Target Dose Levels Research Articles

Tolerability and Safety of Large-Volume Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% Administered with or without Dose Ramp-Up: A Phase 1 Study in Healthy Participants

PurposeFacilitated subcutaneous immunoglobulin (fSCIG; immune globulin infusion 10% [human] with recombinant human hyaluronidase [rHuPH20]) permits high-volume subcutaneous immunoglobulin (SCIG) infusion, shorter infusion times and reduced dosing frequency relative to conventional SCIG. It is initiated by gradually increasing infusion volumes over time (dose ramp-up) to achieve target dose level (TDL). Whether ramp-up strategies have tolerability or safety advantages over direct initiation at full TDL has not been evaluated clinically.MethodsThis phase 1 open-label study assessed tolerability and safety of fSCIG 10% with accelerated or no ramp-up compared with conventional ramp-up in healthy adults (NCT04578535). Participants were assigned to one of the three ramp-up arms to achieve TDLs of 0.4 or 1.0 g/kg/infusion. The primary endpoint was the proportion of infusions completed without interruption or infusion rate reduction owing to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint.ResultsOf 51 participants enrolled, 50 (98.0%) tolerated all fSCIG 10% infusions initiated (n = 174). Infusion rate was reduced in one participant owing to headache in the 0.4 g/kg/infusion conventional ramp-up arm. Study discontinuations were higher in the no ramp-up arm (70%) versus the conventional (0%) and accelerated (22%) arms at the 1.0 g/kg/infusion TDL. Safety outcomes did not substantially differ between treatment arms.ConclusionThe favorable tolerability and safety profiles of fSCIG 10% in healthy participants support initiating treatment with fSCIG 10% with accelerated ramp-up at TDLs up to 1.0 g/kg. Data support no ramp-up at TDLs close to 0.4 g/kg but additional data are needed for higher doses.

Lisocabtagene Maraleucel in Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis of the Mantle Cell Lymphoma Cohort From TRANSCEND NHL 001, a Phase I Multicenter Seamless Design Study.

To report the primary analysis results from the mantle cell lymphoma (MCL) cohort of the phase I seamless design TRANSCEND NHL 001 (ClinicalTrials.gov identifier: NCT02631044) study. Patients with relapsed/refractory (R/R) MCL after ≥two lines of previous therapy, including a Bruton tyrosine kinase inhibitor (BTKi), an alkylating agent, and a CD20-targeted agent, received lisocabtagene maraleucel (liso-cel) at a target dose level (DL) of 50 × 106 (DL1) or 100 × 106 (DL2) chimeric antigen receptor-positive T cells. Primary end points were adverse events (AEs), dose-limiting toxicities, and objective response rate (ORR) by independent review committee per Lugano criteria. Of 104 leukapheresed patients, liso-cel was infused into 88. Median (range) number of previous lines of therapy was three (1-11) with 30% receiving ≥five previous lines of therapy, 73% of patients were age 65 years and older, 69% had refractory disease, 53% had BTKi refractory disease, 23% had TP53 mutation, and 8% had secondary CNS lymphoma. Median (range) on-study follow-up was 16.1 months (0.4-60.5). In the efficacy set (n = 83; DL1 + DL2), ORR was 83.1% (95% CI, 73.3 to 90.5) and complete response (CR) rate was 72.3% (95% CI, 61.4 to 81.6). Median duration of response was 15.7 months (95% CI, 6.2 to 24.0) and progression-free survival was 15.3 months (95% CI, 6.6 to 24.9). Most common grade ≥3 treatment-emergent AEs were neutropenia (56%), anemia (37.5%), and thrombocytopenia (25%). Cytokine release syndrome (CRS) was reported in 61% of patients (grade 3/4, 1%; grade 5, 0), neurologic events (NEs) in 31% (grade 3/4, 9%; grade 5, 0), grade ≥3 infections in 15%, and prolonged cytopenia in 40%. Liso-cel demonstrated high CR rate and deep, durable responses with low incidence of grade ≥3 CRS, NE, and infections in patients with heavily pretreated R/R MCL, including those with high-risk, aggressive disease.

Phase I Study of a CD19-Directed CAR-T Cell Therapy for Relapsed/Refractory Mantle Cell Lymphomas(MCL)

Background: IM19 is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product, which is manufactured in China using a commercial process. We aimed to evaluate the efficacy and safety of IM19 in patients with relapsed or refractory mantle cell lymphomas in a Phase I clinical study. Methods: A phase 1 clinical trial has been launched to evaluate the safety and efficacy of IM19 for the treatment of relapsed/refractory MCL. We enrolled adult patients (aged ≥18 years) with relapsed or refractory MCL who had received at least 2 prior treatment regimens(including BTK inhibitor). Patients were assigned to one of two target dose levels of IM19 as they were sequentially tested in the trial (100×10⁶ CAR+ T cells [one or two doses], 200×10⁶ CAR+ T cells [one or two doses]). Leukapheresed patients could receive bridging chemotherapy based on investigator assessment of disease burden and tumor progression risk. Lymphodepleting (LD) chemotherapy was administered over 3 days, including fludarabine (30 mg/m2 i.v. daily) and cyclophosphamide (300 mg/m 2 i.v. daily), followed 2 days later by intravenous infusion of IM19 at the assigned dose. The first three subjects in each dose group will receive the second LD chemotherapy and infusion of IM19 CAR-T cells for consolidation treatment (with the same dosage as the first treatment) if the efficacy evaluation after the first infusion shows no progression and no DLT occurs. The investigators can determine the start time of consolidation treatment based on the patient's tolerance, but no later than 60 days after the first infusion. Efficacy was assessed at 1, 3, 9, 12, 18, and 24 months post first infusion. Safety events were monitored from beginning of LD through 2 years follow-up. The primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate. Results: Between Mar 3, 2022, and May 5, 2023, Five patients underwent leukapheresis for manufacture of CAR+ T cells (IM19) and all received bridging chemotherapy during the production of IM19. ALL 5 patients received LD and first infusion of IM19 at a dose of 100*10^6 CAR+ cells and no DLTs were observed. CRS was reported only in 1 patient(grade 1) and no patients developed ICANS. ALL 5 patients achieved CR on 28 days after first infusion. The median maximum CAR-T cells expansion (Cmax) was 156×10⁶ CAR+ cells/L, and median area under the curve from 0-28 days post-first infusion (AUC0-28d) was 860 day×CAR+ cells/L. 2 patients received the second LD chemotherapy and infusion of IM19 CAR-T cells for consolidation treatment (with the same dosage as the first treatment) at 44th days post first infusion. No DLTs，CRS or ICANS were observed after second infusion. Meanwhile, CAR-T cells can not be detected at 1, 4, 7, 10, 14, 21 and 28 days post second infusion by Flow cytometry in 2 patients. One patient maintained complete remission after 9 months of follow-up and another patient experience PD at 7th month after first infusion. For three patients who received single infusion of IM19, one maintained complete remission after 6 months of follow-up，one progressed at 3th month after infusion and one are still waiting for second efficacy evaluation. Conclusions: Initial data from this Phase I study demonstrate that use of IM19 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 MCL. We observed that CAR-T cells cannot expand in vivo after secondary infusion. Therefore, secondary infusion may not be necessary.

Results from the Completed Dose Escalation Portion of the Phase 1 Study of HPN217, a Half-Life Extended Tri-Specific T Cell Activating Construct (TriTAC®) Targeting B Cell Maturation Antigen (BCMA) for Relapsed/Refractory Multiple Myeloma (MM)

Background HPN217 is a B Cell Maturation Antigen (BCMA)-targeting tri-specific T cell engager (TCE). HPN217 contains three binding domains including anti-BCMA for MM cell binding, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. HPN217 is a small (~50 kDa) globular protein, designed to increase the therapeutic window by minimizing off-target toxicities and cytokine release syndrome (CRS). HPN217 is under investigation in patients (pts) with heavily pretreated relapsed/refractory MM (RRMM). Methods This study is designed to assess the safety, pharmacology and early clinical activity of HPN217 using fixed and step-dose (prime dose followed by target doses) regimens in dose escalation cohorts along with expansion of selected regimens for further evaluation. Pts with RRMM who have received at least 3 prior therapies including a proteasome inhibitor, an immunomodulatory drug, and CD38-targeted therapy are eligible. Prior exposure to a BCMA-targeting agent is permitted. Primary objectives include evaluation of safety, tolerability, pharmacokinetics (PK), and determination of the Recommended Phase 2 Dose(s) (RP2D). Secondary objectives include preliminary efficacy. HPN217 is administered IV once weekly or once every 2 weeks. Adverse events (AEs) are graded by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS) and ICANS. Clinical activity is assessed per IMWG Response Criteria. Results Dose escalation has been completed. 97 pts were enrolled across 15 dose escalation cohorts and expansion of 3 regimens with the highest target dose levels from dose escalation (12mg weekly; 24mg every 2 weeks; 24mg weekly for 1 cycle followed by 24mg every 2 weeks). As of 26 June 2023, across all cohorts, 94 pts were treated and had received a median (range) of 6 (2-19) prior lines of treatment (62% penta-exposed, 17% BCMA-targeted therapy, 68% prior transplantation). Median age was 70 (38-85) years. 36 pts (38%) remain on treatment. The most common (≥25%) treatment-emergent adverse events (TEAEs) across all cohorts and in the 12mg and 24mg cohorts are summarized in Table 1. Dose limiting toxicities (DLTs) of reversible transaminitis (Gr 3, n=1; Gr 4, n=1) in 2 pts at 2.86 mg fixed dose during dose escalation informed the choice of 2.15 mg as priming dose in the highest step dose cohorts; a maximum tolerated dose (MTD) has not been reached in step dose cohorts. All CRS events were grade 1-2 except one event of grade 3 CRS at 24 mg. Grade 1 ICANS was reported in 2 pts. Responses were observed at doses ≥ 2.15 mg. Among the 12mg and 24mg cohorts, 55% (22/40) of efficacy-evaluable pts currently have had a confirmed response (PR or better) including 2 pts with prior BCMA directed CAR-T cell therapy; disease assessments for recently enrolled patients are pending. Among pts with a response, 73% (16/22) have had a confirmed response of VGPR or better. Across all dose levels, the median time on treatment for pts with a confirmed response was 40 weeks (range 8.3-114 weeks), including 9 patients on treatment for over 12 months, with data maturing to include longer follow-up on patients recently enrolled. HPN217 exhibited linear and dose proportional PK across all dose groups with a median half-life of 68 hours (range 26-197 hours). Transient cytokine increases were higher with the initial/priming dose compared to subsequent/target doses. Conclusions Dose escalation of HPN217, a novel half-life extended BCMA-targeting T-cell engager, has been completed; the MTD was not reached in step dose cohorts. The 12mg and 24mg target doses are well tolerated with manageable adverse event profiles similar to those at lower dose levels and are associated with robust and durable clinical responses. Additional follow up of recently enrolled pts in 12 mg and 24 mg cohorts will inform the choice of the RP2D(s), and complete data on all pts enrolled will be presented. NCT04184050

Adaptation of a channelized Hotelling observer model to accommodate anthropomorphic backgrounds and moving test objects in X-ray angiography.

Prior implementations of the channelized Hotelling observer (CHO) model have succeeded in assessing the performance of X-ray angiography systems under a variety of imaging conditions. However, often times these conditions do not resemble those present in routine clinical imaging scenarios, such as having complex anthropomorphic backgrounds in conjunction with moving test objects. This work builds up on prior established CHO methods and introduces a new approach to switch from the already established "multiple-sample" CHO implementation to a "single-sample" technique. The proposed implementation enables the inclusion of moving test objects upon nonuniform backgrounds by allowing only a single sample to represent the test object present condition that is to be used within the statistical test to estimate the detectability index. To assess the proposed method, two image data sets were acquired with a clinical X-ray angiography system. The first set consisted of a uniform background in combination with static test objects while the second consisted of an anthropomorphic chest phantom in conjunction with moving test objects. The first set was used to validate the proposed approach against the multiple-sample method while the second was used to assess the feasibility of the proposed method under a variety of imaging conditions, including seven object sizes and seven detector target dose (DTD)levels. For the uniform background data set, considering all detectability indices greater or equal than 1, the ratio between the detectability indices of the proposed single-sample approach versus the multiple-sample method was 0.997 ± 0.056 (range 0.884-1.159). The average single-direction width of the 95% confidence intervals (CIs) of the detectability index estimates for the multiple-sample method was 0.38 ± 0.43 (range 0.03-2.20). For the single-sample approach, the average width was 2.52 ± 0.63 (range 1.11-5.44). For the anthropomorphic background image set, the results were consistent with classical quantum-limited signal-to-noise ratio (SNR) theory. The magnitude of the detectability indices varied predictably with changes in both object size and DTD, with the highest value associated with the highest dose and the largest object size. Additionally, the proposed method was able to capture differences in the imaging performance for a given test object across the field of view, which was associated with the attenuation levels provided by different features of the anthropomorphicbackground. A new single-sample variant of the CHO model to assess the performance of X-ray angiography imaging systems is proposed. The new approach is consistent with quantum-limited image quality theory and with a standard implementation of the CHO model. The proposed method enables the assessment of moving test objects in combination with complex, nonuniform image backgrounds, thereby opening the possibility to assess imaging conditions which more closely resemble those used in clinicalcare.

P11.84.A PHASE 1 TRIAL OF MARIZOMIB ALONE AND IN COMBINATION WITH PANOBINOSTAT IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Abstract BACKGROUND DIPG is an aggressive brainstem tumor with no effective therapy beyond the temporizing effects of radiation (RT). Preclinical studies demonstrated synergistic activity of marizomib (MRZ), an irreversible CNS-penetrant, pan-proteosome inhibitor, when administered with the HDAC inhibitor, panobinostat. In a study of adults with glioblastoma, MRZ was associated with significant CNS adverse events of interest (ataxia, balance disorder, dizziness, dysarthria, fall, gait disturbance, hallucination) in the majority of patients. We performed a novel Bayesian design, dual phase 1 trial of MRZ administered as a single agent and in combination with panobinostat to children with DIPG. Primary objectives were to determine the toxicity profile, dose limiting toxicities (DLT), and maximum tolerated dose (MTD) of MRZ at doses up to 0.8 mg/m2 alone and when administered in combination with panobinostat, and to characterize the plasma pharmacokinetics of MRZ as a single agent in children with DIPG. MATERIAL AND METHODS Eligible patients were <22 years with DIPG who received prior standard RT. When available, tumor tissue was centrally reviewed for molecular diagnosis. Patients initially received MRZ alone (Course A1). If tolerated, they received the combination of MRZ and panobinostat on subsequent courses (Course B1, B2, etc.). MRZ starting dose was 0.6 mg/m2IV on Days 1 and 15 of a 28-day cycle. If no DLT was observed during Course A1, patients received MRZ in combination with panobinostat 22 mg/m2/dose p.o. every other day, 3 times/week, on a one week on, one week off schedule. Dose escalation/ de-escalation for single agent and combination was guided using the Bayesian optimal interval design. RESULTS Four patients enrolled; one withdrew prior to initiating therapy due to disease progression (PD). Median age at study entry was 7.7 (range, 4.8-8.7)yrs. Three were evaluable for MRZ toxicities, two were evaluable for the combination MRZ + panobinostat. All patients were treated at dose level 1. No DLTs or CNS AEs attributed to MRZ were observed. Adverse events were related to disease/tumor progression or considered mild (grade 1 headache, emesis, diarrhea, fatigue, lymphopenia, thrombocytopenia) with the exception of sinus tachycardia and dyspnea (grade 2) (n=1). All patients died of PD; median time from on study to death for 3 treated patients was 95 days (range, 50-112). Pre- and post-study tissues were obtained where possible for qualitative exploratory pharmacokinetic, pharmacodynamic, molecular and patient model analyses. The study was terminated early due to withdrawal of support from BMS. CONCLUSION Children with DIPG tolerated single agent MRZ at a dose of 0.6 mg/m2/dose on Days 1 and 15 and in combination with panobinostat without any DLT or CNS toxicity. Target dose levels were not evaluated as clinical development program for marizomib ended and the study was discontinued early.

Sodium molybdate dihydrate does not exhibit developmental or reproductive toxicity in Sprague-Dawley rats maintained on a marginal copper diet

Groups of 24 weanling female Sprague-Dawley rats were administered molybdenum (Mo) as sodium molybdate dihydrate (SMD) in drinking water at target dose levels of 0, 20, or 40 mg Mo/kg bw/day and fed a semi-purified marginal copper (6.2 ppm Cu) AIN-93 G diet for 8 weeks prior to mating, through cohabitation and pregnancy until Gestation Day 21. The objective was to confirm the reproductive and developmental effects of SMD reported by Fungwe et al. (1990) at estimated doses as low as 1.5 mg Mo/kg bw/day in a similarly designed study with marginal Cu diet (6.3 ppm). There were no test material-related effects at 20 or 40 mg Mo/kg bw/day on mortality, clinical observations, body weight, body weight gain, food consumption, estrous cycling, reproductive performance, maternal macroscopic pathology, ovarian or uterine parameters, litter size, resorptions, fetal sex ratio, fetal weight, or external fetal malformations or variations. Water consumption was increased compared to controls at both dose levels during the pre-mating and gestation periods, with no apparent adverse impact. There was no evidence of copper depletion in serum at any dose level. In conclusion, the no-observed-adverse-effect levels (NOAELs) for systemic, maternal reproductive, and developmental toxicity in this marginal Cu diet study are 40 mg Mo/kg bw/day, consistent with the results of guideline developmental and reproductive toxicity studies of SMD. The results of Fungwe et al. were not replicated, even at higher dose levels of Mo, and their inconsistencies with guideline toxicity studies of Mo are not explained by the marginal dietary Cu level.

Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1–2 study

Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma. We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 106 (dose level 1) or 100 × 106 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198. Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis). A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable. Juno Therapeutics, a Bristol-Myers Squibb Company.

Facilitated subcutaneous immunoglobulin 10% at a target dose of 0.4 g/kg/infusion is well tolerated with accelerated or no dose ramp-up in healthy participants

IntroductionTransitioning to recombinant human hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) infusions from intravenous immunoglobulin therapies in primary immunodeficiency disease (PID) is implemented using a gradual dose ramp-up schedule, whereby infusion volumes are increased over a number of weeks to achieve the target dose level (TDL). This study investigated the tolerability and safety of fSCIG 10% at a TDL of 0.4 g/kg/infusion (i.e. 4 mL/kg/infusion) with accelerated and no dose ramp-up schedules in comparison with conventional dose ramp-up. MethodsThis was a phase 1, open-label, single-center trial (NCT04578535). This analysis compared three fSCIG 10% treatment arms at a TDL of 0.4 g/kg/infusion: (i) conventional dose ramp-up from 0.1 g/kg/infusion at Week 1 increasing to the TDL at Week 8; (ii) accelerated dose ramp-up from 0.2 g/kg/infusion at Week 1 increasing to the TDL at Week 5; (iii) the TDL administered without dose ramp-up. Participants were healthy adults aged 19–50 years. The primary endpoint was the tolerability of fSCIG 10% infusions, assessed as the proportion of participants who completed all initiated infusions without interruptions, stoppages or reductions in infusion rate due to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint. ResultsTwenty-four participants (mean [standard deviation] age 35.3 [8.6] years; 62.5% female) were assigned equally to the three treatment arms. All participants completed all initiated infusions except for one participant who experienced a headache resulting in an infusion rate reduction in the conventional dose ramp-up arm. All participants experienced local TEAEs, including infusion site swelling, erythema, pain and pruritus. Systemic TEAEs were experienced by 1/8 (12.5%), 2/8 (25.0%) and 2/8 (25.0%) participants in the conventional, accelerated and no dose ramp-up arms, respectively. All TEAEs were mild in severity. ConclusionsfSCIG 10% at a target dose of 0.4 g/kg/infusion showed a favorable safety and tolerability profile in healthy adults, with comparable tolerability and safety outcomes between the dose ramp-up treatment arms. Accelerated and no dose ramp-up schedules could be considered as potential alternatives to conventional dose ramp-up.Takeda Development Center Americas, Inc. funded this study. Takeda Pharmaceuticals International AG funded writing support.

First in Human Clinical Responses and Persistence Data on TEG001: A Next Generation of Engineered Αβ T Cells Targeting AML and MM with a High Affinity γ9δ2TCR

Introduction: γδT cells target malignant cells by sensing cancer mediated metabolic changes via their γδTCR[1]. We have developed the TEG001 cell product as an 'academic in house product', which are αβ T cells expressing the high affinity Vγ9Vδ2 TCR clone 5 [2]. TEG001 showed tumor reactivity towards a range of malignant cell lines, primary material from patients with various hematological malignancies as well as efficacy in murine models[3]. Here we present the results of dose level 1 and 2, addressing the safety and tolerability of TEG001 in patients with acute myeloid leukemia (AML) or multiple myeloma (MM) (NL6357). Methods: The TEG001 study (NL6357), is a single center, investigator-initiated study, with a standard 3+3 dose escalation design. Cohorts receive a single infusion of 1x106 TEG001 cells/kg (dose level 1), 3x106 TEG001 cells/kg (dose level 2) and 1x107 TEG001 cells/kg (dose level 3). Relapsed and/or refractory AML/high risk MDS and MM patients were eligible. AML patients with > 30% blasts or circulating blasts required bridging therapy. TEG001 cells were produced as previously described[2]. The conditioning regimen consisted of fludarabine i.v. 25 mg/m2 (day -4 to -2) and cyclophosphamide i.v. 900 mg/m2 (day -2). Pamidronate (PAM) (30 mg I.V.) was administered on day 0 and on day 28 to propagate TEG001 activity. TEG001 is detected in peripheral blood samples by flow cytometry as part of immune monitoring (details in Fig. 2). The primary endpoint was the development of dose-limiting toxicities (DLTs) in order to determine the maximum tolerated dose. Main criteria for reaching DLTs were TEG001 related adverse events (AEs) requiring ventilator support and grade 4 AEs not related to the underlying disease. AEs contributable to cytokine release syndrome (CRS) and/or immune effector cell-associated neurotoxicity syndrome (iCANS) grade 3 responding to tocilizumab and/or steroids were not defined as a DLT. Results: Fourteen patients were included. Of the six patients that were not infused, three patients did not respond to bridging chemotherapy, for two patients TEG001 product could not be manufactured for the intended target dose level and one patients went off study due to COVID-19 induced hospital restrictions. Eight patients were dosed: three patients in dose level 1 and three patients in dose level 2. Two patients received an 'out of specification' dose (77% of dose level 1; and 36% of dose level 2, respectively). Of the six patients infused in dose level 1 and 2, five patients had AML and one patient had MM (Fig. 1). No DLTs were observed. No AEs > grade 3 related to TEG001 were observed. Patient 16 (dose level 2), who received PAM according to the protocol on day 0 and 28, developed 2 seizures at day 29 and 30. The seizure responded well to levetiracetam and no other neurological signs associated with iCANS were observed. No infections or abnormalities in the spinal fluid or brain imaging were identified and connection of the seizure to TEG001 remained inconclusive. In all patients TEG001 cells were detectable in peripheral blood by flowcytometry (dose level 2 depicted in Fig. 2). In dose level 1, patient 7 had stable disease (SD, duration 3M). In dose level 2, patient 9 had a blast reduction (not meeting criteria for partial remission (PR); duration 12M) and patient 16, who had 28% bone marrow blasts prior to TEG001 infusion showed full hematological recovery (Fig. 2) and achieved a complete remission (CR, duration 6M). Conclusion: TEG001 cells are well-tolerated at the first 2 dose levels tested. TEG001 cells show persistence up to day 56. One out of three AML patients in dose level 2 achieved a CR one month after TEG001 infusion and SD was observed in both dose levels. The TEG001 study is currently recruiting patients for dose level 3 (1x107 cells/kg). This study was financially supported by Gadeta b.v. [1] Sebestyen, Z., et al., Translating gammadelta (gammadelta) T cells and their receptors into cancer cell therapies. Nat Rev Drug Discov, 2019. [2] Straetemans, T., et al., GMP-Grade Manufacturing of T Cells Engineered to Express a Defined gammadeltaTCR. Front Immunol, 2018. 9: p. 1062 [3] Johanna, I., et al., Evaluating in vivo efficacy - toxicity profile of TEG001 in humanized mice xenografts against primary human AML disease and healthy hematopoietic cells. J Immunother Cancer, 2019. 7(1): p. 69. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Already low drug dose antagonism of the renin-angiotensin aldosterone system decreases 1-year mortality and rehospitalization in old heart failure patients

AimsHospitalization for heart failure treatment (HHF) is an incisive event in the course of HF. Today, the large majority of HHF patients is ≥ 65 years and discharge HF drugs are most often not applied at dose levels acknowledged to provide prognostic benefit. This study therefore aims to investigate the treatment effect size of discharge HF drugs in old HHF patients. MethodsDrugs are analyzed according to pharmacological class. Individual discharge HF drug dose is reported as percentage of guidelines-recommended target dose. Primary endpoint was 1-year all-cause mortality (ACM) after discharge; the secondary endpoint combined 1-year ACM and first cardiovascular hospitalization within 1 year after discharge. Comparison between 65–80 years and > 80 years old study participants tested the relative treatment effect size as a function of respective age group. ResultsThe 875 consecutive HHF patients had a median age of 82 years [76–87 years]; 48.6 % were females. Betablocker and diuretic treatment did not change the incidence of endpoints. Inhibition of the renin-angiotensin system (RASi), when compared to no treatment, decreased the incidence of endpoints both at the 1–25 % and the > 25 % target dose level. Antagonists of the mineralocorticoid receptor (MRA), when compared to no treatment, decreased the secondary endpoint at the 1–25 % target dose level but not at the > 25 % target dose level. The relative treatment effect size of RASi or MRA corresponded between the age strata for both endpoints. ConclusionLow-dose RASi and MRA had beneficial effects in these old HHF patients.

Cevostamab Monotherapy Continues to Show Clinically Meaningful Activity and Manageable Safety in Patients with Heavily Pre-Treated Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from an Ongoing Phase I Study

Cevostamab Monotherapy Continues to Show Clinically Meaningful Activity and Manageable Safety in Patients with Heavily Pre-Treated Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from an Ongoing Phase I Study

OAB-027: Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T-cell therapy, for the treatment of patients with relapsed and refractory multiple myeloma (RRMM): updated results from KarMMa

OAB-027: Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T-cell therapy, for the treatment of patients with relapsed and refractory multiple myeloma (RRMM): updated results from KarMMa

Extended One-Generation Reproductive Toxicity (EOGRT) study of benzoic acid in Sprague Dawley rats

Benzoic acid (BA) was administered in the diet to male and female Sprague Dawley Crl:CD(SD) rats in an OECD Test Guideline 443 Extended One-Generation Reproductive Toxicity (EOGRT) study to test for effects that may occur as a result of pre- and postnatal exposure. The study included cohorts of F1 offspring to evaluate potential effects of benzoic acid on reproduction, the developing immune system, and the developing neurological system with the inclusion of learning and memory assessments. Benzoic acid was incorporated in the diet at concentrations of 0, 7,500, 11,500, and 15,000 mg/kg diet (ppm). These concentrations were selected based on the results of preliminary studies, and, based on average food consumption, were intended to supply BA doses of approximately 0, 500, 750, and 1000 mg/kg bw/day. To avoid exceeding these target dose levels, the dietary concentrations were adjusted (based on historical control body weight and food consumption data) to maintain the target mg/kg bw/day dose levels during those life periods when food intake per unit of body weight was increased to support milk production by females (gestation and lactation) and rapid pup growth (post-weaning).In the parental (F0) generation, survival, clinical observations, organ weights, pathology, hematology, serum chemistry, urinalysis, and bile acids were unaffected by BA administration. Reproductive parameters were also unaffected by BA administration.In the F1 generation, survival, growth and developmental landmarks, organ weights, pathology, immunotoxicity assessment, and neurotoxicity and neurobehavioral parameters such as auditory startle response, locomotor activity, learning and memory assessments were unaffected by BA administration, as were clinical pathology (hematology, serum chemistry, urinalysis, bile acids and thyroid hormones) and reproductive performance. Similarly, no adverse effects or systemic toxicity were observed in the F2 generation.Overall, the highest dietary concentration (15,000 ppm), providing a dosage of approximately 1000 mg/kg bw/day, was the NOAEL for benzoic acid in this EOGRT study.

Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T Cell Therapy, in Patients with Relapsed and Refractory Multiple Myeloma: Updated Results from Phase 1 CRB-401 Study

Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T Cell Therapy, in Patients with Relapsed and Refractory Multiple Myeloma: Updated Results from Phase 1 CRB-401 Study

Updated Results from the Phase I CRB-402 Study of Anti-Bcma CAR-T Cell Therapy bb21217 in Patients with Relapsed and Refractory Multiple Myeloma: Correlation of Expansion and Duration of Response with T Cell Phenotypes

Updated Results from the Phase I CRB-402 Study of Anti-Bcma CAR-T Cell Therapy bb21217 in Patients with Relapsed and Refractory Multiple Myeloma: Correlation of Expansion and Duration of Response with T Cell Phenotypes

Secondary Quality-of-Life Domains in Patients with Relapsed and Refractory Multiple Myeloma Treated with the Bcma-Directed CAR T Cell Therapy Idecabtagene Vicleucel (ide-cel; bb2121): Results from the Karmma Clinical Trial

Secondary Quality-of-Life Domains in Patients with Relapsed and Refractory Multiple Myeloma Treated with the Bcma-Directed CAR T Cell Therapy Idecabtagene Vicleucel (ide-cel; bb2121): Results from the Karmma Clinical Trial

Efficacy and Safety of Idecabtagene Vicleucel (ide-cel, bb2121) in Elderly Patients with Relapsed and Refractory Multiple Myeloma: KarMMa Subgroup Analysis

Efficacy and Safety of Idecabtagene Vicleucel (ide-cel, bb2121) in Elderly Patients with Relapsed and Refractory Multiple Myeloma: KarMMa Subgroup Analysis

Characterization of Cytokine Release Syndrome in the KarMMa Study of Idecabtagene Vicleucel (ide-cel, bb2121) for Relapsed and Refractory Multiple Myeloma

Characterization of Cytokine Release Syndrome in the KarMMa Study of Idecabtagene Vicleucel (ide-cel, bb2121) for Relapsed and Refractory Multiple Myeloma

Cell Density of NK Cells during Ex Vivo Expansion Impacts NK Cell Surface TRAIL Expression

Introduction Natural Killer (NK) cells are an emerging form of cancer immunotherapy currently being tested in clinical trials world-wide. NK cells are innate immune cells that can kill tumor cells via release of cytotoxic granules and via surface expression of the death receptor ligands tumor-related apoptosis-inducing ligand (TRAIL) and Fas ligand. We and others have recently shown that the proteasome inhibitor bortezomib sensitizes tumor cells to NK cell TRAIL-mediated killing by upregulation of death receptor 5. In a recent phase I NK cell dose-escalation study conducted at the NIH (NCT00720785) we have attempted to exploit TRAIL sensitization by administering ex vivo-expanded autologous NK cells to patients with solid tumors or hematologic malignancies that have been pretreated with bortezomib. Ex vivo cultures used to expand clinical grade NK cells for this trial utilize irradiated EBV-LCL feeder cells and IL-2 containing media which upregulates surface expression of TRAIL, substantially augmenting NK cell killing of bortezomib-treated tumors in vitro. Here we characterize the impact of specific expansion conditions used to generate high numbers of NK cells for clinical use on NK cell TRAIL expression. Methods To generate clinical grade ex vivo-expanded NK cells, we first isolated NK cells from patient apheresis products by CD3+ depletion followed by CD56+ selection, and stimulated these enriched NK cells with irradiated EBV-LCL feeder cells at a ratio of 1:10 in X-VIVO 20 supplemented with 10% inactivated human AB serum and recombinant human IL-2 (500 IU/ml). The clinical trial evaluated 8 escalating NK cell dose levels (Figure 1). Cohorts 1-4 received a single infusion of ex vivo-expanded NK cells on day 0 in a dose-escalating fashion (3-6 pts per cohort) and cohorts 5-7 received 1 x 108 NK cells/kg on day 0 and a second escalating dose of NK cells infused on day +5. A "closed bag" Baxter PL732 culture system was used for cohorts 1-7 which was later changed to a GREX500-CS (Wilson Wolf) system in cohorts 7-8. Using flow cytometry, we monitored surface expression of TRAIL on the day NK cells were harvested and infused fresh into patients. We also assessed TRAIL expression on NK cells from a single patient cultured at 6 different cell densities (range: 2.03-16.95 x 106/cm2) using culture conditions mimicking the phase I trial. Results A total of 137 NK cell cultures were harvested and administered fresh to 32 patients. NK cells on the day of harvest expanded a median of 198-fold, 895-fold, and 3637-fold on culture days 14-16, 19-22, and 24-27, respectively. NK cells at harvest contained a median of 99.7% CD3−/CD56+ NK cells, were 68.65% CD16+ and had a median of 88% viability. TRAIL was assessed by mean fluorescence intensity (MFI) with a median surface expression of of 1245 (range 132-4913) at the time of infusion (Figure 1). Expansions for cohort 8 generated 10-14 x109 (1 vessel) and 50-70 x109 NK cells (4-5 vessels) for fresh infusion, enough to support the target dose level of 1x108 (1st harvest) and 5x108 (2nd harvest) NK cells/kg. Remarkably, NK cells grown at higher cell density to reach the target cell numbers for cohort 8 exhibited substantially reduced TRAIL expression (median: 255, range 132-691). Subsequent experiments conducted on NK cells expanded in vitro for 14 days at different cell densities/concentrations showed TRAIL expression (MFI range: 319-1627) inversely correlated with both cell density and concentration (Figure 2). NK cells grown at the highest cell density (16.95 x 106/cm2) and concentration (4.23 x 106/mL) expressed the least amount of TRAIL (MFI 319), in contrast to those cultured at the lowest cell density (2.03 x 106/cm2) and concentration (0.51 x 106/mL), which demonstrated a TRAIL MFI of 1627. Conclusions Although ex vivo cultures using feeder cells make it possible to expand large numbers of NK cells for clinical use in humans, the higher concentrations and density of cells in these cultures reduce NK cell surface expression of TRAIL. In vitro, TRAIL expression appears to inversely correlate with cell density. These data highlight the need to avoid overly concentrating ex vivo expanded NK cells to maximize TRAIL surface expression as a method to potentiate the anticancer effects of adoptively infused NK cells. Disclosures No relevant conflicts of interest to declare.