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Patients with relapsed or refractory large B-cell lymphoma after first-line treatment who are not intended for haematopoietic stem-cell transplantation (HSCT) have poor outcomes and limited treatment options. We assessed the antitumour activity and safety of lisocabtagene maraleucel, an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell product, as second-line treatment in adults with relapsed or refractory large B-cell lymphoma not intended for HSCT.PILOT, an open-label, phase 2 trial done at 18 clinical sites in the USA, included adults aged 18 years or older who had relapsed or refractory large B-cell lymphoma and PET-positive disease, had received first-line therapy containing an anthracycline and a CD20-targeted agent, were not intended for HSCT by their physician, and met at least one prespecified transplantation not intended criterion. Patients received lymphodepleting chemotherapy (intravenous fludarabine 30 mg/mBetween July 26, 2018, and Sept 24, 2021 (data cutoff for the primary analysis), 74 patients underwent leukapheresis and 61 received lisocabtagene maraleucel (efficacy and safety sets); median age was 74 years (IQR 70-78), 24 (39%) patients were women versus 37 (61%) men, and 54 (89%) patients were White. 16 (26%) of 61 patients had an Eastern Cooperative Oncology Group performance status of 2, 33 (54%) had refractory disease, 13 (21%) relapsed within 1 year of first-line therapy, and 15 (25%) relapsed after 12 months of first-line therapy. Median on-study follow-up was 12·3 months (IQR 6·1-18·0). 49 (80% [95% CI 68-89]; p0·0001) patients had an overall response. The most common grade 3 or worse treatment-emergent adverse events were neutropenia (29 [48%] patients), leukopenia (13 [21%]), and thrombocytopenia (12 [20%]). Lisocabtagene maraleucel-related serious treatment-emergent adverse events were reported in 13 (21%) patients. There were no treatment-related deaths. Cytokine release syndrome occurred in 23 (38%; grade 3 in one) patients and neurological events in 19 (31%; grade 3 in three) patients, with no grade 4 events or deaths.These results support lisocabtagene maraleucel as a potential second-line treatment in patients with large B-cell lymphoma for whom HSCT is not intended.Juno Therapeutics, a Bristol-Myers Squibb company.

Azacitidine-mediated hypomethylation promotes tumor cell immune recognition but may increase the expression of inhibitory immune checkpoint molecules. We conducted the first randomized phase 2 study of azacitidine plus the immune checkpoint inhibitor durvalumab vs azacitidine monotherapy as first-line treatment for higher-risk myelodysplastic syndromes (HR-MDS). In all, 84 patients received 75 mg/m2 subcutaneous azacitidine (days 1-7 every 4 weeks) combined with 1500 mg intravenous durvalumab on day 1 every 4 weeks (Arm A) for at least 6 cycles or 75 mg/m² subcutaneous azacitidine alone (days 1-7 every 4 weeks) for at least 6 cycles (Arm B). After a median follow-up of 15.25 months, 8 patients in Arm A and 6 in Arm B remained on treatment. Patients in Arm A received a median of 7.9 treatment cycles and those in Arm B received a median of 7.0 treatment cycles with 73.7% and 65.9%, respectively, completing ≥4 cycles. The overall response rate (primary end point) was 61.9% in Arm A (26 of 42) and 47.6% in Arm B (20 of 42; P = .18), and median overall survival was 11.6 months (95% confidence interval, 9.5 months to not evaluable) vs 16.7 months (95% confidence interval, 9.8-23.5 months; P = .74). Durvalumab-related adverse events (AEs) were reported by 71.1% of patients; azacitidine-related AEs were reported by 82% (Arm A) and 81% (Arm B). Grade 3 or 4 hematologic AEs were reported in 89.5% (Arm A) vs 68.3% (Arm B) of patients. Patients with TP53 mutations tended to have a worse response than patients without these mutations. Azacitidine increased programmed cell death ligand 1 (PD-L1 [CD274]) surface expression on bone marrow granulocytes and monocytes, but not blasts, in both arms. In summary, combining azacitidine with durvalumab in patients with HR-MDS was feasible but with more toxicities and without significant improvement in clinical outcomes over azacitidine alone. This trial was registered at www.clinicaltrials.gov as #NCT02775903.

Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor T-cell product for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after 2 or more lines of systemic therapy. In vivo cellular expansion after single-dose administration of liso-cel has been characterized. In this article, in vivo liso-cel expansion in the pivotal study TRANSCEND NHL 001 (ClinicalTrials.gov identifier, NCT02631044) was further characterized to assess the relationship between in vivo cellular expansion after single-dose administration of liso-cel and efficacy or safety after adjusting for key baseline characteristics. Two bioanalytical methods, quantitative polymerase chain reaction and flow cytometry, were used for the assessment of cellular kinetics of liso-cel, which showed high concordance for in vivo cellular expansion. Multivariable logistic regression analyses demonstrated that higher in vivo cellular expansion of liso-cel was associated with a higher overall response and complete response rate, and a higher incidence of cytokine release syndrome and neurological events in patients with relapsed or refractory LBCL. Age and tumor burden (by sum of the product of perpendicular diameters) were likely to confound the relationship between in vivo cellular expansion and efficacy, where the association became stronger after controlling for these factors. Repeat dosing of liso-cel was tested in the study; however, in vivo cellular expansion of liso-cel was lower after repeat dosing than after the initial dose. These findings should enable a comprehensive understanding of the in vivo cellular kinetics of liso-cel and the association with outcomes in relapsed/refractory LBCL.

This global, phase 3 study compared lisocabtagene maraleucel (liso-cel) with standard of care (SOC) as second-line therapy for primary refractory or early relapsed (≤12 months) large B-cell lymphoma (LBCL). Adults eligible for autologous stem cell transplantation (ASCT) were randomized 1:1 to liso-cel (100×106 CAR+ T cells) or SOC (3 cycles of platinum-based immunochemotherapy followed by high-dose chemotherapy and ASCT in responders). The primary end point was event-free survival (EFS) by independent review. A total of 184 patients were randomized. In this primary analysis with a median follow-up of 17.5 months, median EFS was not reached (NR) for liso-cel versus 2.4 months for SOC (hazard ratio [HR] = 0.356; 95% confidence interval [CI]: 0.243‒0.522). Complete response (CR) rate was 74% for liso-cel versus 43% for SOC (P.0001) and median progression-free survival (PFS) was NR for liso-cel versus 6.2 months for SOC (HR = 0.400; 95% CI: 0.261‒0.615; P.0001). Median overall survival was NR for liso-cel versus 29.9 months for SOC (HR = 0.724; 95% CI: 0.443‒1.183; P = .0987). When adjusted for crossover from SOC to liso-cel, median overall survival was NR for liso-cel and SOC (HR = 0.415; 95% CI: 0.251‒0.686). Grade 3 cytokine release syndrome and neurological events occurred in 1% and 4% of patients in the liso-cel arm, respectively (no grade 4/5 events). These data show significant improvements in EFS, CR rate, and PFS for liso-cel over SOC and support liso-cel as a preferred second-line treatment compared with SOC in patients with primary refractory or early relapsed LBCL. (ClinicalTrials.gov; NCT03575351.).

Fedratinib, an oral, selective Janus kinase 2 inhibitor, has been shown to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) 1 and MATE2-K in vitro. The objective of this study was to evaluate the influence of fedratinib on the pharmacokinetics (PK) of digoxin (P-gp substrate), rosuvastatin (OATP1B1/1B3 and BCRP substrate), and metformin (OCT2 and MATE1/2-K substrate). In this nonrandomized, fixed-sequence, open-label study, 24 healthy adult participants received single oral doses of digoxin 0.25 mg, rosuvastatin 10 mg, and metformin 1000 mg administered as a drug cocktail (day 1, period 1). After a 6-day washout, participants received oral fedratinib 600 mg 1 h before the cocktail on day 7 (period 2). An oral glucose tolerance test (OGTT) was performed to determine possible influences of fedratinib on the antihyperglycemic effect of metformin. Plasma exposure to the three probe drugs was generally comparable in the presence or absence of fedratinib. Reduced metformin renal clearance by 36% and slightly higher plasma glucose levels after OGTT were observed in the presence of fedratinib. Single oral doses of the cocktail ± fedratinib were generally well tolerated. These results suggest that fedratinib has minimal impact on the exposure of P-gp, BCRP, OATP1B1/1B3, OCT2, and MATE1/2-K substrates. Since renal clearance of metformin was decreased in the presence of fedratinib, caution should be exercised in using coadministered drugs that are renally excreted via OCT2 and MATEs. Clinicaltrials.gov NCT04231435 on January 18, 2020.

Fedratinib is an oral and selective Janus kinase 2 inhibitor that is indicated for treatment of adults with intermediate-2 or high-risk primary or secondary myelofibrosis. Fedratinib is metabolized by cytochrome P450s (CYPs), primarily CYP3A4. The objective of this study was to determine the effects of the strong CYP3A4 inducer rifampin and moderate CYP3A4 inducer efavirenz on the pharmacokinetics of single doses of fedratinib. This Phase 1, open-label, two-part study (Part 1 for rifampin and Part 2 for efavirenz) was conducted in healthy adult men and women. A single dose of fedratinib (500 mg) was administered on Day 1. Participants received rifampin 600 mg daily or efavirenz 600 mg daily on Days 9–18. On Day 17, a single dose of fedratinib (500 mg) was coadministered with rifampin or efavirenz. Plasma fedratinib concentrations were measured using validated liquid chromatography–tandem mass spectrometry. Maximum observed plasma fedratinib concentrations were lowered by approximately 70% and 30% during coadministration with rifampin or efavirenz, respectively, compared with fedratinib alone. Geometric means of fedratinib area under the plasma concentration–time curve from 0 to infinity were decreased by 81% (90% confidence interval [CI], 77–83%) and 47% (90% CI, 40–53%) during coadministration with rifampin or efavirenz, respectively. Fedratinib was generally well tolerated when administered alone or in combination with rifampin or efavirenz. Significant reductions in fedratinib exposure were observed in the presence of strong or moderate CYP3A4 inducers. These results suggest that agents that are strong or moderate inducers of CYP3A4 should be avoided when coadministered with fedratinib. NCT03983239 (Registration date: June 12, 2019).

Background Pomalidomide, an immunomodulatory drug, was investigated for pediatric brain tumors. The objectives of this analysis were to characterize the PK of pomalidomide and to examine exposure-response relationship in pediatric patients with recurrent or progressive primary brain tumors. Methods Nonlinear mixed effects modeling was employed in developing a population PK model of pomalidomide using a total of 343 concentrations from 70 patients. Logistic regression models were used for exposure-response analyses. Results The PK of pomalidomide was adequately described with a one compartment model with first-order absorption and elimination. Body surface area (BSA) was identified as a statistically significant covariate of apparent clearance and volume of distribution; however, the impact of BSA on exposure parameters was not deemed clinically relevant. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse events or pomalidomide dose interruptions during Cycle 1. Covariates such as BSA, weight, sex, age, and race had no significant effect on safety endpoints. The PK of pomalidomide in pediatric patients with brain tumors was generally consistent with that in adult patients with multiple myeloma after adjustment for BSA. Conclusions This is the first study to characterize PK of pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. Impact This is the first study to characterize PK of pomalidomide in pediatric patients, which supports BSA-based dosing for pediatric patients. There is no significant pomalidomide PK difference between adults and pediatrics. Pomalidomide exposure was not associated with higher probabilities of treatment-emergent adverse event or pomalidomide dose interruptions during Cycle 1.

Background: Patients with large B-cell lymphoma (LBCL) primary refractory to or relapsed within 12 months of first-line therapy are at high risk for poor outcomes with current standard of care, platinum-based salvage immunochemotherapy and autologous haematopoietic stem cell transplantation (HSCT). Lisocabtagene maraleucel (liso-cel), an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has previously demonstrated efficacy and manageable safety in third-line or later LBCL. In this Article, we report a prespecified interim analysis of liso-cel versus standard of care as second-line treatment for primary refractory or early relapsed (within 12 months after response to initial therapy) LBCL. Methods: TRANSFORM is a global, phase 3 study, conducted in 47 sites in the USA, Europe, and Japan, comparing liso-cel with standard of care as second-line therapy in patients with primary refractory or early (≤12 months) relapsed LBCL. Adults aged 18–75 years, Eastern Cooperative Oncology Group performance status score of 1 or less, adequate organ function, PET–positive disease per Lugano 2014 criteria, and candidates for autologous HSCT were randomly assigned (1:1), by use of interactive response technology, to liso-cel (100 × 106 CAR+ T cells intravenously) or standard of care. Standard of care consisted of three cycles of salvage immunochemotherapy delivered intravenously—R-DHAP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1–4, two infusions of cytarabine 2000 mg/m2 on day 2, and cisplatin 100 mg/m2 on day 1), R-ICE (rituximab 375 mg/m2 on day 1, ifosfamide 5000 mg/m2 on day 2, etoposide 100 mg/m2 on days 1–3, and carboplatin area under the curve 5 [maximum dose of 800 mg] on day 2), or R-GDP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1–4, gemcitabine 1000 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 1)—followed by high-dose chemotherapy and autologous HSCT in responders. Primary endpoint was event-free survival, with response assessments by an independent review committee per Lugano 2014 criteria. Efficacy was assessed per intention-to-treat (ie, all randomly assigned patients) and safety in patients who received any treatment. This trial is registered with ClinicalTrials.gov, NCT03575351, and is ongoing. Findings: Between Oct 23, 2018, and Dec 8, 2020, 232 patients were screened and 184 were assigned to the liso-cel (n=92) or standard of care (n=92) groups. At the data cutoff for this interim analysis, March 8, 2021, the median follow-up was 6·2 months (IQR 4·4–11·5). Median event-free survival was significantly improved in the liso-cel group (10·1 months [95% CI 6·1–not reached]) compared with the standard-of-care group (2·3 months [2·2–4·3]; stratified hazard ratio 0·35; 95% CI 0·23–0·53; stratified Cox proportional hazards model one-sided p

Purpose Fedratinib is an orally administered Janus kinase (JAK) 2–selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. In vitro, fedratinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Coadministration of fedratinib with CYP3A4 inhibitors is predicted to increase systemic exposure to fedratinib. This study evaluated the effect of multiple doses of the dual CYP3A4 and CYP2C19 inhibitor, fluconazole, on the pharmacokinetics of a single dose of fedratinib. Methods In this non-randomized, fixed-sequence, open-label study, healthy adult participants first received a single oral dose of fedratinib 100 mg on day 1. Participants then received fluconazole 400 mg on day 10 and fluconazole 200 mg once daily on days 11–23, with a single oral dose of fedratinib 100 mg on day 18. Pharmacokinetic parameters were calculated for fedratinib administered with and without fluconazole. Results A total of 16 participants completed the study and were included in the pharmacokinetic population. Coadministration of fedratinib with fluconazole increased maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 to the last quantifiable concentration (AUC0–t) of fedratinib by 21% and 56%, respectively, compared with fedratinib alone. Single oral doses of fedratinib 100 mg administered with or without fluconazole were well tolerated. Conclusions Systemic exposure after a single oral dose of fedratinib was increased by up to 56% when fedratinib was coadministered with fluconazole compared with fedratinib alone. Trial registry: Clinicaltrials.gov NCT04702464.

Fedratinib is an oral and selective kinase inhibitor with activity against wild type and mutationally activated Janus kinase 2 and FMS-like tyrosine kinase 3, for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. This open-label mass balance study in healthy subjects investigated the excretion balance and systemic exposure of radioactivity after oral administration of [14C]-fedratinib; and the pharmacokinetics of fedratinib and its contribution to overall exposure of radioactivity. Six healthy males received a single oral dose of 200 mg [14C]-fedratinib base (2.775 MBq, 75 μCi) as a solution. Blood, urine and feces samples were collected for up to 35 day postdose. Urine and feces samples were collected until the 24-h excretion of radioactivity fell below 0.5% of administered dose (at least 14 day postdose). Expired air was collected up to 8-h postdose. Total radioactivity (blood, plasma, urine, feces, and expired air) and fedratinib concentrations (plasma) were measured. Approximately 77% (23% unchanged) of fedratinib derived radioactivity was excreted in feces and 5% (3% unchanged) was excreted in urine. Excretion via expired air was negligible. The time to maximum concentration for both total radioactivity and parent drug was similar, with unchanged drug representing the majority of the circulating radioactivity. The ratio of blood to plasma concentration of radioactivity ranged from 0.615 to 0.753 indicating limited distribution of fedratinib and/or its metabolites into red blood cells. Fedratinib derived radioactivity was primarily excreted in feces following a single oral dose of radiolabeled fedratinib to healthy subjects.

Fedratinib is an oral, selective Janus kinase 2 inhibitor that is approved in the United States for the treatment of patients with intermediate-2 or high-risk myelofibrosis. Pharmacokinetics and tolerability of fedratinib in subjects with renal impairment (RI) and hepatic impairment (HI) were evaluated in two separate studies. In the renal study, male and female subjects with stable, chronic mild, moderate, and severe RI, as well as those with end-stage renal disease, were included. The hepatic study included subjects with stable, chronic mild HI. Both were phase 1, multicenter, open-label, single-dose studies, and included matched healthy subjects. Subjects received a single oral dose of fedratinib 300 mg on day 1, were discharged on day 4, returned for clinical visits on days 5–12, and had their end-of-study visit between days 14 and 16. Thirty-six and 17 subjects were included in the renal and hepatic studies, respectively. In the renal study, fedratinib area under the plasma concentration–time curve from time 0 to infinity (AUCinf) was 1.9- and 1.5-fold higher in subjects with severe and moderate RI, respectively, than in matched healthy subjects. In the hepatic study, fedratinib AUCinf did not appreciably differ between subjects with mild HI and matched healthy subjects. Overall, most treatment–emergent adverse events were gastrointestinal and mild. Mild RI and HI do not necessitate fedratinib dosage adjustments. Subjects with moderate RI should be monitored (with dosage adjustments made as necessary), whereas those with severe RI should receive a daily dose of 200 mg, reduced from the indicated dose of 400 mg.

Fedratinib is an orally administered Janus kinase 2-selective inhibitor that is indicated for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis in the United States. Fedratinib is metabolized by multiple cytochrome P450s (CYPs) in vitro, with the predominant contribution from CYP3A4. The primary objective of this study was to evaluate the effects of 14-day repeated 200 mg twice daily (BID) oral doses of a strong CYP3A4 inhibitor, ketoconazole, on a sequential ascending single oral dose of fedratinib in healthy male subjects. An open-label, fixed-sequence, two-treatment cross-over study was conducted. Two cohorts of healthy adult males received two single doses of fedratinib (50 mg in Cohort 1 and 300 mg in Cohort 2) with one dose administered alone on Day 1 of Period 1 and the other dose coadministered with ketoconazole in the morning of Day 6 of Period 2. Subjects in both cohorts received 200-mg BID (Days 1–14) ketoconazole during Period 2. Coadministration of repeated 200-mg BID oral doses of ketoconazole for 14 days increased fedratinib exposure by 3.85- and 3.06-fold for area under the plasma concentration–time curve from time zero to infinity following a single oral dose of fedratinib of 50 and 300 mg, respectively. Oral administration of a single dose of 50 or 300 mg of fedratinib, administered alone or coadministered with steady-state ketoconazole, was safe and tolerable in the healthy male subjects. These results serve as the basis for fedratinib dose reduction when fedratinib is coadministered with strong CYP3A4 inhibitors.

Biologics, especially monoclonal antibodies, are increasingly important in the pharmaceutical marketplace. Population pharmacokinetic (PK) analyses could be useful to guide the need for dose adjustments among special populations, yet it is unknown how commonly such analyses are performed during biologics development. We summarized the characteristics of population PK models of biologics and examined their role in informing the drug labels. To do so, we extracted relevant characteristics of 86 biologics approved by the U.S. Food and Drug Administration's Center for Drug Evaluation and Research between 2003 and 2017. Ninety-four percent of monoclonal antibodies (51 of 54 biologics), 75% of fusion proteins with Fc receptor (6 of 8 biologics), and 33% of other proteins (8 of 24 biologics) included population PK analyses. Of these analyses, approximately half (45%) used a 2-compartment model with linear clearance as the base model structure. Body size was the most frequently included covariate in the final models (included in 94% of the 64 biologics in which covariate analysis was performed), although age (11%), sex (35%), race (26%), and renal function (27%) were also included in some models. In 70% to 90% of cases in which the effect of these covariates was examined, information regarding the effect of these on PK was included in the label. These results suggest that population PK analyses provide important information about the impact of intrinsic factors on the PK in the label of biologics by the U.S. Food and Drug Administration.

Purpose Fedratinib (SAR302503, TG101348) is an orally administered Janus kinase (JAK) 2-selective inhibitor that is being developed for the treatment of patients with myelofibrosis (MF). The objectives of this analysis were to develop a population pharmacokinetic (PK) model to characterize fedratinib concentration-time profiles in patients with MF, polycythemia vera (PV) and essential thrombocythemia (ET) following oral fedratinib administration; and to investigate the effects of selected covariates on fedratinib PK parameters. Methods Nonlinear mixed effects modeling was employed in developing a population PK model for fedratinib. Intensive or sparse fedratinib concentration data collected in adult subjects with MF, PV or ET from six studies were pooled, and a total of 452 subjects and 3442 plasma concentration observations were included in the final model. Results Fedratinib PK in patients with MF/PV/ET was adequately described by a two-compartment structural PK model with first-order absorption incorporating a lag time and first-order elimination. Following oral administration, fedratinib undergoes biphasic disposition and exhibits linear, time-invariant PK at doses of 200 mg and above. Compared to MF/ET patients, PV patients had higher apparent clearance (CL/F) and apparent central volume of distribution. Creatinine clearance was a statistically significant covariate on CL/F, and patients with mild and moderate renal impairment had 10% and 37% increases in fedratinib exposure as compared to patients with normal renal function. No clinically meaningful effect on fedratinib exposure was observed regarding age, body weight, sex, race and liver function. Conclusions These results should serve as the basis for dose adjustment of fedratinib for special populations. Electronic supplementary material The online version of this article (10.1007/s00280-019-03929-9) contains supplementary material, which is available to authorized users.

Background and Objectives Durvalumab, a human monoclonal antibody targeting programmed cell death ligand 1, has been approved for urothelial carcinoma and stage III non-small cell lung cancer by the US Food and Drug Administration and is being evaluated in various malignancies. The objective of this study was to develop a population-pharmacokinetic model of durvalumab in patients with various hematologic malignancies and to investigate the effects of demographic and disease factors on the pharmacokinetics in this population. Methods A total of 1812 concentrations from 267 patients with myelodysplastic syndromes, acute myeloid leukemia, multiple myeloma, non-Hodgkin lymphoma, or Hodgkin lymphoma were included in the analysis. Results The pharmacokinetics of durvalumab was adequately described by a two-compartment model with first-order elimination. A decrease in durvalumab clearance over time was mainly explained by incorporation of time-dependent changes in albumin (in all patients) and immunoglobulin G (in patients with multiple myeloma) into the model. For multiple myeloma, patients with immunoglobulin G ≥ 20 g/L showed a 30% lower area under the concentration–time curve at cycle 1 compared with patients with immunoglobulin G < 20 g/L. The impact of any baseline covariates on durvalumab pharmacokinetics did not appear to be clinically relevant. The pharmacokinetics of durvalumab in hematologic malignancies was generally consistent with previously reported pharmacokinetics in solid tumors. Conclusions These results support the same dosing regimen (1500 mg every 4 weeks) for both solid tumors and hematologic malignancies from the perspective of adequate exposure. Additionally, total immunoglobulin G level could be a critical covariate for the pharmacokinetics of monoclonal antibodies in patients with multiple myeloma. Electronic supplementary material The online version of this article (10.1007/s40262-019-00804-x) contains supplementary material, which is available to authorized users.

Background and Objectives Lisocabtagene maraleucel (liso-cel) is a CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T-cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. Large between-subject variability has been noted with CAR T-cell therapies; patient characteristics might contribute to CAR T-cell expansion variability. We developed a population cellular kinetic model to characterize the kinetics of the liso-cel transgene, via quantitative polymerase chain reaction assessment after intravenous infusion of liso-cel, and to understand covariates that might influence liso-cel kinetics in individual patients. Methods We employed nonlinear mixed-effects modeling to develop a population cellular kinetic model for liso-cel. The population cellular kinetic analysis was performed using 2524 post-infusion transgene observations from 261 patients with relapsed/refractory large B-cell lymphoma who were treated with a single dose of liso-cel in TRANSCEND NHL 001. Covariates for the analysis included baseline intrinsic factors such as age, baseline disease characteristics, and liso-cel and coadministration factors. Results Liso-cel cellular kinetics were well described by a piecewise model of cellular growth kinetics that featured lag, exponential growth, and biexponential decay phases. Population means (95% confidence interval) of lag phase duration, doubling time, time to maximum levels, initial decline half-life, and terminal half-life were 3.27 (2.71–3.97), 0.755 (0.667–0.821), 9.29 (8.81–9.70), 5.00 (4.15–5.90), and 352 (241–647) days, respectively. The magnitude of effect on liso-cel expansion metrics demonstrated that the covariate associations were smaller than the residual between-subject variability in the population. Conclusions The covariates tested were not considered to have a meaningful impact on liso-cel kinetics. Clinical Trial Registration NCT02631044.

Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 106 or 100 × 106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 × 106 CAR+ T cells. This trial was registered at clinicaltrials.gov as NCT03331198.

Summary Background Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas. Methods We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 106 CAR+ T cells [one or two doses], 100 × 106 CAR+ T cells, and 150 × 106 CAR+ T cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044. Findings Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1–8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0–19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8–78·0) patients and a complete response by 136 (53%, 46·8–59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T cells. Interpretation Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies. Funding Juno Therapeutics, a Bristol-Myers Squibb Company.

Fedratinib, an oral selective kinase inhibitor with activity against both wild type and mutationally activated Janus kinase 2, has been approved for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis by the US Food and Drug Administration. In vitro studies indicated that fedratinib was an inhibitor of several cytochrome P450 (CYP) enzymes. The primary objective of this study was to evaluate the effects of repeated doses of fedratinib on the activity of CYP2D6, CYP2C19, and CYP3A4 in patients with solid tumors using a CYP probe cocktail. An open-label, one-sequence, two-period, two-treatment crossover study was conducted. Patients were administered a single oral dose cocktail of metoprolol (100 mg), omeprazole (20 mg), and midazolam (2 mg) used as probe substrates for CYP2D6, CYP2C19, and CYP3A4 enzyme activities, respectively, without fedratinib on Day -1 or with fedratinib on Day 15. Coadministration of 500 mg once-daily doses of fedratinib for 15 days increased the mean area under the plasma concentration–time curve from time zero to infinity following a single-dose cocktail containing metoprolol (CYP2D6 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) by 1.77-fold (90% confidence interval [CI] 1.27–2.47) for metoprolol, 2.82-fold (90% CI 2.26–3.53) for omeprazole, and 3.84-fold (90% CI 2.62–5.63) for midazolam, respectively. The mean plasma Day 14/Day 1 ratio of 4β-hydroxycholesterol, an endogenous biomarker of CYP3A4 activity, was 0.59 (90% CI 0.54-0.66), suggesting a net inhibition of CYP3A4 by fedratinib. Fedratinib is a weak inhibitor of CYP2D6, and a moderate inhibitor of CYP2C19 and CYP3A4. These results serve as the basis for dose modifications of these CYP substrate drugs when co-administered with fedratinib.

Fedratinib, an oral, selective Janus kinase 2 inhibitor with activity against both wild-type and mutant Janus kinase 2, has pH-dependent solubility, with free solubility at pH 1. Concomitant administration of drugs that reduce gastric acid secretion, such as pantoprazole, may decrease the absorption of fedratinib and affect patient outcomes. The aim of this study was to evaluate the impact of 7-day repeated 40-mg doses of pantoprazole on the pharmacokinetic (PK) properties of a single 500-mg dose of fedratinib in healthy male subjects. In this phase I, single-center, open-label, two-period, two-treatment, fixed-sequence crossover study, healthy male subjects were administered a single dose of fedratinib 500 mg on day 1 in Period 1, followed by pantoprazole 40 mg daily for 7 days (day 1 to day 7) and a single dose of fedratinib 500 mg on day 7 in Period 2. After the discontinuation of nine subjects due to vomiting, the protocol was amended to provide ondansetron as antiemetic prophylaxis to an additional ten enrolled subjects. Twenty-six subjects were included. Repeated doses of pantoprazole 40 mg resulted in clinically insignificant increases in fedratinib exposure. Maximum plasma concentration increased by 1.09-fold and area under the plasma concentration–time curve from time 0 to infinity increased by 1.15-fold. All treatment-emergent adverse events were mild or moderate, except for one instance of neutropenia, which was considered unrelated to study intervention. Coadministration with pantoprazole did not have clinically meaningful effects on fedratinib PK. No new or unexpected safety signals were observed with fedratinib.

Background: CAR T cell therapies are generally administered in an inpt setting owing to concerns of AE management. Infusion and monitoring of pts who receive CAR T cell therapy at nonuniversity medical centers (NMC) and in outpt settings have not been studied specifically. Liso-cel is an autologous CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In TRANSCEND NHL 001 (NCT02631044) in pts with third- or later-line LBCL, liso-cel treatment showed an ORR of 73% (CR rate, 53%), with grade ≥ 3 cytokine release syndrome (CRS) in 2%, and grade ≥ 3 neurological events (NE) in 10% of pts (Abramson et al. Lancet 2020). We report outcomes of liso-cel in pts with R/R LBCL across inpt and outpt settings at NMCs in the United States treated in the OUTREACH study (NCT03744676). Methods: The study enrolled pts at NMCs, including those with university affiliations and centers naïve to CAR T cell therapy. Adults with R/R PET-positive LBCL after ≥ 2 lines of therapy and ECOG PS ≤ 1 were eligible. Pts with grade 3-4 cytopenias, mild to moderate organ function (LVEF ≥ 40%; serum CrCl > 30 mL/min), secondary CNS lymphoma, and prior autologous HSCT were eligible. After leukapheresis and lymphodepleting chemotherapy (LDC), pts received liso-cel at a target dose of 100 × 10 6 CAR + T cells. Primary endpoint was incidence of grade ≥ 3 CRS, NEs, prolonged cytopenias (Day 29 grade ≥ 3 lab values), and infections. Secondary endpoints included safety, ORR, CR rate, duration of response (DOR), and liso-cel PK. B-cell depletion analyses were exploratory. AEs, including NEs, were graded using NCI CTCAE v4.03; CRS was graded per Lee criteria (2014). NEs were defined as investigator-identified neurological AEs related to liso-cel. All study sites had a multidisciplinary CAR T cell therapy team and standard operating procedures (SOP) for outpt monitoring of toxicity and admission for CRS/NE management. Results: At data cutoff, 71 pts were treated with liso-cel at NMCs; 52 and 19 were monitored as outpts and inpts, respectively. Median age was 65 years (range, 28-83; ≥ 65 years, 51%; ≥ 75 years, 18%); 65% of pts had de novo DLBCL, 68% had screening ECOG PS of 1, 82% were chemotherapy refractory, 31% had ≥ 3 prior therapies, and 48% had markers of high tumor burden (pre-LDC LDH ≥ 500 U/L or SPD ≥ 50 cm 2). Demographics and baseline disease characteristics were generally similar in outpts and inpts, respectively, with differences of ≥ 20% noted in incidences of high-grade B-cell lymphoma (4% vs 42%) and DLBCL transformed from indolent lymphoma (29% vs 0%). Overall, any-grade CRS occurred in 39% of pts (no grade ≥ 3) and NEs in 32% (grade 3-4, 10%); 27% received tocilizumab and/or corticosteroids for CRS or NEs. Incidences of any-grade CRS and NEs were similar in outpts and inpts, while grade ≥ 3 NEs, infections, and prolonged cytopenias were numerically higher in outpts, but similar to pivotal trial observations (Table). The most common treatment-emergent AEs were neutropenia (68%), leukopenia (45%), CRS (39%), anemia (38%), thrombocytopenia (37%), and fatigue (35%). No grade 5 AEs were reported. Early (study Day ≤ 4) and overall hospitalization occurred in 33% and 69% of outpts, respectively; median time to hospitalization was 5.0 days (range 2-141) in outpts. The median (range) length of initial hospital stay after liso-cel administration was 6.0 days (1-28; n = 36) for outpts versus 10.0 days (0-31; n = 19) for inpts; 31% of outpts were not hospitalized. All pts were efficacy evaluable. The ORR was 77% and the CR rate was 51%. Median DOR was 14.8 months (95% CI, 3.9‒not reached [NR]) for outpts and was NR (95% CI, 2.0‒NR) for inpts at a median follow-up of 8.1 months and 11.3 months, respectively (Table). PK profiles were similar in outpts and inpts. Target depletion of CD19 + B cells in peripheral blood was also similar between oupts and inpts, and was maintained over the period of 1 year. Conclusions: Pts with R/R LBCL were successfully treated with liso-cel in outpt and inpt settings at NMCs and monitored for CAR T cell therapy-related toxicities using SOPs and multidisciplinary teams. Liso-cel demonstrated durable clinical activity with a favorable safety profile in both outpts and inpts. Incidences of severe CRS and NEs were low, as was tocilizumab and/or corticosteroid use. These data support liso-cel administration at NMCs and in the outpt setting. Figure 1 Figure 1. Disclosures Bachier: Novartis: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; CRISPR: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Varela: Kite: Speakers Bureau; Nexlmmune: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cherry: BMS: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees. Fanning: Sanofi: Speakers Bureau; Takeda: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees. Essell: Gilead: Current Employment, Speakers Bureau; BMS: Speakers Bureau. Yimer: Texas Oncology: Current Employment; Pharmacyclics: Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau. Sharman: AstraZeneca: Consultancy; AbbVie: Consultancy; BMS: Consultancy; TG Therapeutics: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Lilly: Consultancy. Espinola: BMS: Current Employment, Current equity holder in publicly-traded company. Mailley: BMS: Current Employment, Current equity holder in publicly-traded company. Avilion: BMS: Current Employment, Current equity holder in publicly-traded company. Ogasawara: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ou: BMS: Current Employment. Shaughnessy: Sanofi: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau.

Background: Pts with LBCL primary refractory to or relapsed ≤ 12 mo after first-line (1L) therapy may have poor outcomes with SOC, including salvage CT and ASCT, which underscores a critical unmet need. Liso-cel is an autologous CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In the TRANSCEND NHL 001 study (NCT02631044) in pts with R/R LBCL (≥ 2 prior lines of therapy), liso-cel treatment resulted in an ORR of 73% (CR rate, 53%), 2% grade ≥ 3 cytokine release syndrome (CRS), and 10% grade ≥ 3 neurological events (NE) (Abramson et al. Lancet 2020). Here we present a prespecified interim analysis of TRANSFORM (NCT03575351; SOC vs liso-cel as 2L therapy in pts with R/R LBCL). Methods: TRANSFORM is a pivotal, global, randomized, multicenter, phase 3 study comparing efficacy and safety of SOC (Arm A; R-DHAP, R-ICE, or R-GDP per investigator choice followed by BEAM + ASCT) vs liso-cel (Arm B). Pts were adults (aged ≤ 75 years), eligible for ASCT, and with LBCL primary refractory to or relapsed ≤ 12 mo after 1L therapy. Key inclusion criteria were ECOG PS ≤ 1 and adequate organ function (LVEF ≥ 40%; serum CrCl > 45 mL/min); pts with secondary CNS lymphoma were allowed. Key exclusion criteria were prior gene or anti-CD19-targeted therapy, and active infection. Pts in Arm A were to receive 3 cycles of CT. Responding pts (CR or PR) were to proceed to BEAM + ASCT. Pts in Arm B were to undergo lymphodepletion with fludarabine/cyclophosphamide followed by liso-cel at a target dose of 100 × 10 6 CAR + T cells. Bridging therapy with an Arm A CT regimen was allowed. Crossover to receive liso-cel was allowed in Arm A for pts not achieving CR or PR after 3 cycles of CT or not in CR after ASCT, or demonstrating PD at any time. Primary endpoint is event-free survival (EFS) based on independent review committee per Lugano 2014 criteria, defined as time from randomization to death from any cause, PD, failure to achieve CR or PR by 9 weeks after randomization, or start of new antineoplastic therapy, whichever occurred first. Key secondary endpoints included in the testing strategy are CR rate, PFS, and OS. P value significance threshold for endpoints to reject the null hypothesis was ≤ 0.012. Results: A total of 184 pts were randomized, with 92 pts in each arm. Baseline characteristics were well balanced between both arms (Table). Of 91 treated pts in Arm A (1 pt withdrew consent), 43 received BEAM + ASCT, of which 28 achieved CR with CT. Fifty pts crossed over to receive liso-cel. In Arm B, 90 pts received liso-cel infusion; 58 pts (63%) received bridging therapy. Two Arm B pts were not infused (1 each due to manufacturing failure and rapid progression). Median EFS and PFS were significantly longer, and CR rate was significantly improved for Arm B vs Arm A. For Arms A and B, respectively, median EFS was 2.3 vs 10.1 mo (HR, 0.349; P < 0.0001), median PFS was 5.7 vs 14.8 mo (HR, 0.406; P = 0.0001), and CR rate was 39% vs 66% (P < 0.0001). OS data were immature at the time of this analysis with a median follow-up of 6.2 mo (range, 0.9-20.0), but a numerical trend favored Arm B (HR, 0.509; 95% CI, 0.258-1.004; P = 0.0257). Cellular kinetics in Arm B showed a median t max of 10 d (range, 6‒22). No new liso-cel safety signals were detected in the 2L setting. In Arm B, any-grade CRS was reported in 49% of pts, with grade 1 in 37% and grade 2 in 11%. Only 1 pt had grade 3 CRS (onset at Day 9, which resolved in 2 days). Any-grade NEs were reported in 12% of pts and were also primarily low grade (grade 3, 4%). No grade 4 or 5 CRS or NEs were reported. In Arm B, 24% of pts received tocilizumab, 17% received corticosteroids, and none received vasopressors. The most common TEAEs in both arms were cytopenias. Prolonged cytopenias in Arm B (ie, grade ≥ 3 at 35 d after infusion) were reported in 43% of pts; the majority recovered within 2 mo after infusion. Conclusions: In the TRANSFORM study, liso-cel demonstrated statistically significant and clinically meaningful improvement in the primary endpoint, EFS, as well as in key secondary efficacy endpoints (CR rate and PFS) compared with SOC as 2L therapy in pts with LBCL primary refractory to or relapsed ≤ 12 mo after 1L therapy. Safety results in the 2L setting were consistent with the liso-cel safety profile in 3L or later LBCL, and no new safety concerns were identified. Liso-cel improved outcomes vs SOC and exhibited a favorable safety profile, providing support for liso-cel as a potential new SOC for 2L treatment in pts with R/R LBCL. Figure 1 Figure 1. Disclosures Kamdar: SeaGen: Speakers Bureau; ADC Therapeutics: Consultancy; Celgene: Other; TG Therapeutics: Research Funding; KaryoPharm: Consultancy; Celgene (BMS): Consultancy; Genetech: Other; Genentech: Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy. Arnason: Juno/BMS: Honoraria. Glass: BMS: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Riemser: Research Funding; Kite: Consultancy; Novartis: Consultancy; Helios Klinik Berlin-Buch: Current Employment. Bachanova: KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ibrahimi: Karyopharm Theraputics: Divested equity in a private or publicly-traded company in the past 24 months. Mielke: Immunicum: Other: Data safety monitoring board; Novartis: Speakers Bureau; Miltenyi: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Gilead/KITE: Other: Travel support, Expert panel ; Celgene/BMS: Speakers Bureau. Mutsaers: BMS: Consultancy; AstraZeneca: Research Funding. Hernandez-Ilizaliturri: Kite: Other: Advisory Boards; Amgen: Other: Advisory Boards; Pharmacyclics: Other: Advisory Boards; BMS: Other: Advisory Boards; Celgene: Other: Advisory Boards; Incyte: Other: Advisory Boards; AbbVie: Other: Advisory Boards; Gilead: Other: Advisory Boards; Epyzime: Other: Advisory Boards. Izutsu: Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Solasia: Research Funding; Symbio: Honoraria; Takeda: Honoraria, Research Funding; Yakult: Research Funding. Morschhauser: Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Janssen: Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Chugai: Honoraria; Servier: Consultancy; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lunning: Karyopharm: Consultancy; AstraZeneca: Consultancy; Legend: Consultancy; Verastem: Consultancy; Janssen: Consultancy; Myeloid Therapeutics: Consultancy; Daiichi-Sankyo: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AbbVie: Consultancy; Acrotech: Consultancy; Beigene: Consultancy; ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy; Morphosys: Consultancy; Kite, a Gilead Company: Consultancy; Kyowa Kirin: Consultancy. Maloney: Amgen: Honoraria; Celgene: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; A2 Biotherapeutics: Honoraria, Other: Stock options; BMS: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Celgene: Other: Research funding was paid to my institution, Research Funding; Umoja: Honoraria; Janssen: Honoraria; Legend Biotech: Honoraria; Genentech: Honoraria; Novartis: Honoraria; MorphoSys: Honoraria; Juno therapeutics: Other: Research funding was paid to my institution, Research Funding; Navan Technologies: Honoraria, Other: Stock options; Kite Pharma: Honoraria, Other: Research funding was paid to my institution, Research Funding; Juno Therapeutics: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb. Crotta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Montheard: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Previtali: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Stepan: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ogasawara: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Mack: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Abramson: Bluebird Bio: Consultancy; EMD Serono: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Morphosys: Consultancy; C4 Therapeutics: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Genmab: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. OffLabel Disclosure: Liso-cel is a CAR T cell therapy approved for use in the third line for R/R LBCL. This trial reports data from the pivotal trial in the second line.

Background : LBCLs are prevalent and aggressive subtypes of NHL, with limited treatment options and historically poor outcomes in the third- or later-line setting. Liso-cel is an autologous, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. TRANSCEND NHL 001 (NCT02631044) is a seamless design, pivotal, phase 1 study evaluating liso-cel in patients (pts) with R/R LBCLs (Abramson et al. Lancet 2020). We present 2-year follow-up data from the LBCL cohort. Methods: Pts ≥ 18 years of age with R/R DLBCL not otherwise specified (NOS, including de novo and transformed from any indolent lymphoma), high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements, primary mediastinal B-cell lymphoma (PMBCL), or follicular lymphoma grade 3B (FL3B) after ≥ 2 lines of therapy and with ECOG PS 0-2 were eligible. Pts with grade 3 or 4 cytopenias, mild to moderate organ dysfunction, and secondary CNS lymphoma were allowed. Bridging therapy was allowed at clinician discretion but reconfirmation of PET-positive disease was required before lymphodepletion with fludarabine and cyclophosphamide. Primary endpoints were treatment-emergent AEs (TEAE) and ORR. Key secondary endpoints were CR rate, duration of response (DOR), PFS, and OS. TEAEs, including investigator-identified neurological events (NE) related to liso-cel, were graded using NCI CTCAE v4.03; cytokine release syndrome (CRS) was graded per Lee 2014 criteria in the liso-cel-treated set (all pts who received ≥ 1 dose of liso-cel). ORR was assessed by an independent review committee (IRC) per Lugano 2014 criteria in the efficacy-evaluable set (all pts with confirmed PET-positive disease who received ≥ 1 dose of liso-cel). Pts were followed for 2 years after the last dose of liso-cel and were then asked to enroll in a separate long-term follow-up study for up to 15 years (NCT03435796). Results: A total of 345 pts underwent leukapheresis. In the liso-cel-treated set (N = 270), median age was 63 years (range, 18-86); 41% of pts were ≥ 65 years of age. Histologies included DLBCL NOS (de novo, 51%; transformed from indolent lymphoma, 29%), HGBCL (13%), PMBCL (6%), and FL3B (1%). Seven pts (3%) had secondary CNS lymphoma. Pts received a median of 3 prior lines of systemic therapy (range, 1-8) and 33% had prior autologous HSCT (prior allogeneic HSCT, 3%). Of all pts, 67% were chemotherapy refractory, 45% had never achieved CR, and 59% received bridging therapy. As of the Jan 4, 2021 data cut, study is ongoing; 268 pts had ≥ 24 months (mo) of follow-up, died, or withdrew from the study. Responses per IRC (ORR, 73%; CR rate, 53%) in the efficacy-evaluable set (N = 257) were durable with a median (95% CI) DOR of 23.1 mo (8.6-not reached), median PFS of 6.8 mo (3.3-12.7), and median OS of 27.3 mo (16.2-45.6) (Table). At 24 mo, the probabilities (95% CI) of continued response, PFS, and OS were 49.5% (41.4%-57.0%), 40.6% (34.0%-47.2%), and 50.5% (44.1%-56.5%), respectively. During the 90-day treatment-emergent (TE) reporting period, 79% of pts in the liso-cel-treated set (N = 270) had grade ≥ 3 TEAEs; 45% had serious TEAEs. CRS and NE of any grade occurred in 42% and 30% of pts, respectively (grade 3-4 CRS, 2%; grade 3-4 NE, 10%). Median (range) time to onset of CRS and NE was 5 (1-14) and 9 (1-66) days, respectively. Grade ≥ 3 infections and laboratory-based prolonged cytopenia at Day 29 occurred in 12% and 37% of pts, respectively. In the post-TE (Day 91 to end of study) reporting period, which included 17 pts who received liso-cel re-treatment, 23% of pts in the liso-cel-treated set (N = 249) had grade ≥ 3 AEs and 17% had serious AEs. The most common grade ≥ 3 AEs in the post-TE period were neutropenia (7%), anemia (6%), thrombocytopenia (4%), and febrile neutropenia (4%). Grade ≥ 3 infections occurred in 5% of pts. In the post-TE period, 100 pts (37% of all pts) died, mostly due to disease progression (86% of all post-TE deaths; 32% of all pts). CAR T cells were present in peripheral blood for up to 4 years. Conclusions: Liso-cel demonstrated durable remissions with estimated 2-year DOR and PFS rates of 49.5% and 40.6%, respectively, and a favorable safety profile in the extended follow-up analysis of this large CAR T cell study in R/R LBCLs. Most CAR T cell-associated AEs occurred within the initial 90-day TE reporting period. No new safety signals were observed during long-term follow-up. Figure 1 Figure 1. Disclosures Abramson: Genmab: Consultancy; Kite Pharma: Consultancy; C4 Therapeutics: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Kymera: Consultancy; Bluebird Bio: Consultancy; EMD Serono: Consultancy; Novartis: Consultancy; Morphosys: Consultancy; BeiGene: Consultancy; Allogene Therapeutics: Consultancy; Astra-Zeneca: Consultancy; Incyte Corporation: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Palomba: Rheos: Honoraria; Novartis: Consultancy; Lygenesis: Honoraria; Priothera: Honoraria; Juno: Patents & Royalties; Notch: Honoraria, Other: Stock; Pluto: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Magenta: Honoraria; WindMIL: Honoraria; Kite: Consultancy; Ceramedix: Honoraria; Nektar: Honoraria; Wolters Kluwer: Patents & Royalties; PCYC: Consultancy; BeiGene: Consultancy. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Lunning: Myeloid Therapeutics: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy; Morphosys: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Daiichi-Sankyo: Consultancy; Novartis: Consultancy; Kyowa Kirin: Consultancy; Legend: Consultancy; Janssen: Consultancy; ADC Therapeutics: Consultancy; Acrotech: Consultancy; Verastem: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AstraZeneca: Consultancy; Kite, a Gilead Company: Consultancy. Wang: Molecular Templates: Research Funding; BGICS: Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Oncternal: Consultancy, Research Funding; Bayer Healthcare: Consultancy; Physicians Education Resources (PER): Honoraria; InnoCare: Consultancy, Research Funding; CAHON: Honoraria; OMI: Honoraria; Loxo Oncology: Consultancy, Research Funding; The First Afflicted Hospital of Zhejiang University: Honoraria; Lilly: Research Funding; Scripps: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Clinical Care Options: Honoraria; Celgene: Research Funding; Imedex: Honoraria; Pharmacyclics: Consultancy, Research Funding; Chinese Medical Association: Honoraria; Mumbai Hematology Group: Honoraria; Dava Oncology: Honoraria; Moffit Cancer Center: Honoraria; Epizyme: Consultancy, Honoraria; DTRM Biopharma (Cayman) Limited: Consultancy; Genentech: Consultancy; CStone: Consultancy; Kite Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Hebei Cancer Prevention Federation: Honoraria; Newbridge Pharmaceuticals: Honoraria; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Consultancy, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding. Arnason: Juno/BMS: Honoraria. Maloney: Janssen: Honoraria; MorphoSys: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; BMS: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Amgen: Honoraria; Celgene: Other: Research funding was paid to my institution, Research Funding; Juno therapeutics: Other: Research funding was paid to my institution, Research Funding; Kite Pharma: Honoraria, Other: Research funding was paid to my institution, Research Funding; Navan Technologies: Honoraria, Other: Stock options; A2 Biotherapeutics: Honoraria, Other: Stock options; Umoja: Honoraria; Genentech: Honoraria; Legend Biotech: Honoraria; Juno Therapeutics: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb. Andreadis: Merck: Research Funding; BMS: Research Funding; CRISPR Therapeutics: Research Funding; GenMAB: Research Funding; Novartis: Research Funding; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Epizyme: Honoraria; Incyte: Honoraria; TG Therapeutics: Honoraria; Kite: Honoraria; Karyopharm: Honoraria; Atara: Consultancy, Honoraria. Sehgal: Juno/Celgene: Research Funding; Kite/Gilead: Research Funding. Ghosh: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; Karyopharma: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genmab: Consultancy, Honoraria; Epizyme: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau. Kostic: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kim: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ogasawara: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dehner: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Siddiqi: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Therapeutics: 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; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Oncternal: Research Funding.

BackgroundCLL is an incurable hematologic malignancy characterized by progressive accumulation of clonally derived CD19+ B-cell lymphocytes. CAR T cell therapies are promising treatments but inherent T cell dysfunction has limited their development in CLL. Preclinical studies suggest ibrutinib may modulate CAR T cells directly to improve their function independently of antitumor effects. Liso-cel is an autologous, CD19-directed, defined composition, 4–1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. The ongoing TRANSCEND CLL 004 study evaluates the efficacy and safety of liso-cel alone (monotherapy) or with concurrent ibrutinib (combination) in relapsed/refractory (R/R) CLL.1 We investigated the effect of ibrutinib on post-infusion CAR+ and endogenous T cells relative to monotherapy using a novel cell-sorting, low-input RNA-seq method for analysis of patient cells beyond peak expansion, including 1 and 2 months after liso-cel infusion.MethodsCAR+ and endogenous T cells from patients in TRANSCEND CLL 004 (NCT03331198; monotherapy, n=16; combination, n=19) were isolated from peripheral blood mononuclear cells by fluorescence-activated cell sorting. RNA-seq was performed using cell lysate as input material. CAR+ T cell pharmacokinetics were assessed by flow cytometry. Serum interleukin-6 was measured by electrochemiluminescent multiplex immunoassay. Minimal residual disease (ResultsGene set enrichment analyses revealed positive enrichment of cell proliferation-associated gene sets and negative enrichment of inflammation-associated gene sets at peak expansion in CAR+ T cells from combination relative to monotherapy patients. Similar, but less marked, proliferation- and inflammation-associated gene expression changes were also observed in endogenous T cells. Accordingly, increased CAR+ T cell expansion and reduced serum interleukin-6 were observed in combination patients. In addition, an independently derived CLL ibrutinib gene expression score2 was increased and sustained in CAR+ and endogenous T cells from combination but not monotherapy patients over time. A higher ibrutinib score trended with a higher rate of undetectable minimal residual disease, longer progression-free survival (PFS), and longer duration of response. Lastly, a T cell exhaustion-related gene signature was significantly reduced in CAR+ but not endogenous T cells with combination treatment, and this reduction was associated with improved PFS.ConclusionsConcurrent ibrutinib treatment in patients with R/R CLL resulted in measurable effects in CAR+ and endogenous T cells, including changes in gene signatures related to proliferation, inflammation, and T cell exhaustion. These changes were associated with enhanced CAR T cell function and efficacy.AcknowledgementsWe would like to thank the patients, caregivers, investigators, and study personnel. This study was funded by Juno Therapeutics, a Bristol-Myers Squibb Company. All authors contributed to and approved the abstract; writing and editorial assistance were provided by Allison Green, PhD, of The Lockwood Group (Stamford, CT, USA), funded by Bristol Myers Squibb.Trial RegistrationNCT03331198ReferencesWierda WG, Dorritie KA, Munoz J, et al. TRANSCEND CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) combined with ibrutinib (IBR) for patients (pts) with R/R CLL/SLL. Hematol Oncol 2021;39(S2):141–143.Rendeiro AF, Krausgruber T, Fortelny N, et al. Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in CLL. Nat Commun 2020;11:577.Ethics ApprovalThis study used patient cells obtained from a clinical trial that was done in accordance with with the Declaration of Helsinki, International Conference on Harmonization Good Clinical Practice guidelines, institutional review boards at participating institutions approved the study protocol and amendments, and all patients provided written informed consent.

Background: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL). Most patients with MCL relapse after first-line immunochemotherapy, with poor responses to salvage therapy. Chimeric antigen receptor (CAR) T cell therapy has shown clinical efficacy in patients with relapsed/refractory (R/R) NHL. We report the results of the dose-finding and dose-expansion parts of the ongoing phase 1 TRANSCEND NHL 001 study (NCT02631044) in patients with R/R MCL (MCL cohort) who received lisocabtagene maraleucel (liso-cel), an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. Methods: Eligible patients had confirmed MCL (cyclin D1 expression, t[11;14]) with R/R disease after ≥1 prior line of therapy. After lymphodepleting chemotherapy, patients received liso-cel infusion at 1 of 2 dose levels (DLs): DL1 (50 × 106 CAR+ T cells) or DL2 (100 × 106 CAR+ T cells). Bridging therapy was allowed between leukapheresis and initiation of lymphodepleting chemotherapy. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included complete response (CR) rate, duration of response, progression-free survival, overall survival, and pharmacokinetics (PK). Results: At data cutoff, 41 patients had undergone leukapheresis and 32 had received liso-cel (DL1, n = 6; DL2, n = 26). Among the 32 patients who received liso-cel, the median (range) age was 67 (36‒80) years and 27 patients (84%) were male. Twelve patients (37.5%) had blastoid morphology, 23 (72%) had documented Ki67 ≥30%, 7 (22%) had a TP53 mutation, and 11 (34%) had a complex karyotype. Patients had a median (range) sum of the product of perpendicular diameters before lymphodepleting chemotherapy of 28.7 (0-209.6) cm2 and median lactate dehydrogenase of 251.5 (117-811) U/L. Patients had received a median (range) of 3 (1-7) prior systemic therapies, and most (72%) were refractory to their last prior therapy. Of 28 patients (87.5%) who had received a prior Bruton tyrosine kinase inhibitor, 11 (34%) were refractory to the therapy. Seventeen patients (53%) received bridging therapy. Eighteen patients (56%) had serious treatment-emergent adverse events (TEAEs), and 27 (84%) had grade ≥3 TEAEs, primarily neutropenia (41%), anemia (34%), and thrombocytopenia (31%). Grade ≥3 thrombocytopenia was more frequent at DL2 (n = 9/26 [35%]) than at DL1 (n = 1/6 [17%]). Prolonged grade ≥3 cytopenias (present at study Day 29) occurred in 11 patients (34%). Sixteen patients (50%; DL1, n = 2/6 [33%]; DL2, n = 14/26 [54%]) had cytokine release syndrome (CRS), including 1 grade 4 event at DL2. There were no grade 3 or 5 CRS events. Median (range) time to CRS onset and resolution was 6 (2‒10) days and 4 (2‒9) days, respectively. Nine patients (28%) had neurological events (NEs), all at DL2, including 3 grade 3 NEs. No grade 4 or 5 NEs were reported. Median (range) time to NE onset and resolution was 8 (2‒25) days and 3 (1‒51) days, respectively. Ten patients (31%) received tocilizumab and/or corticosteroids for treatment of CRS and/or NEs. Grade 5 TEAEs occurred in 2 patients (at DL2): one patient with high tumor burden had tumor lysis syndrome and 1 patient had cryptococcal meningoencephalitis. DL2 was selected for dose expansion. Of 32 patients, 27 responded to liso-cel (ORR, 84%: DL1, n = 4/6 [67%]; DL2, n = 23/26 [88%]), and 19 (59%) achieved a CR (DL1, n = 2/6 [33%]; DL2, n = 17/26 [65%]). Among the 12 patients with blastoid morphology, 9 patients had a response (ORR, 75%), including 7 (58%) who achieved a CR. Overall, the median (range) time to first CR was 1 (1-6) month. At data cutoff, 20 (74%) of 27 responders were censored with an ongoing response or had completed the study. Median (range) follow-up duration was 10.9 (1.2-24.8) months for DL1 and 3.1 (0.4-23.0) months for DL2. Preliminary PK analysis indicated that median maximum expansion was higher among patients at DL2 than at DL1. Conclusions: In this phase 1 study of patients with R/R MCL, treatment with liso-cel was associated with a low incidence of grade ≥3 CRS and NEs, late onset of CRS/NEs, and promising clinical activity. Dose confirmation is ongoing at DL2 in the MCL cohort. Disclosures Palomba: Pharmacyclics: Honoraria; Juno: Honoraria; Celgene: Honoraria; Merck: Honoraria; Novartis: Honoraria; Regeneron: Research Funding; Juno: Research Funding; Genentech: Research Funding. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Siddiqi:Juno: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DMC member; Juno Therapeutics, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Celgene, Kite Pharma, and BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Janssen, and AstraZeneca: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Juno Therapeutics, KITE Pharma, AstraZeneca, TG Therapeutics, Celgene, Oncternal, and BeiGene: Research Funding; AstraZeneca: Other: Travel/accommodations/expenses; Astrazenca: Membership on an entity's Board of Directors or advisory committees; PCYC: Membership on an entity's Board of Directors or advisory committees. Abramson:Celgene: Honoraria, Other: Scientific Advisory Board; Juno Therapeutics: Other: Scientific Advisory Board; AbbVie: Other: Scientific Advisory Board; EMD Serono: Other: Scientific Advisory Board; Genentech/Roche: Other: Scientific Advisory Board; Janssen: Other: Scientific Advisory Board; Karyopharm: Other: Scientific Advisory Board; Gilead: Other: Scientific Advisory Board; Verastem: Other: Scientific Advisory Board; Bayer: Other: Scientific Advisory Board; Merck: Other; KIte Pharma: Other; Novartis: Other; Amgen: Other; Seattle Genetics: Other; Allogene: Other; Morphosys: Other; C4 Therapeutics: Other; BeiGene: Other; AstraZeneca: Honoraria; Incyte: Honoraria. Kamdar:Seattle Genetics: Speakers Bureau; Karyopharm: Consultancy; BMS: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy. Lunning:Acrotech: Consultancy; ADC Therapeutics: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; Curis: Research Funding; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Research Funding; Verastem: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Legend: Consultancy; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria. Maloney:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; Bioline Rx: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Andreadis:Genentech: Other: Spouse Employee (salary and stock); Novartis: Research Funding; Celgene/Juno: Research Funding; Amgen: Research Funding; Merck: Research Funding; Gilead/Kite: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Astellas: Other: Advisor; Seattle Genetics: Other: Advisor; Karyopharm: Other: Advisor; Incyte: Other. Arnason:Regeneron: Consultancy; Juno: Consultancy. Ghosh:Forty Seven Inc: Consultancy, Other: Research Bureau, Research Funding; Genmab: Consultancy, Speakers Bureau; AbbVie: Speakers Bureau; Karyopharm: Consultancy; Juno/Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Kite/Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Roche/Genentech: Research Funding; SGN: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Celgene/Bristol-Myers Squibb: Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau. Mehta:Innate Pharmaceuticals: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Parmaceuticals/BMS: Research Funding; fortyseven Inc/Gilead: Research Funding; Takeda: Research Funding; Roche-Genentech: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Affimed: Research Funding. Farazi:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Garcia:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Dehner:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Ogasawara:Bristol-Myers Squibb: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Gao:Bristol-Myers Squibb: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current Employment. Wang:Juno: Consultancy, Research Funding; Acerta Pharma: Research Funding; Loxo Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; InnoCare: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Molecular Templates: Research Funding; Verastem: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Pulse Biosciences: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Targeted Oncology: Honoraria; BioInvent: Research Funding; VelosBio: Research Funding.

Background: In CLL/SLL, ibrutinib treatment before leukapheresis improved in vivo and ex vivo expansion of the CD19-directed chimeric antigen receptor (CAR) T cell therapy tisagenlecleucel, and concurrent ibrutinib therapy improved engraftment and therapeutic efficacy of anti-CD19 CAR T cells in human xenograft mouse models (Fraietta et al. Blood. 2016;127:1117-27). Recent studies in patients with R/R CLL suggest that CD19-directed CAR T cell therapy combined with ibrutinib improves response rates with CTL119 and JCAR014 (Gill et al. Blood. 2018;132:298; Gauthier et al. Blood. 2020;135:1650-60). Liso-cel is an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal doses of CD8+ and CD4+ CAR+ T cells. We report initial safety and preliminary efficacy from the phase 1 liso-cel and ibrutinib combination cohort of the ongoing phase 1/2 TRANSCEND CLL 004 study (NCT03331198) in patients with R/R CLL/SLL. Methods: Eligible patients with CLL/SLL met ≥1 of the following: 1) received ibrutinib and progressed at time of study enrollment; 2) had high-risk features and received ibrutinib for ≥6 months (mo) with less than a complete response (CR); 3) had a Bruton tyrosine kinase (BTK) or PLCγ2 gene mutation, with or without progression on ibrutinib; 4) had received prior ibrutinib with no contraindication to reinitiating ibrutinib. Baseline disease assessments included bone marrow (BM) biopsy, complete blood count, lymphocyte enumeration, and CT scan. At enrollment, patients started or continued ibrutinib. Patients continued ibrutinib through leukapheresis and for ≥90 days after liso-cel infusion. Patients received liso-cel infusion at 50 × 106 (dose level [DL]1) or 100 × 106 (DL2) CAR+ T cells after 3 days of lymphodepletion with fludarabine/cyclophosphamide. Primary endpoints were safety and to determine the recommended dose (RD) of liso-cel in combination with ibrutinib for R/R CLL/SLL; overall response (OR) rate (CR + CR with incomplete blood count recovery [CRi] + partial response) and pharmacokinetics (PK) were exploratory endpoints. The RD was selected based on the modified toxicity probability interval algorithm. Results: At data cutoff, 19 patients received liso-cel (DL1, n=4; DL2, n=15) with ibrutinib. Median age was 60 (range, 50‒77) years, and 18 patients (95%) had high-risk cytogenetics (del[17p], n=8; TP53 mutation, n=6; unmutated IGHV, n=16). Patients had a median of 4 (range, 2‒11) prior therapies. All patients were R/R to prior ibrutinib; 14 patients (74%) had BTK inhibitor as last prior therapy and 10 (53%) had prior venetoclax. No dose-limiting toxicities were observed at either DL. The most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia/neutrophil count decrease (n=17; 89%), anemia (n=9; 47%), and febrile neutropenia (n=5; 26%; Table). Six patients had infections at DL2: grade 3 and grade 2 lung infection (n=1 each) and grade 2 coccidioidomycosis, scabies, skin, and gum infections (n=1 each). Ibrutinib-related AEs included diarrhea (n=7), hypertension (n=4), atrial fibrillation (n=1), and rash (n=1). No grade 5 TEAEs occurred. Fourteen patients (74%) had cytokine release syndrome (CRS; 1 grade 3) and 6 (32%) had neurological events (NEs; 3 grade ≥3). Seven patients (37%) required tocilizumab and/or corticosteroids to manage CRS and/or NEs. Preliminary PK data showed a median time to peak liso-cel expansion of 11 days across DLs (DL1, 12 days; DL2, 11 days). Of 19 patients with ≥1-mo follow-up, 18 (95%) had an OR (DL2, 100%; DL1, 75%) and 9 (47%) had a CR/CRi. One patient (5%) had stable disease. All ORs were achieved by Day 30 postinfusion, and 15 (83%) of 18 patients maintained their response at 3-mo follow-up. Of 19 patients evaluable for minimal residual disease (MRD), 17 (89%) achieved undetectable MRD in blood via flow cytometry and 15 (79%) in BM by next-generation sequencing (both sensitivity of ≤10-4). Conclusions: Preliminary data show that liso-cel in combination with ibrutinib is associated with manageable safety, including a low incidence of grade 3 CRS and grade ≥3 NEs, and promising efficacy in heavily pretreated patients with R/R CLL/SLL. No clear difference in safety was observed across DLs, and DL2 was selected as the RD for liso-cel in combination with ibrutinib in patients with R/R CLL/SLL. Updated results from the full combination cohort and additional PK/pharmacodynamic data will be reported. Table Disclosures Dorritie: Juno Therapeutics: Research Funding; Kite-Gilead: Research Funding. Munoz:Portola: Research Funding; Incyte: Research Funding; Acrotech/Aurobindo: Speakers Bureau; Alexion: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Fosunkite: Consultancy; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Innovent: Consultancy; Genentech/Roche: Research Funding, Speakers Bureau; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Millenium: Research Funding; Verastem: Speakers Bureau; Merck: Research Funding; AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau. Stephens:Innate: Consultancy; Verastem: Research Funding; Beigene: Consultancy; Karyopharm: Consultancy, Research Funding; Acerta: Research Funding; Gilead: Research Funding; Juno: Research Funding; MingSight: Research Funding; Arqule: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy. Gillenwater:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Gong:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Yang:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Ogasawara:Bristol-Myers Squibb: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Thorpe:Bristol-Myers Squibb: Current equity holder in publicly-traded company; Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment. Siddiqi:Astrazenca: Membership on an entity's Board of Directors or advisory committees; PCYC: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DMC member; Juno Therapeutics, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Celgene, Kite Pharma, and BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company, Juno Therapeutics, KITE Pharma, AstraZeneca, TG Therapeutics, Celgene, Oncternal, and BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Janssen, and AstraZeneca: Speakers Bureau; AstraZeneca: Other: Travel/accommodations/expenses.

Background: Lisocabtagene maraleucel (liso-cel) is an investigational, CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. Liso-cel is being studied in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in the ongoing, open-label, phase 1/2 TRANSCEND CLL 004 study (NCT03331198). Here, we report outcomes of patients in the phase 1 monotherapy cohort after a median follow-up of 18 months (mo). Methods: Eligible patients had received ≥3 (standard-risk disease) or ≥2 (high-risk disease: del[17p], TP53 mutation, unmutated IGHV, or complex karyotype) lines of prior therapy, including a Bruton tyrosine kinase inhibitor (BTKi) unless contraindicated. Patients with active untreated central nervous system disease, Eastern Cooperative Oncology Group performance status >1, or Richter transformation were excluded. After 3 days of lymphodepletion with fludarabine and cyclophosphamide, patients received liso-cel infusion at 1 of 2 dose levels (DLs): 50 × 106 (DL1) or 100 × 106 (DL2) CAR+ T cells. Dose-limiting toxicities were evaluated for 28 days postinfusion. Responses were assessed using 2018 International Workshop on CLL criteria. Minimal residual disease (MRD) was assessed in blood by flow cytometry and/or in bone marrow (BM) by next-generation sequencing (both with a sensitivity of ≤10-4). Persistence of liso-cel was monitored by quantitative polymerase chain reaction. Results: Overall, 23 and 22 patients were evaluable for safety and efficacy, respectively. Median age was 66 (range, 49‒79) years, median number of prior therapies was 6 (range, 3‒13), and 83% of patients (n=19/23) had high-risk disease. All patients (N=23) had received prior ibrutinib, with 91% (n=21) refractory to, or who relapsed on, ibrutinib and 9% (n=2) who were intolerant to ibrutinib; overall, 48% (n=11) were refractory to both a prior BTKi and venetoclax. The safety profile was similar to that previously reported; no late or delayed adverse events of concern have emerged with the longer follow-up (Table). Among the 22 efficacy-evaluable patients, overall response rate (ORR; complete response [CR]/CR with incomplete blood count recovery [CRi] + partial response) was 82% (n=18); the CR/CRi rate was 45% (n=10). By Day 30, 68% of patients (n=15) achieved an overall response. At 15 mo and 18 mo, 53% (n=10/19; 6 CRs) and 50% (n=7/14; 5 CRs) of patients maintained their responses, respectively. At a median follow-up of 18 mo, the median duration of response was not reached (NR) in patients who had achieved a response to liso-cel (n=18), and median progression-free survival was 18 mo (95% CI, 3.0-NR) in all efficacy-evaluable patients. Two patients who completed the study maintained their response through 24 mo on study and have enrolled in a long-term follow-up study. Five of 8 patients who progressed had Richter transformation. The subgroup of patients refractory to both a prior BTKi and venetoclax had a similar ORR compared with the total evaluable population, with a CR rate of 60% (n=6/10; Table). Of 20 MRD-evaluable patients, 15 (75%) had undetectable MRD (uMRD) in the blood, 13 (87%) of whom also had uMRD in the BM, with most (60%) achieving uMRD in the BM by Day 30. Preliminary data show that liso-cel was detectable in the blood for up to 18 mo postinfusion in 4 (36%) of 11 patients. Conclusions: Liso-cel treatment resulted in a high rate of uMRD in this heavily pretreated, high-risk population of patients with R/R CLL/SLL, including those refractory to both a BTKi and venetoclax. Responses were rapid and durable, with liso-cel detectable for up to 18 mo postinfusion. No late or delayed adverse events of concern emerged with longer follow-up. The phase 2 monotherapy expansion of the study is currently enrolling at DL2. Disclosures Siddiqi: AstraZeneca: Other: Travel/accommodations/expenses; Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Janssen, and AstraZeneca: Speakers Bureau; Juno: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company, Juno Therapeutics, KITE Pharma, AstraZeneca, TG Therapeutics, Celgene, Oncternal, and BeiGene: Research Funding; PCYC: Membership on an entity's Board of Directors or advisory committees; Astrazenca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DMC member; Juno Therapeutics, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Celgene, Kite Pharma, and BeiGene: Consultancy. Soumerai:Genentech/Roche: Research Funding; BostonGene: Research Funding; Beigene: Consultancy, Research Funding; GlaxoSmithKine: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy; AstraZeneca: Consultancy; Verastem: Consultancy. Dorritie:Kite-Gilead: Research Funding; Juno Therapeutics: Research Funding. Stephens:Beigene: Consultancy; Acerta: Research Funding; MingSight: Research Funding; Arqule: Research Funding; Verastem: Research Funding; Janssen: Consultancy; Juno: Research Funding; Gilead: Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Consultancy; Innate: Consultancy. Riedell:Karyopharm Therapeutics: Honoraria; Bayer: Honoraria; Kite Pharmaceuticals/Gilead: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Verastem Oncology: Honoraria; Celgene/Bristol-Myers Squibb Company: Honoraria, Research Funding; Morphosys: Research Funding. Arnason:Juno: Consultancy; Regeneron: Consultancy. Kipps:Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees; Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VelosBio: Research Funding; Celgene: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gillenwater:Bristol-Myers Squibb: Current equity holder in publicly-traded company; Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment. Gong:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Yang:Bristol-Myers Squibb: Current equity holder in publicly-traded company; Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment. Ogasawara:Bristol-Myers Squibb: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current Employment.

Objectives CAR T cell therapy has generally been limited to inpatient treatment. Infusion and management of CAR T cell therapy in the outpatient setting may lead to wider use in nonuniversity centers and improved access. We report on patients (pts) with R/R large B cell NHL treated with liso-cel in the outpatient setting in TRANSCEND NHL 001 (NCT02631044) and two phase 2 studies (≥3rd-line therapy: OUTREACH, NCT03744676; 2nd-line TNE: PILOT, NCT03483103). Methods Eligible pts had R/R large B cell NHL (TRANSCEND/OUTREACH: ≥2 lines of prior therapy and ECOG PS ≤1; PILOT: 1 line of prior therapy and deemed TNE for autologous hematopoietic stem cell transplant based on ECOG PS, organ function, or age). After lymphodepletion with fludarabine/cyclophosphamide, liso-cel was administered. All studies allowed outpatient treatment at nonuniversity (OUTREACH) or university and nonuniversity medical centers (TRANSCEND/PILOT), with hospitalization at the first sign of fever or neurological events (NEs) per management guidelines. Results At data cutoff, 37 pts across studies received liso-cel on study Day 1 and were monitored as outpatients, including pts aged ≥65 years (n = 15) and those with SPD ≥50 cm2 (n = 10) or LDH ≥500 UL (n = 2). Results are shown in the Table. Sixteen pts had any grade cytokine release syndrome (CRS) and 12 had any grade NEs (19 pts had CRS and/or NEs). Only 2 pts had had grade 3 or 4 CRS or NEs, which were reversible. Three pts received tocilizumab and corticosteroids for CRS and/or NEs; none received tocilizumab alone. Overall, 59% of pts (n = 22/37) required hospitalization at any time; all were from TRANSCEND or OUTREACH. Of 37 pts, 3 (8%) were admitted on study Day 3 or earlier (all for CRS) and 1 (3%) required ICU-level care (length of stay, 3 days). Median time to hospitalization post treatment was 5 (range, 2‒22) days; median length of stay was 6 (range, 2‒23) days. Overall, 41% of pts (15/37), including all 5 pts from PILOT, did not require hospitalization in the first 29 days post liso-cel infusion. Across all studies, most pts achieved an objective response (76%), including complete responses. Conclusions A subset of pts with R/R large B cell NHL were successfully treated with liso-cel and monitored for CAR T cell–related toxicity in the outpatient setting, including elderly pts and pts with high tumor burden. Incidences of severe CRS, NEs, and early hospitalization were low; 41% of pts did not require hospitalization in the first month post treatment. Most pts achieved an objective response.

To confirm the safety and tolerability, evaluate the pharmacokinetics (PK), and investigate the antitumor activity of abemaciclib in Japanese patients with advanced cancer.We conducted a non-randomized, single-arm, open-label, dose-escalation phase 1 study of abemaciclib administered orally every 12 h (Q12H) on a 28-day cycle at doses of 100 mg (Cohort 1, n = 3), 150 mg (Cohort 2, n = 3), or 200 mg [Cohort 3, n = 6, maximum tolerated dose (MTD)]. Dose escalation was based on the frequency of dose-limiting toxicity (DLT). MTD, as established in the previous phase 1 study in non-Japanese patients, was the highest dose level at which33 % of patients experienced DLT.Eleven of the 12 patients who received treatment with abemaciclib discontinued: 10 patients due to progressive disease, and 1 due to a DLT (Cohort 3, grade 2 nausea). Diarrhea, the most common treatment-emergent adverse event (AE), was managed supportively and did not require study treatment discontinuation. There were no drug-related serious AEs and no patients with corrected QT (QTc) 480 ms or QTc change of60 ms from baseline. The abemaciclib PK profile was characterized by slow absorption and high PK variability after single or repeated doses. Two patients, one with breast cancer and one with neuroendocrine tumor, experienced30 % decrease in tumor size from baseline.In Japanese patients with advanced cancer, single-agent abemaciclib has an acceptable safety profile and demonstrates antitumor activity at a dose of 200 mg Q12H. These findings support ongoing development of abemaciclib for diverse populations with advanced cancer.

We describe a sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) based method for label-free, simultaneous, relative quantification of drug metabolism enzymes in human liver microsomes (HLM; n = 78). In-solution tryptic digestion was aided by a pressure cycling method, which allowed a 90 min incubation time, a significant reduction over classical protocols (12–18 h). Digested peptides were separated on an Acquity UHPLC Peptide BEH C18 column using a 60 min gradient method at a flow rate of 0.100 mL/min. The quadrupole-time-of-flight mass spectrometer (ESI-QTOFMS) was operated in positive electrospray ionization mode, and data were acquired by data-dependent acquisition (DDA) and SWATH-MSALL mode. A pooled HLM sample was used as a quality control to evaluate variability in digestion and quantification among different batches, and inter-batch %CV for various proteins was between 3.1 and 7.8%. Spectral library generated from the DDA data identified 1855 distinct proteins ...

Purpose Biological drug products, or products derived from living cells, represent an increasingly important part of the pharmaceutical market. Despite this, little is known about how sponsors determine the dose to be studied in registrational trials or to be proposed in labeling for biologics. We examined how exposure–response and dose–response analyses were used to determine dosing in pivotal trials or the labeling for all biologics approved by the Center for Drug Evaluation and Research, the US Food and Drug Administration (FDA) between 2003 and 2016. Methods We extracted relevant characteristics of each biologic from its review package by FDA. We used descriptive statistics to characterize the rationale for the selected dose(s) in registration trials, with a particular focus on the role of exposure–response/dose–response analyses. We also examined how exposure–response/dose–response analyses were used to support the labeling dose and the basis for postmarketing requirements or commitments related to dose optimization. Findings A total of 79 biologics license applications were examined. Dose selection in registrational trials was more often attributed to clinical efficacy (73% of applications) than to clinical safety (42%). The dosing of products whose dose was apparently selected based on clinical efficacy was often (72%) determined by the dose–response relationship. In support of doses that were described in labeling, exposure–response analyses for efficacy were performed more commonly (53%) than dose–response analyses (21%). This trend was apparent after 2012. Implications This is the first study to summarize the justification of dose selection and the labeled dose of biologics approved by the FDA. Dose–response analyses have been often used as the rationale for dose selection of registrational studies, although exposure–response analyses are becoming more prevalent in support of the dosing guidelines in labeling.

The corticosteroid prednisone is an important component of posttransplantation immunosuppressive therapy. Pharmacokinetic parameters of prednisone or its pharmacologically active metabolite, prednisolone, are not well characterized in transplant recipients. The objective of this study was to compare the pharmacokinetics of total and unbound prednisone and prednisolone in diabetic and nondiabetic stable kidney transplant recipients and to evaluate the factors influencing plasma protein binding of prednisolone.Prednisone and prednisolone concentration-time profiles were obtained in 20 diabetic and 18 nondiabetic stable kidney transplant recipients receiving an oral dose of 5-10 mg prednisone per day. In addition to drug and metabolite exposures, factors influencing prednisolone protein binding were evaluated using a nonlinear mixed-effects modeling approach. This model takes into account the binding of prednisolone and cortisol to corticosteroid-binding globulin (CBG) in a saturable fashion and binding of prednisolone to albumin in a nonsaturable fashion. Finally, we have investigated the influence of several covariates including diabetes, glucose concentration, hemoglobin A1c, creatinine clearance, body mass index, gender, age, and time after transplantation on the affinity constant (K) between corticosteroids and their binding proteins.In patients with diabetes, the values of dose-normalized area under the concentration-time curves were 27% and 23% higher for total and unbound prednisolone, respectively. Moreover, the ratio of total prednisolone to prednisone concentrations (active/inactive forms) was higher in diabetic subjects (P0.001). Modeling protein binding results revealed that the affinity constant of corticosteroid-binding globulin-prednisolone (KCBG,PL) was related to the patient's gender and diabetes status.Higher prednisolone exposure could potentially lead to the increased risk of corticosteroid-related complications in diabetic kidney transplant recipients.

Background: To date, CAR T cell therapy has generally been limited to inpatient treatment at university medical centers. However, most patients (pts) in the US with R/R diffuse large B cell lymphoma receive therapy at non-university medical centers where outpatient delivery of cancer therapy is common. Infusion and management of CAR T cell therapies in the outpatient setting may lead to wider utilization in community/non-university centers and improve access. In TRANSCEND NHL 001, lisocabtagene maraleucel (liso-cel), an investigational, anti-CD19, defined composition, 4-1BB, CAR T cell product administered at target doses of CD4+ and CD8+ CAR T cells, demonstrated efficacy as ≥3rd-line therapy in pts with R/R large B cell NHL. With fewer than half of pts developing cytokine release syndrome (CRS) and/or neurological events (NE) and its delayed onset (median 5 and 10 days, respectively; Abramson, ASCO 2018; 7505) outpatient treatment was allowed with hospitalization at the first sign of fever or neurological symptoms. We report on pts with R/R large B cell NHL who were treated with liso-cel in the outpatient setting in TRANSCEND NHL 001 (NCT02631044) and in two phase 2 studies assessing the safety and efficacy of liso-cel, as ≥3rd-line therapy (OUTREACH; NCT03744676) or as therapy for 2nd-line transplant noneligible (TNE) pts (PILOT; NCT03483103). Methods: Eligible pts had R/R large B cell NHL, adequate organ function, and prior systemic chemoimmunotherapy (TRANSCEND and OUTREACH: ≥2 prior lines of therapy and ECOG PS ≤1; PILOT: 1 prior line of therapy and deemed TNE for autologous hematopoietic stem cell transplantation based on ECOG PS, organ function, and/or age). After lymphodepletion with fludarabine/cyclophosphamide, liso-cel was administered at 1 of 3 dose levels (DL) (DL1 = 50 × 106, DL2 = 100 × 106, DL3 = 150 × 106 total CAR+ T cells) in TRANSCEND and at DL2 in OUTREACH and PILOT. All studies allowed outpatient treatment at non-university (OUTREACH) or at both university and non-university medical centers (TRANSCEND, PILOT). Outpatient treatment required pts to have a caregiver for 30 days post-liso-cel infusion, receive safety-monitoring education (recognizing critical adverse events; eg, fever), and to stay within 1 h travel to the site of care. Outpatient treatment was at the discretion of the investigator. All sites had a multidisciplinary CAR T cell therapy team and standard operating procedures for outpatient administration and toxicity monitoring. CRS (Lee criteria, 2014) and NEs (defined as related to liso-cel; CTCAE criteria) were managed in the hospital. Results: At data cutoff, 37 pts across studies had received liso-cel on study Day 1 and were monitored as outpatients, including pts ≥65 yr old and those with high tumor burden. Patient characteristics are shown in the Table. The most frequent grade ≥3 treatment-emergent AEs were cytopenias (neutropenia 43%, anemia 30%, thrombocytopenia 14%). Sixteen pts had any grade CRS and 12 had any grade NE (19 pts had CRS and/or NE). Severe CRS and/or NE occurred in only 2 pts and were reversible (Table). Three pts received tocilizumab and corticosteroids and 4 pts received corticosteroids alone for CRS and/or NE. No pts received tocilizumab alone. Twenty-two of the 37 pts (59%) required hospitalization at any time; all pts were from TRANSCEND or OUTREACH. Three of those pts (8%) were admitted on study Day 3 or earlier, all for CRS; 1 patient required ICU-level care (length of stay, 3 days). Median (range) time to hospitalization post treatment was 5 (2‒22) days and median (range) length of stay was 6 (2‒23) days. Fifteen (41%) of the 37 pts, including all 5 pts from PILOT, were not admitted to hospital in the first 29 days post liso-cel infusion. Across all 3 studies, most pts achieved an objective response, including CR (Table). Median time to peak CAR+ T cell expansion in each study was 10 days (range: 3-21 in TRANSCEND; 7-10 in OUTREACH; 7-10 in PILOT). Conclusions: A subset of pts with R/R large B cell NHL were successfully treated with liso-cel and monitored for CAR T cell-related toxicity in the outpatient setting, including elderly pts and pts with high tumor burden. Severe CRS and NEs occurred with low incidence. The number of early hospitalizations was low, and 41% of pts did not require hospitalization in the first month post liso-cel infusion. Most pts (65%) achieved an objective response. Updated data with longer follow-up will be presented. Disclosures Bachier: Sanofi: Speakers Bureau; Viracyte: Consultancy; Kadmon Corporation, LLC: Consultancy. Palomba:Noble Insights: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties. Abramson:AbbVie Inc, Amgen Inc, Bayer HealthCare Pharmaceuticals, Celgene Corporation, EMD Serono Inc, Genentech, Gilead Sciences Inc, Janssen Biotech Inc, Juno Therapeutics, a Celgene Company, Karyopharm Therapeutics, Kite Pharma Inc, Merck, Novartis, Seattle Gen: Consultancy. Andreadis:Roche: Equity Ownership; Novartis: Research Funding; Celgene: Research Funding; Juno: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Kite: Consultancy; Genentech: Consultancy, Employment; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy. Sehgal:Juno/Celgene: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding. Hildebrandt:Juno Therapeutics: Equity Ownership; crispr therapeutics: Equity Ownership; CVS Health: Equity Ownership; Immunomedics: Equity Ownership; IDEXX laboratories: Equity Ownership; Pfizer: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Cellectis: Equity Ownership; Clovis Oncology: Equity Ownership; Aetna: Equity Ownership; Bluebird Bio: Equity Ownership; Celgene: Equity Ownership; Abbvie: Equity Ownership; Cardinal Health: Equity Ownership; Johnson & Johnson: Equity Ownership; Insys Therapeutics: Equity Ownership; Axim Biotechnologies: Equity Ownership; Axim Biotechnologies: Equity Ownership; Novartis: Equity Ownership; Kite Pharma: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Sangamo: Equity Ownership; Procter & Gamble: Equity Ownership; Vertex: Equity Ownership; Bristol-Myers-Squibb: Equity Ownership; Bayer: Equity Ownership; Scotts-Miracle: Equity Ownership; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Astellas: Other: Travel; Endocyte: Equity Ownership; GW Pharmaceuticals: Equity Ownership; Kite Pharma: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other; Novartis: Equity Ownership. Siddiqi:PCYC: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau; Kite, A Gilead Company: Research Funding; TG Therapeutics: Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Juno Therapeutics: Consultancy, Other: travel support, Research Funding. Stevens:Astellas: Consultancy. Farazi:Juno Therapeutics/A Celgene Company: Employment. Kostic:Juno Therapeutics, a Celgene Company: Employment. Trede:Celgene Corporation: Employment, Equity Ownership. Wang:Celgene Corporation: Employment. Lymp:Celgene Corporation: Employment, Equity Ownership. Thelen:Celgene Corporation: Employment. Ogasawara:Celgene Corporation: Employment, Equity Ownership. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; A2 Biotherapeutics: Honoraria, Other: Stock options ; BioLine RX, Gilead,Genentech,Novartis: Honoraria.

1. Disposition of tacrolimus and its major metabolites, 13-O-desmethyl tacrolimus and 15-O-desmethyl tacrolimus, was evaluated in stable kidney transplant recipients in relation to diabetes mellitus and genetic polymorphism of cytochrome P450 (CYP) 3A. 2. Steady-state concentration-time profiles were obtained for 12-hour or 2-hour post-dose, in 20 (11 with diabetes) and 32 (24 with diabetes) patients, respectively. In addition, single nucleotide polymorphisms of the following genes: CYP3A4 (CYP3A4: CYP3A4*1B, -392AG), 3A5 (CYP3A5: CYP3A5*3, 6986AG) and P-glycoprotein (ABCB1: 3435CT) were characterized. 3. Dose-normalized concentrations of tacrolimus or metabolites were higher in diabetic patients. CYP3A4*1B carriers and CYP3A5 expressers, independently or when assessed as a combined CYP3A4-3A5 genotype, had significantly lower dose-normalized pre-dose (C0/dose) and 2-hour post-dose (C2/dose) concentrations of tacrolimus and metabolites. Non-diabetic patients with at least one CYP3A4*1B and CYP3A5*1 allele had lower C0/dose as compared to the rest of the population. 4. Genetic polymorphism of CYP3A5 or CYP3A4 influence tacrolimus or metabolites dose-normalized concentrations but not metabolite to parent concentration ratios. The effect of diabetes on tacrolimus metabolism is subject to debate and requires a larger sample size of genetically stratified subjects.

SummaryBackgroundThe effect of early statin initiation on secondary prevention remains uncertain in unselected Japanese populations with coronary artery disease (CAD).MethodsWe investigated the mortality and morbidity in CAD patients according to presence or absence of statins within 3 months after the diagnosis of CAD in the Shinken Database cohort study. The primary endpoint was all-cause mortality.ResultsData were available on 789 Japanese patients with CAD (male 78.8%). Among those, 351 patients (44.5%) received a statin. The mean (SD) baseline low-density lipoprotein (LDL)-cholesterol levels were 113.6 (35.7) mg/dL in the statin group and 113.6 (26.4) mg/dL in the non-statin group (p=0.992). Unadjusted 2-year survival in patients with or without statins was 98.4% and 92.1%, respectively (p

Patients with coronary artery disease (CAD) frequently have impaired renal function, but the prevalence and influence of renal dysfunction on their prognosis in Japan remain uncertain. With a prospective study comprising all the new patients who had visited our hospital between 2004 and 2007 (n=6562), we investigated the prevalence of renal dysfunction and its influence on the prognosis of CAD patients. The glomerular filtration rate (GFR) was calculated by using the GFR equation used for the Japanese population. Of those, 797 patients with CAD and blood tests available were analyzed (median follow-up periods of 693 days). Patients were further classified into four subgroups according to estimated GFR value (eGFR): normal (90or =eGFR, 12.2%), mildly impaired (60or =eGFR90, 58.3%), moderately impaired (30or =eGFR60, 23.6%) and severely impaired renal function (eGFR30, 5.9%). The 2-year survival and cardiovascular event (cardiac death, nonfatal myocardial infarction or readmission for heart failure)-free rates were significantly different among the four subgroups: 98.9, 97.7, 89.3 vs. 67.8%, respectively (P0.001 for trend), and 100, 98.8, 89.0 vs. 70.0%, respectively (P0.001 for trend). The age- and gender-adjusted mortality increased significantly in moderately impaired (hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.383-7.017) and in severely impaired subgroups (HR 10.1, 95% CI 4.244-24.178) compared with those with eGFR of 60 or more. After adjustment for baseline differences, eGFR was independently associated with death and cardiovascular events (HR 0.983 and 0.981, 95% CI 0.968-0.998 and 0.965-0.998, respectively). In conclusion, our study identified the prevalence and association of eGFR with prognosis in Japanese patients with CAD, suggesting that strict care for not only CAD but also renal dysfunction is needed for further prevention of cardiovascular events.