ALBERT

Description: Abstract 2771 Background: NIL is a potent, highly selective Bcr-Abl kinase inhibitor approved for newly diagnosed adult pts with Philadelphia-chromosome positive (Ph+) CML-CP and in Ph+ CML-CP and accelerated-phase pts who are resistant or intolerant to IM. Achieving complete cytogenetic response (CCyR) and major molecular response (MMR, 3-log reduction of Bcr-Abl transcript level from the baseline mean) are favorable prognostic factors for CML. This multicenter, open-label study (ENABL) was designed to explore nilotinib Bcr-Abl effects in pts with CCyR but who have suboptimal molecular response to IM. Methods: This study evaluates change in Bcr-Abl trends in 2 groups of CML-CP pts (total n = 18) who achieved CCyR but have suboptimal molecular response to IM defined as: (Group 1) treated ≥ 1 year with IM, but Bcr-Abl transcript levels did not reach ≤ 0.1% on the international scale (IS) (MMR); or (Group 2) 〉 1-log increase in Bcr-Abl transcript levels from best response regardless of IM treatment duration. Pts are treated with NIL 300 mg twice daily for ≥ 1 year. RQ-PCR analysis is performed by a central lab at screening, then every 3 months (mos) for Group 1. Group 2 pts are monitored by RQ-PCR monthly for the first 3 mos, then every 3 mos. The 1° end point is change in Bcr-Abl transcript levels from a standardized baseline value by RQ-PCR at 12 mos. The data cutoff date for this analysis was June 30, 2011. Results: Eighteen pts (Group 1, n = 17; Group 2, n = 1) have been treated with NIL for a median of 17 mos on study (range 3–34 mos). Thirteen pts have been treated for ≥ 6 mos and 10 for ≥ 12 mos. One pt was deemed ineligible due to lack of evidence of CCyR at baseline but is included in the analysis because there was at least 1 post-baseline evaluation performed. The remaining 17 pts had CCyR at baseline. Before enrollment, pts were treated with at least 400 mg once-daily IM; the mean dose of prior IM treatment was 487 mg/day (range 342–786 mg/day). Median duration of prior IM treatment was 3.4 yrs (range 1.3–10.2 yrs). Three pts had prior interferon treatment. All 18 pts were treated for ≥ 3 mos and had ≥ 1 post-baseline RQ-PCR result. Overall, 15 of 18 evaluable pts (83%) achieved MMR during treatment; 10 pts by 3 mos, 1 pt by 4.5 mos (measured at end of study), 1 pt by 6 mos, 2 pts by 9 mos, and 1 pt by 30 mos (Figure 1). The 3 pts who did not reach MMR at any point were only followed for up to 3 mos before discontinuing from the trial but showed a decreasing Bcr-Abl trend. Overall, pts achieved a median log reduction of PCR transcript levels of 3.1 (0.08% IS) at 3 mos; median 3.3-log reduction (0.05% IS) at 6 mos, and median 3.5-log reduction (0.035% IS) at 9 mos. Four pts had 〉 4-log (≤ 0.01% IS) reduction in Bcr-Abl; of these, 2 pts reached 〉 4.5-log (≤ 0.0032% IS) reduction in Bcr-Abl at least once during the study. Median Bcr-Abl transcript log reduction at 12 mos was 3.6 (0.025% IS, 1° end point) for 10 evaluable pts. All these pts reached MMR during NIL treatment; 9 pts by 12 mos, 1 pt after 30 mos. NIL was well tolerated and brief dose interruptions were sufficient to manage most adverse events (AEs). Seven of 18 pts were dose reduced for NIL-related AEs and re-escalated if the patient recovered from the AEs. Patients were permitted to dose escalate to 400 mg b.i.d. per physician's discretion if MMR was not achieved after 6 mos (n = 1). The Grade 3 AEs reported include 2 cases of rash and 1 case each of pneumonia, squamous cell carcinoma, bladder prolapse, uterine prolapse, bradycardia, hypertension, hyperbilirubinemia and hypophosphatemia. The rashes and bradycardia were suspected to be related to NIL. No Grade 4 AEs were reported. The median dose intensity was 600 mg/day (range 300–683 mg/day). Five pts were discontinued from the study (3 due to abnormal laboratory values, 1 due to an AE, and 1 due to protocol violation). No pts who experienced QTcF changes had differences 〉 33 msec from baseline. No QTcF prolongation 〉 500 msec was observed. Conclusions: NIL treatment results in high molecular response rates in CML-CP pts with suboptimal molecular responses to IM. Overall 83% of pts who switched to NIL achieved MMR, and the median Bcr-Abl log reduction for pts who reached 12 mos on study was 3.6 (0.025% IS). The IRIS study has shown that MMR rates increase with time in pts treated with IM (Hughes Blood 2010); however, this study appears to demonstrate that MMR is achieved relatively quickly in suboptimal molecular IM-treated pts when switched to NIL. Disclosures: Ailawadhi: Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Akard:Eisai: Speakers Bureau; Bristol Myers-Squibb: Speakers Bureau; Novartis: Speakers Bureau; Millenium: Speakers Bureau; Chemgenex: Consultancy. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Lin:Novartis: Employment, Equity Ownership. Radich:Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. DeAngelo:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy.

Description: AMD3100 is a reversible inhibitor of the binding of SDF-1α to its cognate receptor CXCR4. Patients with MM and NHL given AMD3100 alone have increased circulating C D34+ cells. The purpose of the present study is to determine if AMD3100 added to a chemotherapy and G-CSF mobilization regimen can increase the circulating levels of PBSC, and the removal of such cells by leukapheresis. The only change to the standard care is the addition of AMD3100 to a cyclophosphamide (2.5 g/m2) mobilization for MM and either (R)ESHAP or (R)ICE in the case of NHL. In both arms G-CSF is given at 10 mcg/kg/d. AMD3100 is given after the first apheresis collection. To date, 10 patients (8 MM, 2 NHL) have completed the mobilization phase of the protocol. During recovery the mean number of PB CD34+ cells/μL was 191. This rose to 304 [2.0 fold increase, p=0.008] following the administration of AMD3100. The baseline collection resulted in a mean of 16.7 x 106 CD34+ cells/kg. This rose to 24.0 [1.8 fold increase, p=0.007] following the administration of AMD3100. Historic controls with MM receiving cyclophosphamide (4 g/m2), etoposide (400 mg/m2) and G-CSF had an inferior collection on day 2 [37.9 x 106 CD34+ cells/kg day 1 vs. 29.5 day 2, p=0.009]. Untoward events related to the combination of chemotherapy, G-CSF, and AMD3100 have not been noted. The 9 patients transplanted following this mobilization strategy have achieved an ANC 〉 500 at a median of 10 days, and platelet independence (〉20k) at a median of 11 days. Validation of this strategy continues in additional patient cohorts to assess alternative AMD3100 administration schedules and to define CD34+ cell recruitment/release during recovery from mobilizing chemotherapy.

Description: Abstract 2206 Poster Board II-183 Background Nilotinib is a potent, highly selective Bcr-Abl kinase inhibitor approved for adult patients with Ph+ CML in chronic and accelerated phase who are resistant or intolerant to imatinib. The achievement of a major molecular response (MMR), defined as a 3 log reduction of the Bcr-Abl transcript level from the baseline mean, is a favorable prognostic factor for the disease at any time point. This multi-center, open-label study was designed to assess the impact of nilotinib on Bcr-Abl molecular response dynamics in patients who have achieved complete cytogenetic response but have demonstrated a suboptimal molecular response to imatinib. Methods This study evaluates the change in Bcr-Abl kinetics in 2 groups of CML-CP patients (n=160) who achieve CCyR but have a suboptimal molecular response to imatinib defined either as: (Group 1) treated 〉 1 year with imatinib, but Bcr-Abl transcript levels did not reach ≤ 0.1% on the international scale (IS) (MMR); or (Group 2) 〉 1 log increase in Bcr-Abl transcript levels regardless of the imatinib treatment duration. At study entry, patients are treated with nilotinib 300 mg b.i.d. The primary endpoint is to measure the change on a logarithmic scale of Bcr-Abl transcript levels from a standardized baseline value by RQ-PCR after 12 months on treatment with nilotinib. Since there is a paucity of efficacy data published for suboptimal responders to imatinib, this preliminary analysis was performed on a small cohort of patients enrolled as of the data cut-off date of July 21, 2009. Results 11 CML-CP suboptimal molecular responding patients have been treated with a median of 2.6 months on nilotinib. One patient entered the study as a Group 2 patient and ten entered into Group 1. 1 patient was deemed ineligible due to lack of evidence of CCyR at baseline. The remaining 10 entered the trial with a baseline CCyR. Prior to enrollment, patients were treated with at least 400mg QD imatinib; the mean dose of prior imatinib treatment was 463 mg/day (range 377 – 573 mg/day). The median duration of prior imatinib treatment was 39.5 months (range 14.0-106.4 mo). 1 patient was previously treated with interferon. 8 patients have been treated for 〉3 months. Out of these 8 patients, 2 have been treated for 〉 6 months and 1 patient has been treated for 〉 9 months. Aside from these 8 patients, another 3 did not yet reach end of Month 3 at the time of analysis. Six out of 8 evaluable patients (75%) achieved MMR; 4 patients after three months on nilotinib, 1 patient after 4.5 months on nilotinib (measured at end of study), and 1 patient after 9 months on nilotinib. Overall, patients achieved a median log reduction of PCR transcript levels of 3.1 (range 2.1-4.5) from the standardized baseline (based on the IS) at the end of Month 3. 4 out of 11 patients were dose reduced for nilotinib related adverse events (AEs). No grade 4 AEs were reported. 1 patient experienced a grade 3 headache and two cases of grade 3 elevated ALT were reported. Brief dose interruptions were sufficient to manage most AEs. The median dose intensity was 600 (range 400-600 mg/day). No patients discontinued from the study due to an AE as of the data cut-off date. No patients who experienced QTcF changes had differences 〉34 msec from baseline. No QTcF prolongation 〉500 msec was observed. Conclusions Nilotinib treatment results in high rates of molecular response in CML-CP patients with suboptimal molecular responses to imatinib. 75% of the evaluable patients who switched to nilotinib achieved MMR at the time of analysis, and all evaluable patients achieved a median 〉 3 log reduction of PCR transcripts from the standardized baseline within 3 months of starting therapy. No patients were discontinued due to AEs. Outcomes for additional patients enrolled and longer term follow-up will become available. Disclosures: Yang: Bristol Myers Squibb: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Esai: Speakers Bureau; Therepi: Equity Ownership. Off Label Use: Nilotinib for suboptimal responders to imatinib therapy. Miller:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Akard:Novartis: Consultancy, Research Funding. DeAngelo:Bristol-Myers Squibb: Speakers Bureau; Celgene: Speakers Bureau; Enzon Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Speakers Bureau. Goldberg:Novartis Pharmaceuticals: Research Funding, Speakers Bureau. Williams:Novartis Pharmaceuticals: Employment. Radich:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding.

Description: Background: B cell maturation antigen (BCMA) has recently emerged as a promising candidate antigen for therapeutic targeting in multiple myeloma (MM), with several targeted agents in clinical studies including antibody-drug conjugates and bispecific T cell engagers as well as CAR T cells. The Antibody-Coupled T cell Receptor (ACTR) platform is a universal, engineered autologous T cell therapy developed to mediate anti-tumor activity in combination with tumor-targeting antibodies. The ACTR construct is composed of the ectodomain of CD16 fused to intracellular co-stimulatory and CD3ζ signaling domains (Kudo et al., Cancer Res. 2014), which allow ACTR T cells to exert antibody-dependent cell-mediated cytotoxicity, a function otherwise physiologically limited to CD16-expressing natural killer cells and macrophages. ACTR087 expresses a 4-1BB-containing receptor and has been evaluated in combination with rituximab in subjects with relapsed or refractory (R/R) CD20+ B cell lymphoma as previously reported (Akard et al., Blood 2017). SEA-BCMA is a novel, humanized non-fucosylated anti-BCMA IgG1 antibody that has been demonstrated pre-clinically to bind to ACTR087 T cells to mediate ACTR T cell activation, cytotoxicity, cytokine release, and proliferation in the presence of BCMA-expressing MM cell lines. These functional activities were demonstrated to be BCMA-specific and SEA-BCMA dose-dependent (Cheema et al., AACR 2017). Here we present preliminary findings from the first 2 single-subject cohorts of the ATTCK-17-01 study (NCT03266692), an ongoing Phase 1 study of ACTR087 in combination with the first-in-human administration of SEA-BCMA. Methods: ATTCK-17-01 is a multicenter, Phase 1, dose-escalation study of ACTR087 in combination with SEA-BCMA. The primary objectives are to characterize the safety and to determine the recommended Phase 2 dose of ACTR087 in combination with SEA-BCMA in subjects with R/R MM. The secondary objectives include evaluation of anti-myeloma activity, ACTR T cell persistence, cytokines, and SEA-BCMA pharmacokinetics (PK); exploratory objectives include the anti-myeloma activity of SEA-BCMA alone. Subjects must have measurable disease and must have received at least 3 prior lines of therapy including treatment with a proteasome inhibitor and an immunomodulatory agent, and hematopoietic stem cell transplant (HSCT) for HSCT-eligible subjects. BCMA expression on MM cells was not a condition of eligibility. Dose escalation of the 2 investigational agents, ACTR087 and SEA-BCMA, is determined according to adaptive design principles. After study enrollment and leukapheresis, subjects receive SEA-BCMA by IV infusion once every 3 weeks until disease progression or treatment discontinuation. After the third dose of SEA-BCMA and lymphodepleting chemotherapy (cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2, each daily for 3 days), subjects receive a single dose of ACTR087. Results: Two subjects enrolled and received ACTR087 at the first dose level in combination with the first 2 dose levels of SEA-BCMA. First-in-human dosing of SEA-BCMA was well tolerated, with no reported SEA-BCMA-related adverse events (AEs) or dose-limiting toxicities (DLTs). Following ACTR087 infusion, ACTR+ T cells were detectable in the peripheral blood and demonstrated expansion post-infusion. No DLTs were observed with the combination of ACTR087 and SEA-BCMA in the first 2 cohorts. Grade 3 or higher treatment-emergent AEs experienced by at least 1 subject, regardless of causality assessment, include cytopenias, increased ALT, and bone pain. Conclusions: ACTR087 in combination with SEA-BCMA was well tolerated in the first 2 subjects treated, with no DLTs or AEs leading to treatment discontinuation. These results support the continued dose escalation of ACTR087 in combination with SEA-BCMA. Enrollment in Cohort 3 is ongoing. Updated data, including SEA-BCMA PK, biomarkers, and preliminary Cohort 3 data, will be presented. Disclosures Holmes: Unum: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; Novartis: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Rigel: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy. Hari:Kite Pharma: Consultancy, Honoraria; Janssen: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen Inc.: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Exter:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Cheema:Unum Therapeutics Inc.: Employment. Sienczylo:Unum Therapeutics Inc.: Employment. O'Meara:Seattle Genetics: Employment, Equity Ownership. Sussman:Seattle Genetics: Employment. Akard:Gilead: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau.

Description: During acute inflammation, 3 neutrophil subsets are found in the blood: neutrophils with a conventional segmented nucleus, neutrophils with a banded nucleus, and T-cell–suppressing CD62Ldim neutrophils with a high number of nuclear lobes. In this study, we compared the in vivo kinetics and proteomes of banded, mature, and hypersegmented neutrophils to determine whether these cell types represent truly different neutrophil subsets or reflect changes induced by lipopolysaccharide (LPS) activation. Using in vivo pulse-chase labeling of neutrophil DNA with 6,6-2H2-glucose, we found that 2H-labeled banded neutrophils appeared much earlier in blood than labeled CD62Ldim and segmented neutrophils, which shared similar label kinetics. Comparison of the proteomes by cluster analysis revealed that CD62Ldim neutrophils were clearly separate from conventional segmented neutrophils despite having similar kinetics in peripheral blood. Interestingly, the conventional segmented cells were more related at a proteome level to banded cells despite a 2-day difference in maturation time. The differences between CD62Ldim and mature neutrophils are unlikely to have been a direct result of LPS-induced activation, because of the extremely low transcriptional capacity of CD62Ldim neutrophils and the fact that neutrophils do not directly respond to the low dose of LPS used in the study (2 ng/kg body weight). Therefore, we propose CD62Ldim neutrophils are a truly separate neutrophil subset that is recruited to the bloodstream in response to acute inflammation. This trial was registered at www.clinicaltrials.gov as #NCT01766414.

Description: Background Mixed chimerism, a persistent or increasing number of host cells, after allogeneic hematopoietic stem cell transplant (allo-HSCT) is a predictor of disease relapse. Donor lymphocyte infusion (DLI) has the potential to enhance the graft vs. malignancy effect and reduce the risk of relapse in patients with mixed chimerism (MC) and in patients at high-risk (HR) for relapse. Hence, there is a motivation to utilize DLI for patients with hematologic malignancies while in complete remission (CR) after transplant to prevent disease relapse. To assess the safety and efficacy of DLI after allo-HSCT, in both the relapsed and non-relapsed settings, records of 88 patients receiving DLI between 2003 and 2015 at a single institution were retrospectively reviewed. Patients & Methods Median age at time of transplant was 53 (range, 18-68 years). Fifty-four patients received allo-HSCT from related donors (RD) and 34 patients received allo-HSCT from matched unrelated donors (MUD). Reasons for DLI were relapsed/residual disease (n=52, 59%), MC with no evidence of disease (n=29, 33%), and HR with no evidence of disease (n=7, 8%). 44 of 52 relapsed/residual disease patients received treatment before DLI (41 chemotherapy, 4 other, 7 no treatment). 17/52 patients (33%) were treated within 6 months of transplant, the rest after 6 months.DLI was administered according to a dose-escalating protocol in 4-8 week intervals. Starting dose varied based on donor and disease status: 1.0x107 CD3+ cells/kg for relapse/residual RD, 3.0x106 CD3+ cells/kg for relapse/residual MUD, 3.0x106 CD3+ cells/kg for MC/HR RD and 1.0x106 CD3+ cells/kg for MC/HR MUD. Endpoints to discontinue DLI included: full donor chimerism (FDC), remission, GvHD development, disease progression, or lack of further donor cells. Results Median interval from transplant to DLI was 195 days (range, 50-2026 days) and median number of DLI infusions was 2 (range, 1-7 infusions). From first DLI, 1 year overall survival (OS) rates were 52%, 83%, and 86% for relapse/residual, MC, and HR populations respectively. 5 year OS rates were 27%, 70%, and 71%, respectively. Cumulative incidence of acute GvHD grade III-IV and extensive chronic GvHD was 33% (29/88 patients). Six patients died of GvHD-related toxicities (7%). In the relapsed setting, 31/52 patients (60%) responded to DLI with disease control, of whom 12/52 (23%) had durable remissions/disease control while 19/52 (36.5%) eventually relapsed or had disease progression. Thirty-four patients had MC at the time of relapse, and 20/34 patients (59%) returned to FDC after DLI. All 14 patients who did not re-establish FDC after DLI relapsed or had disease progression. Relapse/disease progression remained the most frequent cause of death in the relapsed/residual population, 56%. The 1-year OS was 29% for those who relapsed within 6 months of transplant, 64% for those who relapsed beyond 6 months. The 5 year OS was 18% for those relapsed within 6 months, 33% for those who relapsed beyond 6 months. DLI induced FDC in 27/29 patients (93%) in the MC population, with durable FDC and ongoing CR in 22/29 patients (76%). Seven MC patients (24%) relapsed after DLI. In the HR population, DLI was protective against relapse in 5 patients while 2 patients (29%) relapsed after DLI. Conclusions Ninety three percent of MC patients in the non-relapsed setting achieved FDC after DLI, with a 24% relapse rate over five years. Further, pre-emptive DLI in patients with MC or HR is associated with a 70% 5 year OS. These results suggest a clinically meaningful effect of pre-emptive and prophylactic DLI in MC and HR patient populations. For patients with MC, both relapsed and non-relapsed, achieving FDC after DLI is essential for disease control. All 17 patients in both populations that did not achieve FDC had non-durable responses or no responses to DLI with subsequent disease progression. Fifteen of the 17 patients who did not achieve FDC after DLI died due to disease progression, while the remaining 2 underwent a second allo-HSCT. DLI for HR was associated with significant rates of acute 〉grade II and extensive chronic GvHD. In this population, development of GvHD may not be the optimal endpoint, in order to limit GvHD-attributable mortality. Table Table. Disclosures Akard: Ariad, BMS, Celgene, Gilead, Novartis, Takeda: Speakers Bureau.

Description: Abstract 4422 Background: Nilotinib is a potent, highly selective Bcr-Abl kinase inhibitor approved for newly diagnosed adult patients (pts) with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) and for adult pts with imatinib-resistant or -intolerant Ph+ CML-CP and CML-AP (accelerated phase). This ongoing study assesses the change in chronic low-grade (LG) non-heme adverse events (AEs) when pts are switched from imatinib (IM) to nilotinib. Methods: Adult CML-CP pts were eligible for the study if they were treated with imatinib 400 mg/d for ≥3 months (mos) and had imatinib-related Grade 1 or 2 non-heme AEs persisting ≥2 mos or recurring ≥3 times and recurring despite best supportive care. Pts are treated with nilotinib 300 mg twice daily on study for up to 1 year. The primary end point is to measure the improvement of imatinib-related LG non-heme AEs at the end of cycle (EOC) 3 after switching to nilotinib therapy. Disease response was monitored and patient-reported outcomes measured by 2 quality-of-life (QoL) questions and the MD Anderson Symptom Inventory (MDASI)-CML. Results: Thirty-eight pts were enrolled as of the data cut-off date (6/27/11) and were included in this analysis. The median time of nilotinib treatment was 7.2 mos. A total of 155 imatinib-related non-heme AEs were reported at baseline; 113 AEs were Grade 1 and 42 AEs were Grade 2. A total of 30 pts completed EOC 3 by the data cut-off date. These pts accounted for 126 of the baseline imatinib-related LG non-heme AEs (Grade 1 = 93, Grade 2 = 33). The median number of IM-related LG non-heme AEs at baseline was 3 per patient. Twenty-one pts reported 1–4 baseline IM-related AEs, 6 pts reported 5–9 IM-related AEs, and 3 pts reported 10–12 IM-related AEs. Of these AEs, 81 (64%) improved (primary end point) by EOC 3; 71 IM-related AEs resolved (51, 15, 5 resolved by mos 1, 2, 3, respectively) and 10 IM-related AEs decreased from Grade 2 to 1. Forty-two AEs were unchanged across 18 pts (20 of which were reported by 3 pts). Three AEs increased in severity by month 3. Overall, 31 (82%) pts had major molecular response (MMR) at entry. MMR is defined as a 3-log reduction of Bcr-Abl from a standardized baseline (Bcr-Abl ≤0.1% IS). All pts maintained MMR after switching to nilotinib on study. The remaining 7 pts achieved MMR during the study. At baseline, 15 pts had a 4-log reduction in Bcr-Abl (Bcr-Abl ≤0.01% IS) and 7 pts with complete molecular response (CMR = Bcr-Abl ≤0.0032% IS). Twelve additional pts achieved a 4-log reduction on study and 9 went on to achieve CMR. Patients completed 2 global QoL questions and the MDASI-CML questionnaire during the study. The MDASI-CML is a patient-reported outcome measure of symptom burden in patients with CML. These were administered at baseline, EOC 1, EOC 3, and then every 3 mos thereafter while on study. Compared to baseline, 68% and 62% of pts (n=34) reported an improvement in global QoL over the last 24 hours and last 7 days, respectively, by EOC 3. The mean reductions from baseline in MDASI-CML severity score and interference score, and therefore improvement in symptoms, were at EOC 1: 1.2 (n=26) and 1.5 (n=25) and at EOC 3: 1.2 (n=24) and 1.6 (n=23), respectively. Thirteen pts were dose reduced for nilotinib-related AEs and subsequently dose re-escalated if the AEs recovered to Grade 1 or resolved. Twenty-seven Grade 3 AEs occurred in 12 pts; of these, 17 AEs were investigator reported and suspected to be nilotinib related (increased bilirubin, hyperglycemia, hypokalemia, hypophosphatemia, increased lipase, pruritus, bronchitis, dehydration, exfoliative rash, rash erythematous, rash, and arthralgia). No pt had a Grade 4 AE. Most AEs were managed by brief dose interruption. A total of 5 pts discontinued, 4 for AEs, and 1 pt withdrew consent. No QTcF prolongation 〉500 msec occurred. Conclusions: In this analysis, at EOC 3, 64% of the chronic LG non-heme IM-related AEs showed improvement after switching to nilotinib. Twenty-eight of 30 pts who completed 3 mos on study had at least 1 LG non-heme IM-related AE improve after switching to nilotinib. At least 62% of pts improved in QoL. In addition, an overall improvement of symptoms as measured by MDASI-CML was seen by the reduction of severity scores. Disclosures: Lipton: Novartis Canada: Consultancy, Research Funding, Speakers Bureau. Mauro:Novartis Oncology: Consultancy, Research Funding, Speakers Bureau. Ailawadhi:Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Miller:Novartis: Consultancy, Research Funding, Speakers Bureau. Busque:Bristol-Myers Squibb: Consultancy; Novartis Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Akard:Eisai: Speakers Bureau; Bristol Myers-Squibb: Speakers Bureau; Novartis: Speakers Bureau; Millenium: Speakers Bureau; Chemgenex: Consultancy. Pinilla-Ibarz:Novartis Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Shah:Novartis Pharmaceuticals: Employment, Equity Ownership. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Ariad Pharmaceuticals: Consultancy, Research Funding; ChemGenex Pharmaceuticals: Consultancy, Research Funding; Pfizer: Research Funding; Deciphera Pharmaceuticals: Research Funding.

Description: Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR087 comprises the extracellular domain of CD16 linked to a CD3ζ-signaling domain and a 4-1BB co-stimulatory domain. Here we present the clinical experience from Study ATTCK-20-2 (NCT02776813), a multicenter, phase 1 study of ACTR087 in combination with rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The main objectives of this first-in-human study were to evaluate the safety and antitumor activity of ACTR087+rituximab. Other objectives included evaluating ACTR T-cell persistence and other correlative biomarkers. Subjects must have had CD20+ NHL that was R/R after prior treatments, which must have included anti-CD20 antibody-containing chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR087. Additional doses of rituximab were administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study included a dose escalation phase (increasing doses of ACTR087) and an expansion phase (ACTR087 at the preliminary recommended phase 2 dose [RP2D]); all subjects received rituximab at a fixed dose of 375 mg/m2 q3w. Results: Two dose levels (DL) of ACTR087 were evaluated during dose escalation (n=17). The MTD was exceeded at DL2, with severe cases of cytokine release syndrome (CRS) and neurotoxicity. Statistical analysis of the relationship between non-hematologic toxicity and ACTR+ T-cell doses was retrospectively performed (two-parameter Bayesian logistic regression model) to estimate an RP2D of 35×106 ACTR+ T cells. Nine subjects enrolled in an expansion cohort and received ACTR087 at this RP2D in combination with rituximab. Among all subjects treated (n=26), the majority (69%) were diagnosed with DLBCL. Subjects had received a median of 3 (range 1-9) prior lines of therapy, with 77% having received ≥3 prior lines. ACTR087 showed dose-dependent expansion with peak levels generally observed 7 to 14 days post administration. In subjects with ongoing clinical response (CR), ACTR remained detectable through the last timepoint evaluated. Across all cohorts, Grade ≥3 TEAEs reported in 〉3 subjects regardless of causality were limited to hematologic events. Potential T cell-mediated toxicities were observed, including 4 serious cases of CRS (Gr 4 in 2 subjects, both with fatal sepsis) and 2 serious cases of neurotoxicity (1 Gr 5, 1 Gr 4 in a subject with fatal septic shock). Elevated baseline inflammatory markers (eg, ferritin, CRP) were observed in patients who developed Gr ≥3 CRS and neurotoxicity post ACTR087. Of note, severe CRS presented without fever and events occurred 〉7 days post ACTR087. Clinical activity was reported with an ORR of 50% in all dose levels tested, including durable complete responses, with one subject in CR for 869+ days (Table 1). Conclusions: ACTR087+rituximab demonstrated antitumor activity, with observed safety events that are expected with other autologous T-cell products. The time to onset and clinical presentation of severe CRS and neurotoxicity events in this study informed the safety monitoring and adverse reaction management guidance across clinical studies of ACTR T-cell products. Data from this first-in-human study of ACTR087+rituximab confirm the proof of concept and will be used to guide further development for the ACTR platform. Updated clinical data, as well as expanded biomarker correlations to efficacy and safety, will be presented. Disclosures Munoz: Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Portola: Research Funding; Incyte: Research Funding; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Juno: Consultancy, Other: advisory board. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Stiff:Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Akard:Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau.

Description: Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR707 comprises the extracellular domain of CD16 linked to a CD3ζ signaling domain and a CD28 co-stimulatory domain. ACTR707 is in clinical development in combination with rituximab (NCT03189836) or trastuzumab (NCT03680560). Here we present clinical findings from the dose escalation phase of Study ATTCK-20-03, an ongoing, multicenter, phase 1 study of ACTR707+rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The primary objectives of this first-in-human study are to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Other objectives include evaluating antitumor activity and ACTR T-cell persistence. Subjects must have CD20+ NHL that is R/R after prior treatments, which must include anti-CD20 antibody-containing chemotherapy. Subjects receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR707. Additional doses of rituximab are administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study includes a dose escalation phase (increasing doses of ACTR707 with fixed dose of rituximab at 375 mg/m2 q3w) and an expansion phase at the RP2D. Results: Six subjects received ACTR707 at Dose Level 1 (DL1; 23-38×106 ACTR+ T cells), 3 subjects at DL2 (30-50×106 ACTR+ T cells), and 5 subjects at DL3 (45-55×106 ACTR+ T cells). The majority of the subjects were diagnosed with DLBCL (93%) and had refractory disease (71%), defined as progressive disease as the best response to any prior treatment or relapse 2 subjects, regardless of causality or grade, included neutropenia, thrombocytopenia, anemia, febrile neutropenia, pyrexia, cough, constipation, diarrhea, nausea, and vomiting. SAEs considered possibly related to ACTR707 were febrile neutropenia (n=2) and cytopenia (n=1). ACTR707 expansion generally reached peak levels within 1 to 2 weeks after administration. All subjects with complete response (CR) up to 1 year had detectable ACTR at the last timepoint evaluated. Higher ACTR707 CD8:CD4 T-cell ratios were associated with clinical responses. Clinical activity was reported across DL1 through DL3, with an overall response rate of 64% including durable complete responses (CRs), with one subject in CR for 387+ days (Table 1). Conclusions: Data available from DL1 through DL3 of ACTR707+rituximab suggest that clinical responses can be achieved without severe T cell-mediated toxicities (eg, CRS and neurotoxicity) that have been reported with other autologous T-cell products. Dose escalation continues at a target dose of 80×106 ACTR+ T cells; enrollment in DL4 (n=6) was recently completed. Updated data, including identified correlates of clinical outcomes, will be presented for DL1 through DL4. Disclosures Flinn: TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Westin:Genentech: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; 47 Inc: Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding. Cohen:Genentech, Inc.: Consultancy, Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Bristol-Meyers Squibb Company: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy. Akard:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau. Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Bachanova:Celgene: Research Funding; Gamida Cell: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Novartis: Research Funding.