ALBERT

Description: Introduction: A variety of chemically diverse drugs are known to alter cardiac repolarization and to produce sudden cardiac death. Current regulatory guidelines therefore require the characterization of a new drug's effect on cardiac repolarization, and in particular, the effects on the QTc interval in a thorough QT/QTc study (ICH E14 Guidance, 2005). QTc studies are usually performed with healthy volunteers but may be performed in the targeted patient (pt) population if the toxicity profile of a drug precludes its use in healthy individuals. Early-phase oncology dose-escalation studies generally include pharmacokinetic/pharmacodynamic (PK/PD) evaluations from relatively large pt populations, which could provide a robust data set for concurrent cardiac safety evaluation. We have combined these approaches and present the results from a first-in-human phase 1 study of CC-223, a potent and selective dual inhibitor of mechanistic target of rapamycin (mTOR) kinases. Patients and Methods: Adult (aged 〉 18 years) pts with histologically confirmed advanced non-Hodgkin lymphoma, multiple myeloma, or advanced, unresectable solid tumors who had progressed on (or were unable to tolerate) standard therapy or for whom standard therapy does not exist were eligible. The dose of CC-223, administered orally, ranged from 7.5 to 60.0 mg/day in 28-day continuous cycles. PK blood samples and corresponding triplicate electrocardiograms (ECG) were collected at 2 time points: predose and 1.5-3 hours after the dose in cycle 2. ECG analysis was performed on all pts who received ≥ 1 dose of CC-223 with baseline and on-treatment ECG results available. The primary cardiac assessment was the by time point change from baseline for cardiac interval duration measurements, including heart rate (HR), PR interval, QRS duration, and QTcF interval (QT interval corrected for HR using the Fridericia formula). Secondary analyses included a time-averaged central tendency analysis, analysis of morphology and measurement outliers, and PK/PD analysis of the relationship between the plasma concentration of CC-223 and its M1 metabolite vs QTcF change from baseline. Results: As of April 1, 2013, 158 pts met the requirements for inclusion in the ECG analysis, and of those, 149 were also included in the PK/PD analysis. The data revealed no effect of CC-223 on cardiac interval duration measurements. The by time point analyses of HR, PR, QRS, and QTcF demonstrated no clinically significant ECG effects of CC-223 during cycle 1 or subsequent cycles. The time-averaged central tendency analyses also demonstrated only small changes in cardiac interval duration. For QTcF, the time-averaged mean change from baseline was −18.5 to −1.0 ms in cycle 1 and −8.7 to 7.3 ms in subsequent cycles. There were few nonspecific ECG morphological findings and few measurement outliers. The PK/PD analysis showed no evidence of any significant exposure-effect relationship between CC-223 or the M1 metabolite and QTcF (Figure). The estimated QTcF change at the maximum concentration (Cmax) of 354 ng/mL for CC-223 was −0.2 ms, with an upper 1-sided 95% CI of 1.2 ms, and the estimated QTcF change at Cmaxof 1532 ng/mL for the M1 metabolite was 0.4 ms, with an upper 1-sided 95% CI of 1.8 ms. Adverse events (AEs) related to cardiac function included 2 reports of ventricular arrhythmias; neither event was serious, both resolved while the pts were on study, and neither were considered study drug related. Conclusions: The QTcF intervals and PK/PD relationships for CC-223 and its active metabolite revealed no significant effect on cardiac repolarization or other ECG parameters. This study used a robust data set in pts, avoided potential AE exposure in healthy volunteers, and had the additional benefit of fulfilling the QTc study requirement for new drugs by the Food and Drug Administration. As such, combining a phase 1 study with the required QTc analysis can be an improved, cost-effective approach for assessing cardiac safety during early drug development. Disclosures Kleiman: Celgene Corporation: Consultancy. Chopra:Celgene: Employment, Equity Ownership. Hans:Celgene Corporation: Consultancy. Hege:Celgene Corporation: Employment, Equity Ownership. James:Celgene Corporation: Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. O'Mara:Celgene Corporation: Employment, Equity Ownership.

Description: Background: Relapsed/refractory (R/R) DLBCL remains an unmet medical need with no approved or standard therapy in the third-line setting. Several new promising classes of drugs are being developed based on emerging understanding of the molecular pathology of DLBCL. These include CC-122, a pleiotropic pathway modifier that promotes CRBN-dependent Aiolos and Ikaros degradation, CC-223, a potent selective ATP-competitive inhibitor of mTOR kinase, and CC-292, a highly selective irreversible-inhibitor of Btk. Early phase studies with these compounds indicated single-agent activity in B cell malignancies including DLBCL. CC-122-DLBCL-001 is a Phase 1b dose escalation and expansion study of CC-122, CC-223 and CC-292 administered orally as doublets, and as triplets in combination with rituximab (R), as well as a CC-122 plus R doublet, in subjects with high risk R/R DLBCL. Methods: The dose escalation phase of the study explores combinations of one or more doses for each novel agent using a modified 3+3 dose escalation design with higher dose cohorts including the addition of a fixed dose of rituximab 375 mg/m2 IV Q28 days. CC-122 1mg, 2mg, 3mg, or 4mg is given orally QD or for 5 out of 7 days/week (5/7d). CC-223 15mg, 20mg, or 30mg is given orally QD. CC-292 500mg is given orally BID. Subjects were treated until progression or intolerable side effects. Study endpoints were: safety, tolerability, PK, PD and preliminary efficacy [overall response rate (ORR) and complete response (CR)]. Subjects were considered efficacy evaluable if they received at least one cycle of treatment and had one post-baseline tumor assessment. Peripheral blood PD biomarkers on treatment were compared to baseline levels by flow cytometry for CC-223 mTOR pathway targets p4EBP1 and pAKT and CC-122 target Aiolos. CC-292 500mg BID was previously demonstrated to result in 〉90% Btk receptor occupancy at 24 hours (Blood 2013 122:4169). Results: As of May 02, 2016, a total of 102 subjects were enrolled into the ongoing dose escalation phase of the study. The median no. of prior anti-lymphoma regimens was 3 (range, 1-10), 30% had prior ASCT and 30% were refractory to any prior therapy. Arm A (CC-122 + CC-223 +/- R) enrolled 31 subjects (28 treated) on 5 dose levels. As of the data-cutoff, the MTD had not been established. The most common (〉 10%) related grade 3/4 adverse events (AEs) were neutropenia (43%), thrombocytopenia (14%), diarrhea (18%), and rash (11%). Arm B (CC-122 + CC-292 +/- R) enrolled 28 (27 treated) subjects on 5 dose levels. The MTD was determined to be CC-122 1mg 5/7d + CC-292 500mg BID + R. The most common (〉 10%) related grade 3/4 AEs were neutropenia (37%), thrombocytopenia (22%), anemia (11%) and febrile neutropenia (15%) Arm C (CC-223 + CC-292) included 14 enrolled (all treated) subjects on 2 dose levels. A tolerable dose demonstrating sufficient PD biomarker inhibition was not established. The most common (〉 10%) related grade 3/4 AEs were neutropenia (14%), thrombocytopenia (29%) and diarrhea (14%). Arm D (CC-122 + R) included 29 subjects enrolled (28 treated) on 5 dose levels. As of the data-cutoff, the MTD had not been established. The most common (〉 10%) related grade 3/4 AEs were neutropenia (32%). Generally, response rates of interest were noted in Arms A, B and D (Table 1). ORR increased at higher dose levels and responses were durable. Preliminary PD data (Table 2) demonstrated differential effects of CC-223 20mg dose on p4EBP1 inhibition between Arms A and C and differential effects of low and high dose CC-122 dosing on Aiolos inhibition between Arms A, B and D. Preliminary PK analysis for drug-drug interactions will be presented. Conclusions: Preliminary data from this ongoing novel-novel dose escalation study indicate that safe and tolerable combinations of CC-122 with CC-223, CC-292, and/or rituximab can be achieved. Combination effects on toxicity, efficacy and PD biomarkers were seen. The observed signals of efficacy are encouraging in this R/R DLBCL population and will be further explored in dose expansion of selected arms at the optimized doses. Disclosures Ribrag: Infinity: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Pharmamar: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Chavez:Janssen: Speakers Bureau. Kaplan:Janssen: Research Funding; Seattle Genetics: Research Funding. Vitolo:Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria; Celgene: Honoraria. Santoro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; ArQule: Membership on an entity's Board of Directors or advisory committees. Corradini:Servier: Honoraria; Sanofi: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Takeda: Consultancy, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Gentium: Honoraria, Speakers Bureau. Cassier:Celgene Corporation: Research Funding; AstraZeneca: Research Funding; MSD: Research Funding; Merck Serono: Research Funding; Roche: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Eli Lilly: Research Funding; Bayer: Research Funding; Amgen: Honoraria. Flinn:Janssen: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Advani:Janssen: Research Funding; Celgene: Research Funding; Merck: Research Funding; Kura: Research Funding; Millennium: Research Funding; Infinity: Research Funding; Kyowa Hakko Kirin: Consultancy, Honoraria; FortySeven: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Sutro: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Stanford University: Employment; Seattle Genetics: Research Funding; Regeneron: Research Funding; Agensys: Research Funding; Pharmacyclics: Research Funding. Sangha:Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria; Eli-Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Hagner:Celgene Corporation: Employment, Equity Ownership. Trowe:Celgene Corporation: Employment, Equity Ownership. Gandhi:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Kuruvilla:BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria.

Description: Background: Multiple myeloma (MM) negatively affects health-related quality of life (HRQoL), and with each relapse, patients with MM experience further declines in HRQoL. Patient-reported HRQoL is therefore an important treatment outcome, in addition to clinical response to therapy. CARTITUDE-1 (NCT03548207) is a phase 1b/2 study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel; JNJ-68284528; LCAR-B38M CAR-T cells), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed/refractory (R/R) MM. We evaluated symptoms, functioning, and overall HRQoL through patient-reported outcome measures, which is a secondary objective of CARTITUDE-1. Methods: Patients were ≥18 years of age with a diagnosis of MM per International Myeloma Working Group criteria, measurable disease, and Eastern Cooperative Oncology Group performance status ≤1. Patients had received ≥3 prior regimens for MM or were double-refractory to a proteasome inhibitor and immunomodulatory drug, and had received an anti-CD38 antibody. Cilta-cel was given as a single infusion on Day 1 (target dose: 0.75×106 [range: 0.5-1.0×106] CAR+ viable T cells/kg) 5-7 days after start of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 daily for 3 days). In the phase 2 portion of CARTITUDE-1, HRQoL was assessed at baseline, on Days 7, 28, 56, 78, and 100, and every 28 days thereafter using 3 patient-reported instruments: the European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30), 4 items from the EORTC QLQ-Multiple Myeloma (MY20) module, and the 5-level EuroQol Five Dimension (EQ-5D-5L) measure. Raw EORTC QLQ-C30 and EORTC QLQ-MY20 scores were linearly transformed to a scale ranging from 0 to 100; the EQ-5D-5L visual analog scale (VAS) score ranges from 0 to 100. Clinically meaningful changes in EORTC QLQ-C30 symptoms, physical functioning, and overall HRQoL were based on anchor-based methods using a patient global impression of change item. Repeated-measures mixed-effects models were used to analyze mean changes in HRQoL from baseline to subsequent assessment time points in patients in the modified intent-to-treat population with ≥1 post-baseline assessment. Median time to event of HRQoL scores was calculated descriptively, using a change in score ≥0.5×standard deviation of values prior to cilta-cel infusion as improvement/worsening with death due to progression defined as worsening. Results: For the 68 patients in the phase 2 portion of CARTITUDE-1 (63.2% male; median age: 62.0 years [range: 43-78]), questionnaire completion rates at baseline and Day 100, respectively, were 92.6% and 69.2% for both the EORTC QLQ-C30 and EORTC QLQ-MY20 items and 92.6% and 70.8% for the EQ-5D-5L. For EORTC QLQ-C30 subscales, clinically meaningful improvements at Day 100 were seen for 71.1% of patients for pain, 62.2% for fatigue, 72.1% for physical functioning, and 51.1% for global health status. Mean changes in pain and fatigue showed a reduction in these symptoms over time (following an initial worsening of fatigue at Day 7; Figure). This trend of improvements over time was also observed for overall HRQoL and EORTC QLQ-MY20 single items. Clinically meaningful improvements at Day 100, defined by a literature-based minimal important difference of 10 points in mean score, were observed for the EORTC QLQ-MY20 single items: thinking about illness and worries about dying or future health. Approximately 50% of the population reported an event of improvement or worsening in EORTC QLQ-C30 and EQ-5D-5L scales, with the rest censored in this early data cut; among these patients, median time to improvement was approximately 1-2 months (with median time to worsening occurring less than 1 month after cilta-cel treatment). There was a trend for an improvement in mean EORTC QLQ-C30 global health status, physical functioning, pain, and fatigue, and EQ-5D-5L VAS at Day 100 with increased depth of response. Conclusions: Some patients with heavily pretreated MM showed rapid and clinically meaningful improvements in pain, fatigue, physical functioning, overall HRQoL, and future perspectives, consistent with their clinical outcomes. With additional follow-up, it is possible that these early improvements in symptoms will translate into greater improvement in overall HRQoL in the long term. Disclosures Martin: Janssen: Research Funding; Sanofi: Research Funding; AMGEN: Research Funding; Seattle Genetics: Research Funding; GSK: Consultancy. Lin:Vineti: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Legend BioTech: Consultancy; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cohen:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Patents/Intellectual property licensed, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees. Htut:City of Hope Medical Center: Current Employment. Stewart:Janssen, BMS, Sanofi-Aventis, GSK: Honoraria; Tempus, Inc., Genomics England LLC: Membership on an entity's Board of Directors or advisory committees. Hari:GSK: Consultancy; BMS: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Incyte Corporation: Consultancy; Janssen: Consultancy. Berdeja:Teva: Research Funding; Cellularity: Research Funding; Kesios: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CURIS: Research Funding; EMD Sorono: Research Funding; Genentech, Inc.: Research Funding; Karyopharm: Consultancy; Poseida: Research Funding; Novartis: Research Funding; Lilly: Research Funding; Amgen: Consultancy, Research Funding; Acetylon: Research Funding; Glenmark: Research Funding; Janssen: Consultancy, Research Funding; Vivolux: Research Funding; Takeda: Consultancy, Research Funding; Servier: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Constellation: Research Funding; Bluebird: Research Funding; Abbvie: Research Funding; Prothena: Consultancy; Bioclinica: Consultancy; Kite Pharma: Consultancy; Legend: Consultancy. Madduri:Foundation Medicine: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; AbbVie: Consultancy, Honoraria; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Celgene: Consultancy, Honoraria. Usmani:Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; GSK: Consultancy, Research Funding; Abbvie: Consultancy; Array Biopharma: Research Funding; Celgene: Other; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Yeh:Janssen: Current Employment. Allred:Janssen: Current Employment. Olyslager:Janssen: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Schecter:Janssen: Current Employment. Jackson:Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Deraedt:Janssen: Current Employment, Current equity holder in publicly-traded company. Gries:Janssen: Current Employment, Current equity holder in publicly-traded company. Fastenau:Janssen: Current Employment, Current equity holder in publicly-traded company. Wu:Legend Biotech USA Inc.: Current Employment. Carrasco:Legend Biotech USA Inc.: Current Employment. Akram:Legend Biotech USA Inc.: Current Employment. Hossain:Legend Biotech USA Inc.: Current Employment. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy.

Description: Background: Ciltacabtagene autoleucel (cilta-cel; JNJ-68284528; LCAR-B38M CAR-T cells) is a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen-targeting single-domain antibodies designed to confer avidity. In the phase 1 LEGEND-2 study in China, LCAR-B38M yielded deep, durable responses with a manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (R/R MM). The phase 1b/2 CARTITUDE-1 study (NCT03548207) is further evaluating cilta-cel in this pt population in the US. We present updated data from the phase 1b portion along with initial phase 2 data. Methods: Eligible pts (aged ≥18 y) were diagnosed with MM per International Myeloma Working Group (IMWG) criteria and had measurable disease, Eastern Cooperative Oncology Group performance status ≤1, received ≥3 prior regimens or were double-refractory to a proteasome inhibitor and immunomodulatory drug, and received an anti-CD38 antibody. After apheresis, bridging therapy was permitted. Cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily for 3 d were used for lymphodepletion. A single infusion of cilta-cel at a target dose of 0.75×106 (range 0.5-1.0×106) CAR+ viable T cells/kg was administered 5-7 d after start of lymphodepletion. The primary objective of the phase 1b portion was to characterize cilta-cel safety and establish the recommended phase 2 dose; the primary objective of the phase 2 portion was to evaluate cilta-cel efficacy. Response was assessed per IMWG criteria and minimal residual disease (MRD) by next-generation sequencing. Adverse events (AEs) were graded using CTCAE v5.0. In the phase 1b portion, cytokine release syndrome (CRS) was graded by Lee et al (Blood 2014) and neurotoxicity by CTCAE v5.0; in the phase 2 portion, CRS and neurotoxicity were graded by American Society for Transplantation and Cellular Therapy (ASTCT) criteria. In this combined analysis, Lee et al and CTCAE v5.0 were mapped to ASTCT criteria for CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), respectively. Results: As of the May 20, 2020 clinical cutoff, 97 pts (58.8% male; median age 61.0 y [range 43-78]) with R/R MM received cilta-cel (29 in phase 1b; 68 in phase 2). Median follow-up duration was 8.8 mo (range 1.5-20.4). Pts had received a median of 6 prior lines of therapy (range 3-18); 83.5% were penta-exposed, 87.6% were triple-refractory, 41.2% were penta-refractory, and 97.9% were refractory to last line of therapy. Overall response rate per independent review committee (primary endpoint) was 94.8% (95% CI 88.4-98.3), with a stringent complete response rate of 55.7% (95% CI 45.2-65.8), very good partial response rate of 32.0% (95% CI 22.9-42.2), and partial response rate of 7.2% (95% CI 3.0-14.3). All pts achieved a reduction in M-protein. Median time to first response was 1.0 mo (range 0.9-5.8; 80.4% ≤1.0 mo), and median time to complete response or better was 1.8 mo (range 0.9-12.5; 74.1% ≤3.0 mo); responses deepened over time (Figure). Median duration of response was not reached (NR). Of 52 MRD-evaluable pts, 94.2% were MRD-negative at 10-5. The 6-mo progression-free survival (PFS) and overall survival (OS) rates (95% CI) were 87.4% (78.9-92.7) and 93.8% (86.7-97.2), respectively; median PFS and OS were NR. Ten deaths occurred during the study; 8 were due to AEs (both related and unrelated; CRS/hemophagocytic lymphohistiocytosis, neurotoxicity, respiratory failure, sepsis, septic shock, pneumonia, lung abscess, and acute myelogenous leukemia [n=1 each]), and 2 due to progressive disease. AEs reported in 〉70% of pts were CRS (94.8%; grade [gr] 3/4 4.1%), neutropenia (90.7%; gr 3/4 90.7%), anemia (81.4%; gr 3/4 68.0%), and thrombocytopenia (79.4%; gr 3/4 59.8%). Median time to CRS onset was 7.0 d (range 1-12) and median duration 4.0 d (range 1-27, excluding n=1 with 97 d). CAR-T cell-related neurotoxicity was reported in 20.6% of pts (gr 3/4 10.3%). Cilta-cel CAR+ T cells showed maximum peripheral expansion at 14 d (range 9-43). Among pts with 6 mo' individual follow-up, 67% had cilta-cel CAR+ T cells below the level of quantification (2 cells/µL) in peripheral blood. Conclusions: Preliminary phase 1b/2 data from CARTITUDE-1 indicate a single low-dose infusion of cilta-cel leads to early, deep, and durable responses in heavily pretreated pts with MM with a safety profile consistent with LEGEND-2. Further investigation of cilta-cel in other MM populations is underway. Disclosures Madduri: Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau. Berdeja:Teva: Research Funding; Bluebird: Research Funding; Bioclinica: Consultancy; Celgene: Consultancy, Research Funding; EMD Sorono: Research Funding; Kite Pharma: Consultancy; Prothena: Consultancy; Cellularity: Research Funding; Karyopharm: Consultancy; Servier: Consultancy; Legend: Consultancy; Poseida: Research Funding; Lilly: Research Funding; Acetylon: Research Funding; CURIS: Research Funding; Janssen: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Glenmark: Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding; Kesios: Research Funding; Novartis: Research Funding. Usmani:Celgene: Other; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; GSK: Consultancy, Research Funding; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Research Funding; Array Biopharma: Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cohen:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Other: Patents/Intellectual property licensed, Research Funding. Stewart:Janssen, BMS, Sanofi-Aventis, GSK: Honoraria; Tempus, Inc., Genomics England LLC: Membership on an entity's Board of Directors or advisory committees. Hari:Amgen: Consultancy; BMS: Consultancy; GSK: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy. Htut:City of Hope Medical Center: Current Employment. Munshi:OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; C4: Current equity holder in private company. Deol:Novartis: Consultancy; Kite, a Gilead Company: Consultancy. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Janssen: Research Funding; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; GenMab: Consultancy, Honoraria. Singh:Janssen: Current Employment. Zudaire:Janssen: Current Employment. Yeh:Janssen: Current Employment. Allred:Janssen: Current Employment. Olyslager:Janssen: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Schecter:Janssen: Current Employment. Jackson:Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Deraedt:Janssen: Current Employment, Current equity holder in publicly-traded company. Zhuang:Janssen: Current Employment. Infante:Janssen: Current Employment. Geng:Legend Biotech USA Inc.: Current Employment. Wu:Legend Biotech USA Inc.: Current Employment. Carrasco:Legend Biotech USA Inc.: Current Employment. Akram:Legend Biotech USA Inc.: Current Employment. Hossain:Legend Biotech USA Inc.: Current Employment. Rizvi:Legend Biotech USA Inc.: Current Employment. Fan:Legend Biotech USA Inc.: Current Employment. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Lin:Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Vineti: Consultancy; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:AMGEN: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; GSK: Consultancy; Sanofi: Research Funding.

Description: Background: The phase 1b/2 CARTITUDE-1 study (NCT03548207) is evaluating ciltacabtagene autoleucel (cilta-cel; JNJ-68284528; LCAR-B38M CAR-T cells), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed/refractory (R/R) multiple myeloma (MM). Cytokine release syndrome (CRS), a known side effect of CAR-T therapy, can be mild to life-threatening and requires careful monitoring and management. Here, we analyzed CRS and cytokine profiles in CARTITUDE-1. Methods: Eligible patients (aged ≥18 years) had a diagnosis of MM per International Myeloma Working Group criteria, measurable disease, Eastern Cooperative Oncology Group performance status ≤1, received ≥3 prior regimens or were double-refractory to a proteasome inhibitor and immunomodulatory drug, and received an anti-CD38 antibody. Bridging therapy was permitted after apheresis. At 5-7 days prior to cilta-cel infusion, lymphodepletion was performed with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily for 3 days. Cilta-cel was administered as a single infusion at a target dose of 0.75×106 (range: 0.5-1.0×106) CAR+ viable T cells/kg. CRS was graded using Lee et al (Blood 2014) in the phase 1b portion and American Society for Transplantation and Cellular Therapy (ASTCT) in the phase 2 portion. In this combined analysis, Lee et al criteria were mapped to ASTCT criteria for patients in the phase 1b portion. Serum samples for cytokine profiling were collected prior to lymphodepletion, prior to cilta-cel infusion and 2 hours post-infusion on Day 1, at regular time points until Day 100, and if CRS was suspected or reported. Results: A total of 97 patients with R/R MM were treated with cilta-cel; median follow-up for this analysis was 8.8 months (range: 1.5-20.4). CRS was reported in 92 (94.8%) patients. A total of 48 (49.5%) patients had grade 1 CRS, 38 (39.2%) had grade 2, 4 (4.1%) had grade 3, and 1 had grade 5 (1.0%); maximum toxicity grade according to the ASTCT consensus grading system could not be derived for 1 patient with CRS in the phase 1b portion. Median time to CRS onset from cilta-cel infusion was 7.0 days (range: 1-12). Median duration of CRS was 4.0 days (range: 1-27, excluding n=1 with 97 days). Supportive measures to treat CRS or CRS symptoms were administered to 87 (89.7%) patients, most commonly tocilizumab (69.1%), acetaminophen (68.0%), corticosteroids (20.6%), and anakinra (18.6%). CRS resolved in 91 (98.9%) patients; the patient with grade 5 CRS/hemophagocytic lymphohistiocytosis died on Day 99 subsequent to sequelae of grade 4 CRS. Across all patients, levels of interleukin (IL)-6, IL-10, and interferon-γ peaked at Days 7-14 post-cilta-cel infusion. Conclusions: CRS after cilta-cel treatment was low grade and manageable in most patients with R/R MM. The low rate of grade ≥3 CRS, median time to CRS onset of 7.0 days, and median duration of 4.0 days suggests outpatient dosing of cilta-cel may be feasible; this approach is being explored in the phase 2 CARTITUDE-2 study (NCT04133636). Disclosures Lin: Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Research Funding; Vineti: Consultancy; Takeda: Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding. Martin:Janssen: Research Funding; AMGEN: Research Funding; Sanofi: Research Funding; Seattle Genetics: Research Funding; GSK: Consultancy. Cohen:Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Usmani:Celgene: Other; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; GSK: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Array Biopharma: Research Funding; Merck: Consultancy, Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Incyte: Research Funding. Madduri:AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Foundation Medicine: Consultancy, Honoraria; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau. Stewart:Janssen, BMS, Sanofi-Aventis, GSK: Honoraria; Tempus, Inc., Genomics England LLC: Membership on an entity's Board of Directors or advisory committees. Singh:Janssen: Current Employment. Zudaire:Janssen: Current Employment. Yeh:Janssen: Current Employment. Allred:Janssen: Current Employment. Olyslager:Janssen: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Schecter:Janssen: Current Employment. Jackson:Memorial Sloan Kettering Cancer Center: Consultancy; Janssen: Current Employment. Deraedt:Janssen: Current Employment, Current equity holder in publicly-traded company. Geng:Legend Biotech USA Inc.: Current Employment. Wu:Legend Biotech USA Inc.: Current Employment. Carrasco:Legend Biotech USA Inc.: Current Employment. Akram:Legend Biotech USA Inc.: Current Employment. Hossain:Legend Biotech USA Inc.: Current Employment. Wang:Legend Biotech USA Inc.: Current Employment. Berdeja:CRISPR Therapeutics: Consultancy, Research Funding; EMD Sorono: Research Funding; Teva: Research Funding; Servier: Consultancy; Vivolux: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy; Kesios: Research Funding; Kite Pharma: Consultancy; Legend: Consultancy; Genentech, Inc.: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Constellation: Research Funding; Glenmark: Research Funding; CURIS: Research Funding; Bioclinica: Consultancy; Amgen: Consultancy, Research Funding; Bluebird: Research Funding; Poseida: Research Funding; Acetylon: Research Funding; Prothena: Consultancy; Lilly: Research Funding. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy.