capable of binding to the targeted epitope of ROR1. Peak concentrations were detected within one hour after the completion of each infusion. The serum concentrations of active cirmtuzumab increased with each subsequent infusion. We detected significant levels of cirmtuzumab for at least eight weeks following the last infusion and determined that it has half-life of 〉24 days (d). Twenty-four hours following the 1st infusion, the leukemic cells of pts treated at doses 〉/= 2 mg/kg had inactivation of RhoA and Rac1, which were each observed to be activated in all cases prior to therapy. Loss of GTPase activation also was observed for CLL cells sampled at later time points. Clinically, we observed that most pts had an initial increase in the ALC without evidence of disease progression, similar to what is observed with targeted therapies that inhibit B-cell-receptor/chemokine signaling. Such a redistributive lymphocytosis (defined as an increase in the ALC of 10% or more) was observed in 5 of 9 pts who received doses /=2mg/kg. The lymphocytosis typically peaked 24 hours after dosing (median 36% increase, range 10-76%), with a subsequent reduction to at or below baseline levels. Most pts had stable disease when assessed at the completion of treatment. Of evaluable pts, 12 had stable disease and 2 had progressive disease, both of whom received

Description: Background: Venetoclax (Ven), an orally bioavailable BCL2 inhibitor, is approved as monotherapy (Ven-mono) and in combination with rituximab (R; VenR) for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and combined with obinutuzumab in 1L CLL. Herein, we present the long-term efficacy data, including durability of response of continuous and fixed-duration therapy, from the initial phase 1b study (Seymour, et al. Lancet Oncol. 2017) of VenR in R/R CLL with median follow-up on study of 4.9 yrs. Methods: Pts with relapsed CLL received Ven daily (200 - 600 mg) and 6 - 9 doses of R over 6 mo, then Ven-mono (NCT01682616). Minimal residual disease (MRD) was assessed in bone marrow (BM) using multicolor flow cytometry (1 pt were pneumonia (n=2) and osteoarthritis (n=2). Thirty-three pts (67%) achieved CR or BM uMRD by 12 mo and opted to remain on Ven-mono (n=15) or stopped therapy with Ven due to good response (n=18) and stayed on study; DOR and PFS estimates using Kaplan-Meier methodology are presented in the Table. Of the 16 pts not achieving CR or uMRD by 12 mo and continuing therapy, all subsequently discontinued the trial (withdrew consent [n = 2], AEs [n = 2], progressive disease [PD] with CLL [n = 7], or Richter transformation [n = 5]). One pt (1/16) had PD at 36.9 mo (best response on therapy was partial response [PR]) and received an additional round of R treatment starting at 51.9 mo, but the disease did not respond to intensified treatment and the pt came off Ven at 58.4 mo. Of the 15 pts (CR or BM uMRD by 12 mo) who remained on Ven-mono long-term, PD occurred in 5 pts and 1 pt died in ongoing response due to myocardial ischemia (unrelated) (Figure). Two pts received an additional round of R treatment after PD, one at 55.3 mo (achieved uMRD CR [DOR post-R, 11.3+ mo]) and the other at 70.5 mo (recently restarted R). At data cut-off, 10 pts were in remission: 6 in CR (including 1 pt retreated with R and 1 pt who recently stopped Ven after 4.3 yr due to being disease-free) and 4 in uMRD PR. Response for the last pt post-R retreatment is pending. Of the 18 pts who stopped Ven in deep response (14 uMRD CR, 2 MRD-positive CR, 2 uMRD PR [Figure]), the median time on Ven prior to cessation was 16 mo (5 - 40) and median time off Ven is 40.3 mo (1.1 - 70.0) to date. Four have discontinued study without progression (withdrew consent [n = 2], elected for stem cell transplant [n = 1], lost to follow-up [n = 1]). Four pts (2 MRD-positive CR and 2 uMRD CR) had PD after stopping Ven (all asymptomatic) at 25.5, 29.0, 33.3 and 42.0 mo off Ven and have been re-treated with VenR or Ven-mono, and 3 have been re-evaluated for response. All achieved at least PR (2 without BM assessment so unevaluable for CR), with 2 having ongoing response. One pt with PR but residual BM infiltrate had subsequent PD 18 mo later. The fourth pt was recently re-treated with Ven-mono; response is pending. Two additional pts had PD off Ven and had not been re-treated as of the data cutoff; both remain on study. Conclusions: In relapsed CLL, VenR induces deep responses within 12 mo in 67% of pts. These responses are highly durable whether on continuous or limited duration therapy, with treatment-free remissions of 〉4 yr now being observed. Re-treatment of pts with Ven or VenR re-exposure has resulted in response in some pts. In addition to long PFS, which represents time to first PD or death, pts who cease Ven in deep response have the opportunity for further disease control through reintroduction of Ven. Disclosures Brander: AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; MEI: Research Funding; Acerta: Research Funding; Tolero: Research Funding; BeiGene: Research Funding; DTRM Biopharma: Research Funding. Seymour:Acerta: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy. Kipps:Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Velos-Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceutical Companies of Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Ma:Abbvie: Research Funding; Beigene: Research Funding; Janssen: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Acerta: Research Funding; Kite: Consultancy; Bioverativ: Consultancy; Incyte: Research Funding; Juno: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Xeme: Research Funding. Anderson:Walter and Eliza Hall Institute: Employment, Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.. Choi:Oncternal: Research Funding; Gilead: Consultancy, Speakers Bureau; Rigel: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. Humphrey:F. Hoffmann-La Roche Ltd: Employment. Masud:AbbVie: Employment, Other: Stock/stock options. Nandam:AbbVie: Employment, Other: Stock/stock options. Jacobson:AbbVie: Employment, Other: Stock or options. Roberts:Australasian Leukaemia and Lymphoma Group: Membership on an entity's Board of Directors or advisory committees; Walter and Eliza Hall Institute: Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.; AbbVie: Other: Unremunerated speaker for AbbVie, Research Funding; Janssen: Research Funding; BeiGene: Research Funding.

Description: Introduction: Venetoclax (VEN) based therapy has become a standard of care in front line and relapsed-refractory (R/R) CLL based on favorable efficacy and toxicity. Whereas prospective data regarding activity of therapies following ibrutinib (IBR) or idelalisib (IDE) are available in the settings of progression (VEN, non-covalent BTKi) and intolerance (acalabrutinib), how best to manage patients (pts) who discontinue (dc) VEN remains a key unanswered question. With the increased use of VEN in early lines of therapy (LOT; CLL 14, MURANO), the activity of BTK inhibitors (BTKi) and cellular therapies following VEN becomes a critical issue. No prospective study has addressed this question, and currently reported VEN clinical trials have limited information about subsequent treatments. While recent data describe VEN resistance mechanisms (Guieze 2018, Blombery 2019), the impact of VEN resistance on efficacy of post VEN therapies is unknown. To address this gap, we conducted an international study to identify a large cohort of pts who dc VEN and have been subsequently treated. Methods: We conducted an IRB approved multicenter (31 US, EU, South American sites, in partnership with UK CLL Forum and CORE registry), retrospective cohort study of CLL pts who dc VEN for any reason. We examined demographics, dc reasons, responses, survival, adverse events (AEs) and activity of post VEN therapies. Primary endpoints were overall response rate (ORR) and progression free survival (PFS) for the post VEN treatments stratified by treatment type (BTKi, PI3Ki and cellular therapy: CAR-T or alloHSCT). ORR was defined by iwCLL criteria and PFS was defined from VEN dc to disease progression (PD), death, or last follow up for next treatment. Pts were further stratified by BTKi (resistant / intolerant) and PI3Ki exposure prior to VEN. PFS-2 was defined as time from VEN start to tumor progression on IBR or death from any cause. Results: 326 CLL pts who dc VEN in the front line (4%) and R/R settings (96%) were identified. The cohort was 69% male, 87% white, median (med) age 66 (38-91) at VEN start, 27% treated with VEN based combinations (n=88, med 6 cycles anti-CD20 abs). Pre VEN prognostic features: 82% IGHV unmutated (n tested=166), 47% del17p (n=306), 45% TP53 mut (n=217), 39% complex karyotype (n=273), 23% BTK mut (n=79), 18% NOTCH1 mut (n=103), 10% PLCγ2 mut (n=74). Pts received med 3 therapies (0-11) prior to VEN; 40% were BTKi naïve (n=130), 60% were BTKi exposed (196) and 81% were IDE naïve (n=263). Most common reasons for VEN dc were PD (38%), AE (20%), Richter's transformation (RT, 14%), 8% pt preference, and HSCT 5%. Of 326 pts who dc VEN, 188 (58%) were treated with a subsequent LOT, 61 are alive and untreated and 77 died prior to a subsequent LOT. Post VEN sequencing analyses focused on BTKi, PI3Ki and cellular therapy (CAR-T or alloHSCT) activities following VEN dc (Table1). ORR to BTKi was 84% (n=44) vs. 54% (n=30, p

Description: Introduction Treatment of patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) with the combination of venetoclax (VEN), an oral, selective Bcl-2 inhibitor, and rituximab yielded an ORR of 84% (Roberts et al. Haematologica 2015). Treatment of such pts with VEN in combination with obinutuzumab (Gazyva®, Gazyvaro™, G), a Type II, glycoengineered anti-CD20 antibody, may yield even better treatment outcomes. We present preliminary efficacy and updated safety data from an ongoing phase 1b study (NCT01685892) evaluating this combination in R/R or treatment-naïve (TN) pts with CLL in alternate treatment schedules. Methods Pts with CLL with an ECOG PS ≤1 and adequate organ function are enrolled in a study with a 3+3 design and cohorts ranging from 100 to 600 mg/day of VEN. Pts are assigned to one of two dosing schedules, starting treatment with either VEN (Schedule A) or G (Schedule B). Both schedules include tumor lysis syndrome (TLS) risk mitigation based on disease burden at screening, which includes a gradual VEN ramp-up to the assigned cohort dose. Six cycles of combination therapy will be given and then pts with R/R disease continue single-agent VEN until disease progression; TN pts will receive single-agent VEN for an additional 6 months. Dose-limiting toxicities (DLTs) are identified during the first 21 days of combination therapy in Schedule A or the first 35 days of combination therapy in Schedule B, and focus on TLS, infusion related reactions, and cytopenias. Based on a safety review of data from this trial, the 600 mg cohort will not be explored. Response is first assessed before Cycle 4 according to 2008 International Workshop on CLL guidelines. Results As of April 20, 2015, 32 pts (26 R/R and 6 TN) have been enrolled. Four R/R pts were unenrolled after a sponsor-initiated clinical hold secondary to TLS events in other VEN studies. Patient characteristics include a median age 62.5 (range, 45-80) years, and 62.5% male pts. TLS risk was assessed in 28 pts following protocol modifications adopted after a Sponsor-initiated clinical hold; 96.4% were at medium or high risk for TLS. The highest VEN dose administered in this study was 400 mg/day (administered to 11 R/R and 6 TN pts). Median time on study was 5.5 (range, 0.1-19.6) mo. for all pts and 2.8 (range, 0.9-2.8) mo. for TN pts. Among pts exposed to VEN, dose interruptions were observed in 17/27 (63%) pts. A summary of AEs is presented in Figure 1. Laboratory TLS was observed in 4/32 (12.5%) pts and all were able to continue study treatment after resolution of electrolyte changes; no cases of clinical TLS occurred. One pt with R/R disease in cohort 1 discontinued study participation following disease progression (the pt completed 6 cycles of combination treatment). A second pt with R/R disease in cohort 1 died secondary to acute respiratory failure; Richter's transformation also was suspected in this pt but not confirmed. Twenty pts with R/R disease and 6 TN pts remain on the study. At least 1 response evaluation has been performed in 17 pts with R/R disease. The overall response rate (ORR) by investigator assessment was 100%; 4/17 (23.5%) pts achieved complete response/complete response with incomplete bone marrow recovery (CR/CRi). Among the 13 (76.5%) pts with PRs after 3 cycles of therapy, 3 have improved to CR/CRi at assessments 28 days after completing C6D1. Full MRD data will be available in the near future but early analyses suggest some patients may achieve MRD negative status by Cycle 4. Conclusion These preliminary data suggest that VEN + G can be safely administered in pts with CLL with no difference in tolerability between R/R and TN subgroups. AEs appear to be manageable and no pt has discontinued study participation secondary to cytopenia, the most frequently observed AE. Data suggests that the TLS prophylaxis measures are effective even in patients with a higher disease burden. An expansion phase is planned using a 400 mg per day dose of VEN in R/R and TN pts following a review of safety data assessing potential differences between dosing schedules. The preliminary efficacy data suggest this regimen may be an important option in patients with CLL; a phase 3 study evaluating VEN+G is ongoing. Disclosures Flinn: Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication. Brunvand:Celgene: Speakers Bureau; Millenium: Speakers Bureau. Choi:Gilead: Consultancy, Other: Advisory Board, Speakers Bureau; AbbVie: Consultancy, Other: Advisory Board, Research Funding. Dyer:Roche Pharmaceuticals: Speakers Bureau; ONO Pharmaceuticals: Research Funding; Gilead: Research Funding. Gribben:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Gilead: Honoraria; Roche/Genentech: Honoraria; Pharmacyclics: Honoraria. Hillmen:Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Research Funding. Jones:Acerta Pharma BV: Research Funding. Li:Genentech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Vosganian:Genentech, Inc.: Employment. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor; Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor.

Description: Introduction: Venetoclax (VEN) is a selective, orally bioavailable BCL-2 inhibitor. This is a phase 1b, study of VEN plus rituximab (R) to determine safety, PK and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). The recommended phase 2 dose for VEN plus R was previously reported to be 400mg/day. The aims of this analysis were to evaluate progression-free survival (PFS), overall survival (OS), and the durability of responses off all therapy in pts achieving CR. We also assessed minimal residual disease (MRD) status, which has previously been shown to be strongly predictive of PFS and OS after chemoimmunotherapy. Methods: Pts began once daily VEN (20 or 50 mg) to final cohort doses (200-600 mg/day) followed by R, given every 4 weeks for a total of 6 doses. VEN dosing was continuous. Responses were assessed by iwCLL criteria with CT scan and bone marrow (BM) biopsy after combination therapy (Month 7). MRD was assessed on BM aspirates in local laboratories using ≥4 color flow cytometry (minimum sensitivity of 0.01%). Results: 49 pts (48 CLL/1 SLL) were enrolled in 5 dose escalation cohorts (n=41; 200-600mg/day) and a safety expansion cohort (n=8; 400mg/day); results herein combine data from all cohorts. Median (range) age was 68 (50-88) years. The median (range) number of prior regimens was 2 (1-5). 45 (92%) received prior R and 14 (29%) had R-refractory disease; 29 (59%) received prior fludarabine and 9 (18%) had fludarabine-refractory disease. Of pts with available data, 9/46 (20%) had del(17p); 19/27 (70%) expressed unmutated IGHV. As of June 4, 2015, 12 pts have discontinued the study: 6 due to PD (5 were Richter's transformation), 3 due to AEs (neuropathy, TLS, and myelodysplasia [heavily pretreated and hypocellular marrow at study entry; pt achieved MRD-negative CR with incomplete marrow recovery, CRi, and proceeded to transplant]), and 3 withdrew consent (1 after achieving MRD-negative CR). The investigator-assessed ORR was 86% (42/49) with 20 (41%) CR/CRi, 1 (2%) nPR and 21 (43%) PR. 4 had SD, 2 had PD, and 1 died before assessment (fatal TLS). 9 with PR or SD at the 7 month assessment achieved CR after a median (range) additional time of VEN monotherapy of 6 (2-9) months. BM MRD was evaluated in 40 pts. MRD-negativity was achieved in 15/20 (75%) pts who achieved a CR/CRi and 26/49 (53%) overall. Disease has progressed in 5/42 (12%) responders; 89% are free from progression at 12-months. The median PFS has not been reached. At 12 and 24 months, actuarial PFS is 87% and 84%, respectively, with a median (range) follow-up for pts without events of 17.5 (0.03-32) months. 94% were alive at 12 months; the median OS has not been reached. Although the numbers are small, the ORR, CR rates, PFS, and OS were not significantly impacted by high-risk subgroups. 8 pts stopped VEN after achieving CR/CRi, 6 of whom were MRD-negative at the time. 2 withdrew from the study after achieving CR/CRi without evidence of progression; 6 remain in follow-up with a median (range) of 15 (4-24) months off VEN. The 2 MRD-positive pts had asymptomatic progression with rising lymphocytosis after 19 and 24 months off VEN; both are eligible for retreatment with VEN when clinically appropriate. Treatment-emergent AEs in 〉25% of pts were neutropenia (55%), diarrhea (53%), nausea (49%), upper respiratory tract infection (45%), fatigue and pyrexia (each 37%), cough (35%), and headache (33%). Grade 3/4 AEs in 〉10% were neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (10%). 1 treatment-emergent AE (TLS) led to death; no other fatal TLS events occurred after a protocol modification aimed at TLS risk management and prophylaxis. 2 deaths occurred after PD. Key efficacy data are summarized in the table. Conclusions: VEN plus R induces a high rate of deep and durable responses, independent of adverse prognostic factors, with a tolerable safety profile. 41% of pts achieved CR/CRi and 53% achieved BM MRD-negativity. Remission off all therapy has been maintained in pts achieving MRD-negative CR. The median PFS and OS have not yet been reached; 24-month PFS is estimated to be 84%. The high rate of MRD-negativity is an encouraging step towards prolonged PFS and durable elimination of CLL/SLL. VEN plus R versus bendamustine plus R is being evaluated in a phase 3 trial in pts with previously treated CLL (MURANO; NCT02005471). Table 1. Table 1. Disclosures Ma: Genentech, Pharmacyclics/Janssen and Gilead: Speakers Bureau; Genentech, Pharmacyclics/Janssen and Gilead: Consultancy; NCCN, AbbVie, Pharmacyclics, Novartis, Gilead, Celgene, and Xeme: Research Funding. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Seymour:Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: 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, Other: Travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kipps:Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria. Barrientos:Gilead, Pharmacyclics, and AbbVie: Research Funding; Pharmacyclics, Celgene, and Genentech: Membership on an entity's Board of Directors or advisory committees. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Anderson:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Choi:AbbVie: Consultancy, Other: Advisory Board, Research Funding; Gilead: Consultancy, Other: Advisory Board, Speakers Bureau. Tam:Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Mason-Bright:AbbVie: Employment, Equity Ownership. Prine:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Kim:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Roberts:Walter and Eliza Hall Institute of Medical Research: Employment; Genentech: Research Funding; AbbVie: Research Funding; Servier: Research Funding.

Description: Introduction: The overall outcome of patients (pts) with chronic lymphocytic leukemia (CLL) who relapse after or become refractory to treatment with B-cell receptor (BCR) signaling antagonists, including ibrutinib (IBR) or idelalisib (IDE), is recently being appreciated and appears quite poor. To date, no phase 2 studies have reported efficacy in this population. Venetoclax is a selective, potent, orally bioavailable BCL-2 inhibitor with a BCR-independent mechanism of action and substantial activity in pts with heavily pretreated relapsed or refractory CLL. We report preliminary results from an ongoing phase 2, open-label study evaluating venetoclax monotherapy in CLL pts relapsed after or refractory to IBR or IDE (NCT02141282). Methods: Pts with CLL relapsed after or refractory to IBR (Arm A) or IDE (Arm B) receive venetoclax monotherapy starting at 20 mg followed by a 5-step weekly ramp-up to a final daily dose of 400 mg. Pts with Richter's transformation (RT) suspected by screening PET CT or confirmed by lymph node biopsy are ineligible. The primary objectives are to assess the efficacy (investigator assessed overall response rate, ORR) and safety of venetoclax. Disease and response assessment was performed using iwCLL criteria at weeks 8, 24 and every 12 weeks thereafter. Adverse events (AEs) are monitored throughout the study. Results: As of April 30, 2015, 28 pts were enrolled in the study. Three screened pts were ineligible due to RT. Pt demographics are summarized by treatment arm in the table. Twenty-two entered into Arm A after a median duration on IBR of 15.5 months (range: 1-56). Investigator-reported best responses while on IBR prior to starting venetoclax were 14 partial response (PR), 4 stable disease (SD) and 3 progressive disease (PD); best response for 1 pt is unknown. Six entered into Arm B after a median duration on IDE of 9.7 months (range: 1-34). Investigator-reported best responses while on IDE prior to starting venetoclax were 1 complete response (CR), 3 PR and 2 SD. At last follow-up, the median time on venetoclax was 2.4 months (range: 0.1- 7) for Arm A and 1.7 months (range: 1.2-4.5) for Arm B. Venetoclax discontinuation occurred in 4 pts in Arm A (1 each due to respiratory failure, multi-organ failure, PD of RT, death of unknown cause) and in 1 pt in Arm B (PD prior to first assessment). Fifteen pts in Arm A and 3 in Arm B underwent Week 8 response assessment. In Arm A, 8/15 (53%) achieved a PR, 6/15 (40%) had SD, and 1/15 was inevaluable. In Arm B, 2/4 achieved a PR, 1/4 had SD, and 1/4 had PD prior to first assessment. Pts with SD had evidence of ongoing disease reduction, measured by decreasing circulating lymphocytes and lymph nodes. As of the cutoff date, 23 pts remain on venetoclax therapy. Compared to prior venetoclax monotherapy studies, no new safety signals for venetoclax were observed in either treatment arm. Treatment-emergent AEs (all grades) in 〉25% of the overall population were neutropenia (57%), anemia (35%), diarrhea (32%) and nausea (32%). Treatment-emergent grade 3/4 AEs in 〉10% of the overall population were neutropenia (43%; 3/12 of the neutropenic pts developed febrile neutropenia), anemia (29%), thrombocytopenia (18%), hypophosphatemia, hypoxia, leukopenia, and pneumonia (each 11%). Serious AEs in ≥2 pts overall were febrile neutropenia, increased blood potassium, multi-organ failure, and pneumonia (each 7%). Prior to study entry, 7/22 (32%) in Arm A received G-CSF support. One pt with high disease burden developed laboratory TLS in week 4, upon escalating to the 200 mg daily venetoclax dose, evident by hyperuricemia and hyperphosphatemia. Electrolytes returned to normal levels after a dose interruption and intervention. No pts experienced clinical TLS; laboratory changes were not clinically significant. Conclusions: In this group of pts with aggressive disease relapsed after or refractory to BCR-targeted agents, venetoclax monotherapy demonstrated early activity at the 8 week assessment, which occurred within 3 weeks of reaching the target 400 mg daily dose. The majority of evaluable pts achieved PR or SD. Venetoclax monotherapy exhibited a tolerable safety profile without events of clinical TLS. This is the first phase 2 study to show activity in a relatively uniform population of pts previously treated with BCR kinase inhibitors; the data suggests that venetoclax is active in these pts. Enrollment in both arms was ongoing as of the data cut. Figure 1. Figure 1. Disclosures Jones: Genentech, Pharmacyclics; institutional research funding from Abbvie, Pharmacyclics, Genentech, and Gilead: Other: Advisory Board. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Mato:AbbVie: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding. Coutre:AbbVie: Research Funding. Wierda:Genentech: Consultancy; AbbVie and Genentech: Research Funding. Choi:AbbVie and Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau; AbbVie: Research Funding. Davids:AbbVie and Janssen: Consultancy; Genentech and Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, TG Therapeutics, and Infinity: Research Funding. Lamanna:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Barr:Pharmacyclics: Research Funding; AbbVie and Pharmacyclics: Consultancy. Burns:AbbVie: Employment, Equity Ownership. Montalvo:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Busman:AbbVie: Employment, Equity Ownership. Potluri:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Byrd:Pharmacyclics: Research Funding; Genenttech, AbbVie, Acerta, Pharmacyclics: Other: Unpaid consultant.

Description: INTRODUCTION: Chronic lymphocytic leukemia (CLL) cells of nearly all patients (pts) express ROR1 (Receptor tyrosine kinase-like Orphan Receptor 1), an orphan-receptor tyrosine-kinase-like protein that is normally expressed during embryogenesis, but not by normal post-partum tissues. ROR1 is a receptor for Wnt5a, which can induce non-canonical Wnt signaling to enhance CLL-cell survival and/or proliferation. We have developed antibodies that bind to epitopes that span the extracellular portion of human ROR1, and selected one mAb that had the most potent activity in inhibiting such signaling. We fully humanized this antibody to generate UC-961 (cirmtuzumab). GLP-compliant studies demonstrated that this antibody does not cross-react with normal post-partum tissues. Preclinical pharmacology/toxicology studies in Sprague-Dawley rats showed no evidence of toxicity for cirmtuzumab at doses up to 400 mg/kg by IV administration with an apparent half-life exceeding 7 days. Studies in cynomolgus monkeys again showed no apparent toxicity with an antibody half-life of approximately 14 days. Based on these IND-enabling studies, we have initiated a first-in-human phase 1 dose escalation study to determine the safety and tolerability of cirmtuzumab in the treatment of pts with relapsed or refractory CLL. Here, we report results of planned interim safety analysis of pts in the initial phase 1 cohorts. METHODS: Key eligibility criteria included relapsed or refractory CLL and indication for therapy according to working group guidelines (iwCLL). The starting dose was 15 mcg/kg, based on preclinical modeling of 30% target saturation. Cirmtuzumab was administered every 14 days for a total of 4 doses, with intra-patient dose escalation in the absence of toxicity. Patients were enrolled in cohorts of 3 to 6 patients, with the most recently completed cohort receiving doses of 0.5 mg/kg to 1 mg/kg. Pre-planned analysis of safety and tolerability was conducted at the completion of a 56-day dose-limiting toxicity observation period. RESULTS: Between August 2014 and July 2015, 10 pts have received cirmtuzumab. The median age of the treated pts was 72 (range 58 to 81); the median number of prior therapies was 4 (ranging from 1-9). Nine pts had at least 1 high-risk prognostic factor, including leukemia-cell expression of ZAP-70 (4 pts), unmutated IGHV (5 pts), del(17p) or complex karyotype (5 pts). Cirmtuzumab was well tolerated. We have not observed ≥ grade 2 drug-related adverse events (AE) in any of the treated pts. The only grade 1 drug-related AE that occurred in more than 1 pt was anemia (3 pts), all of which resolved. One patient came off study due to continued disease progression after receiving a single dose of 15 mcg/kg; the rest of the pts received all four doses of cirmtuzumab, as per protocol. The low dose administered to patients in the first few cohorts precluded us from detecting sufficient cirmtuzumab in the plasma for pharmacokinetic studies. However, cirmtuzumab was detected in the plasma of pts in later cohorts, allowing us to estimate a half-life for cirmtuzumab of approximately 14 days. Response was assessed as per iwCLL criteria 2 months after the final dose of cirmtuzumab. 3 pts have not yet reached that time point, and 1 pt was not evaluable due to progresison and early study discontinuation. Of the 6 pts evaluable for response, 2 experienced continued disease progression and 4 met criteria for stable disease. With a median follow-up of 103 days after the completion of cirmtuzumab, 2 pts that had disease progression have required additional therapy; the other 4 have yet to require additional treatment. CONCLUSIONS: Cirmtuzumab is a first-in-class anti-ROR1 monoclonal antibody. In a phase 1 dose-escalation trial, pts with relapsed or refractory CLL have tolerated cirmtuzumab well, without any drug-related grade 2 or higher AEs. This is consistent with the preclinical profile and lack of target expression in normal tissues. The ongoing phase 1 study will evaluate the safety and tolerability of higher doses to determine the maximum tolerated dose or biologically optimal dose of cirmtuzumab. Disclosures Choi: Gilead: Consultancy, Other: Advisory Board, Speakers Bureau; AbbVie: Consultancy, Other: Advisory Board, Research Funding. Jamieson:J&J: Research Funding; GSK: Research Funding. Kipps:Gilead: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; AbbVie: Consultancy, Research Funding.

Description: BACKGROUND: The STAT and Wnt signaling pathways play critical roles in early lymphocyte development and function, with considerable cross-talk between them. STAT1 has been reported to be constitutively phosphorylated at SER727, and often at TYR701, in CLL patients. STAT1 activation can regulate the function of the IRF8 transcription factor. Polymorphisms of the IRF8 gene have been associated with both familial and sporadic CLL, and can influence Wnt signaling. Hence, both STAT1 and Wnt are potential pharmacologic targets for CLL therapy, particularly in patients that are resistant to, or intolerant of BTK and PI3K inhibitors. We previously reported that the electrophilic drug dimethylfumarate (DMF, Tecfidera, Fumaderm) could inhibit Wnt signaling in CLL. Here we have investigated its effects on constitutive and inducible STAT1 signaling, and on IRF8 expression, in primary CLL cells. METHODS: Primary leukemia cells from patients with CLL were cultured with DMF at pharmacologically relevant doses (3 uM to 30 uM) for 4 hours prior to analysis of STAT1 phosphorylation and IRF8 expression. We assessed the effect of DMF with and without pre-stimulation by lipopolysaccharide (LPS), Wnt3a, or a TLR7 agonist. To further evaluate the effect on CLL cells in a microenvironment that stimulates these pathways, we utilized a murine CLL xenograft model. We implanted primary leukemic cells from patients with CLL into the peritoneum of Rag2 deficient immune-compromised mice. Groups of mice were then treated with DMF at a dose of 10 mg/kg by oral gavage. CLL cells were retrieved 4 to 5 hours later by peritoneal lavage and analyzed. RESULTS: We confirmed that both SER727 and TYR701 are phosphorylated in the majority of primary CLL cells from both VH mutated (high risk) and unmutated (low risk) clones, but not in normal peripheral blood mononuclear cells (PBMC). A 4 hours exposure of CLL cells to DMF inhibited TYR701 phosphorylation, but had no effect on SER727 phosphorylation nor on total STAT1 levels. We also confirmed that IRF8 levels are 6-8 fold elevated in CLL cells, compared to normal PBMC. IRF8 expression was inhibited by DMF treatment in 7 out of 11 CLL patients. Similar effects were observed in vivo. Wnt or LPS stimulation increased IRF8 levels in normal PBMC, but did not alter the already elevated IRF8 levels in CLL cells. CONCLUSIONS: Activation of the STAT1/IRF8 pathway, like the Wnt pathway, is highly characteristic of CLL. DMF treatment of CLL cells can interrupt these signaling cascades, interfering with leukemia cell survival. Disclosures Choi: AbbVie: Consultancy, Other: Advisory Board, Research Funding; Gilead: Consultancy, Other: Advisory Board, Speakers Bureau.