Dose Escalation Cohorts Research Articles

Preliminary Results from a Phase I/II Study of Pomalidomide Plus Rituximab, Ifosfamide, Carboplatin, and Etoposide for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (PRIDE)

Background: Relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) patients have limited treatment options and are associated with poor prognosis. Outcomes are particularly poor following immunochemotherapy failure or relapse within 12 months of induction. The addition of the immunomodulatory agent lenalidomide (Len) to rituximab plus ifosfamide-carboplatin-etoposide (RICE) was shown to be feasible with promising efficacy in some studies. Pomalidomide (Pom) is a third-generation immunomodulatory drug that has shown excellent therapeutic activity against relapsed/refractory primary central nervous system lymphoma (PCNSL) with an acceptable toxicity profile. We conducted a phase I/II study combining Pom with RICE (PRICE) as a salvage regimen in first-relapse or primary refractory DLBCL (ChiCTR2100049327). Here we report the phase I results of the study. Methods: In phase I of the study, patients receive escalating doses of pomalidomide (2 mg, 3 mg, or 4 mg daily on d1-10) along with R-ICE therapy every 21 days by 3+3 design. Patients with CR or PR but not eligible for ASCT receive continuous pomalidomide as maintenance therapy for 12 months. The primary objective was to determine the maximum tolerated dose (MTD) or recommended dose, based on the occurrence of treatment-related DLTs. Secondary objectives included tumor response and safety. Results: At data cut-off (July 11, 2023), 14 patients were screened and 10 eligible patients were enrolled. 9 patients had been treated in the first 2 dose-escalation cohorts: 6 patients at 2 mg and 6 patients at 3 mg. Patient characteristics at baseline are shown in Table I. DLT was observed in two patients in the 3 mg cohort (grade 4 thrombocytopenia and grade 4 rash). MTD was determined as 2 mg. Grade (G) ≥ 3 TRAEs were leukopenia (4 patients), lymphopenia (3 patients), thrombocytopenia (3 patients), neutropenia (3 patients), rash (1 patient) and myelosuppression (1 patient). No death was related to the treatment. Five patients (55.6%) achieved an objective response including four patients (44.4%) with CR. ORR for the MTD dose level was (4/6) 66.7% with 3 CR and 1 PR. Notably, among the 7 patients with MYD88 mutations, which are associated with enhanced NF-κB activity, 4 achieved CR and 1 achieved PR. Conclusion: The addition of pomalidomide to the widely used RICE salvage regimen is feasible, and results in promising response rates in this DLBCL population that mostly with non-GCB subtype and double expression. MTD was reached and RP2D was determined to be 2 mg. Further studies are needed to evaluate the efficacy of this regimen, particularly in patients with MYD88 mutations.

A First-in-Human, Phase 1, Dose Escalation Study of Sgr-2921 As Monotherapy in Subjects with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Background Cell division cycle 7-related protein kinase (CDC7), or DBF4-dependent CDC7 kinase (DDK), is a cell cycle kinase that maintains DNA replication by phosphorylation and activation of the minichromosome maintenance protein 2 and 4 (MCMs), components of the replicative DNA helicase. Due to the central role of CDC7 in maintenance of the replication fork integrity, chemical inhibition of CDC7 kinase can ultimately lead to cancer cell death. SGR-2921 is an oral, small molecule inhibitor of CDC7. Preclinical studies demonstrate that, among all cell lines tested, SGR-2921 has the most potent anti-proliferative activity in AML. Potent antitumor activity has also been demonstrated in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) AML models. This antitumor response is observed in animal models representative of difficult to treat patient populations and appears to be agnostic of serious mutations (including those with p53 mutations and FLT3 mutations), BTK resistance, and multiple prior lines of treatment. Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or high-risk (HR) or very high-risk (VHR) myelodysplastic syndrome (MDS) have low response rates and poor overall survival. Considering the potent preclinical activity of SGR-2921 in AML and MDS models, coupled with the high unmet medical need in this population, SGR-2921 is being evaluated in patients with R/R AML and HR/VHR MDS. Study Design and Methods This is a phase 1, FIH, open-label, single-agent, two-arm, dose escalation study (NCT#05961839) designed to evaluate safety and tolerability and identify the recommended phase 2 dose (RP2D) of SGR-2921 as monotherapy in subjects with R/R AML, HR MDS, or VHR MDS. The study utilizes a hybrid accelerated titration design with single patient cohorts that transitions to a 3+3 design once a single Grade 2 event or DLT is observed. This is a multicenter global study (US, Spain and France) with an estimated study recruitment start date in October, 2023. SGR-2921 will be administered orally, once daily, utilizing a 5-day on and 9-day off dosing schedule over a 28-day cycle. Up to a maximum of 144 patients will be enrolled in the dose escalation and exploratory cohort phase of the study. To evaluate the effect of CYP3A4 inhibition on SGR-2921 exposure, subjects will be enrolled into one of two staggered, parallel study treatment arms, according to concomitant administration with (Arm B) or without (Arm A) azole antifungals that are strong CYP3A4 inhibitors at time of first dose. Safety and tolerability must be demonstrated in treatment Arm A, at the first two dose levels before initiating treatment Arm B. A single dose PK run-in will be required for subjects enrolled into the first 3 cohorts of each treatment arm. Subjects will be treated at increasing doses of study drug until all dose levels have been investigated or any dose level is found to exceed the maximum tolerated dose (MTD). A RP2D will be selected from one of the tolerable dose levels which will not exceed the MTD (see Figure 1 for study design). Key study inclusion criteria include: Age ≥ 18 years of age; Life expectancy ≥ 8 weeks; Confirmed diagnosis of R/R AML or HR and VHR MDS; Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Key study exclusion criteria include: Active malignancies not related to AML or MDS within two years prior to the first dose or requiring ongoing treatment; Clinical evidence of central nervous system (CNS) or pulmonary leukostasis; ≥ Grade 3 disseminated intravascular coagulation, or active CNS leukemia; QT interval corrected for heart rate per Fridericia's formula ≥470 msec during screening ECG. The study primary objectives are to evaluate the safety and tolerability of SGR-2921 as monotherapy and identify RP2D including MTD. Secondary objectives include evaluating the pharmacokinetics (PK) of SGR-2921 and investigating preliminary antitumor activity (composite complete remission rate, objective response rate, duration of response, etc.).

Role of Cell Therapy Product Characteristics in Patient Response to TAK-940 (CD19(T2)28z1xx Chimeric Antigen Receptor (CAR) T): Biomarker Analyses from a Phase I Study in Adult Patients with Relapsed or Refractory B-Cell Malignancies

TAK-940 (CD19(T2)28z1XX Chimeric Antigen Receptor (CAR) T) is an autologous CD19 CAR T cell therapy utilizing an optimized 1XX signaling domain substituting for the natural CD3ζ immunoreceptor tyrosine-based activation motifs. This 1XX design extends the functional persistence of CAR T cells with increased potency in mice (Feucht J et al. Nat Med 2019). TAK-940 is being evaluated in a Ph1 trial in patients with Relapsed or Refractory B-cell malignancies (NCT04464200) with demonstrated early signals of clinical efficacy (Park J et al. ASH 2022). The present study aims to provide a better understanding of the clinical performance of CD19(T2)28z1XX CAR T cells by in depth characterization of the cellular products and patient samples from this Ph1 trial. A total of 28 subjects were enrolled and treated in the dose escalation and expansion cohorts of the Ph1 trial. Responses were observed across all dose levels (25x10 6 to 200x10 6 CAR T cells), achieving ORR 82%, CR 71%. Immunophenotyping by flow cytometry was conducted on patient apheresis material, un-transduced cells, transduced cellular drug product and peripheral blood samples from infused subjects. Circulating cytokine profiling was performed on patient serum samples collected pre and post treatment with TAK-940. In the transduced cellular drug products, CAR+ and CAR- CD8+ central memory and transitional memory T cells were more abundant than naïve, stem cell memory or terminal effector populations. This elevation in central and transitional memory T cells seen in the drug product was not observed in the patient apheresis material, indicating that this effect is likely driven by the production process. CD57 and TIM3 expression in both CD4+ and CD8+ CAR+ T cells in the drug product showed a positive association with clinical response, while CTLA4 or LAG3 expression independently was negatively associated with response. The drug product also contained low numbers of dysregulated/exhausted T cells, with no observable difference between responders and non-responders. Interestingly, in the starting apheresis material, increased expression of TIM3 as well as decreased expression of either LAG3 or KLRG1 in CD8 T cells, independently associated with responses. Current analysis is based on associations with complete response. Additional analyses to be reported will include associations with ORR and durability of responses. These findings suggest potential utility of these T cell markers in predicting patient response and warrant evaluation in a larger population. Although CD57 expression has been associated with a senescent phenotype, we hypothesize that the observed increase in CD57 expression in CD4+ and CD8+ CAR+ T cells in the product may indicate higher cytotoxic potential of those cells. Increase in CD57+ CAR+ T cell subsets has been previously associated with durable CRs in large B cell lymphoma patients treated with axi-cel (Good Z et al. Nat Med 2022). Additional analyses to further characterize the CD57+ cell populations and establish their role in clinical responses to CAR T cell therapy with the 1XX CAR design are in progress. The increased expression of CD57 and the activation marker TIM3, and decreased expression of inhibitory receptors CTLA4 and LAG3 in the drug product from responders, together with the robust clinical responses observed with doses as low as 25x10 6 CAR T cells, suggest that the product consists of highly potent T cells, in accordance with the preclinical results obtained with the 1XX CAR. Low levels of circulating cytokines were observed following treatment with TAK-940, including IFNg, IL-6, IL-10, indicating a safe and tolerable CAR T product consistent with the observed clinical safety profile of TAK-940. Correlative analysis of T cell immunophenotypes observed in the product to clinical parameters including durability of responses, metabolic tumor volume/tumor burden, and induction of cytokines and chemokines is ongoing and will be reported. This will further contribute to our understanding of CD19 CAR T cells endowed with a 1XX signaling domain and potentially support the identification of product and/or apheresis biomarkers that may predict patient response.

Valemetostat for Relapsed or Refractory B-Cell Lymphomas: Primary Results from a Phase 1 Trial

Introduction: B-cell non-Hodgkin lymphomas (B-NHLs), including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), are among the most common NHLs. Enhancer of zeste homolog (EZH)2 and EZH1 are methyltransferases that catalyze the trimethylation of histone H3 at lysine 27 (H3K27me3); this repressive transcriptional mark is broadly associated with gene silencing. EZH2 is involved in mediating B-cell development. Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1. The clinical activity of valemetostat in patients (pts) with relapsed or refractory (R/R) NHL was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT02732275) trial. Interim data were reported previously. Here we report primary clinical outcomes for the subgroup of pts in J101 with R/R B-NHLs, including DLBCL and FL. Methods: This phase 1, open-label, multicenter study was conducted in Japan and the United States (US). Eligible pts were aged ≥ 18 years (y; US) or ≥ 20 y (Japan), had confirmed B-NHL or T-cell NHL (T-NHL), and were relapsed from, refractory to, or ineligible for standard therapies. The trial included a dose-escalation portion (Japan only) followed by a dose-expansion phase (Japan & US). Pts with a histological diagnosis of B-NHL were enrolled in the dose-escalation phase and received valemetostat once daily at doses of 150-300 mg/day (d) in continuous 28-d treatment (Tx) cycles. Preliminary efficacy assessment included objective response rate (ORR), complete response (CR) rate, and duration of response (DOR). DOR was estimated for responding pts using Kaplan-Meier methods. Due to the small number of pts with B-NHL, safety was assessed among all enrolled pts, including those with T-NHL in the dose-escalation and dose-expansion cohorts. Results: At the primary trial cutoff (Dec 31, 2022), 19 pts with R/R B-NHLs were registered and had received ≥ 1 dose of study drug, including 7 with DLBCL, 7 with FL, 3 with indolent B-NHL, and 2 with other B-NHLs. Median age was 66 (range 44-88) y. Most (79%) pts had an Eastern Cooperative Oncology Group performance status score of 0. Median number of prior therapies was 2.0 (range 0-6); no pt in this cohort had received prior hematopoietic cell transplantation. Overall, 90 pts with R/R NHLs were enrolled. All pts experienced at least 1 treatment-emergent adverse event (TEAE), including 78 (87%) who had treatment-related TEAEs. The most common TEAEs (any grade) were decreased platelet count (64%), dysgeusia (50%), anemia (43%), decreased neutrophil count (34%), and alopecia (33%). The most common grade ≥ 3 TEAEs were cytopenias, including decreased neutrophil count (24%), platelet count (24%), and lymphocyte count (19%). TEAEs required Tx interruption for 42 (47%) pts, dose reduction for 9 (10%) pts, and Tx discontinuation for 7 (8%) pts. The overall response rate in pts with R/R B-NHL was 47% (9/19; 95% confidence interval [CI], 24.4-71.1). Clinical responses were seen in 3/7 pts with DLBCL and 4/7 pts with FL; 1 pt in each of these groups achieved CR ( Table). Of 19 pts, 9 (47%) achieved reductions of ≥ 50% from baseline in the sum of target lesion areas during valemetostat Tx ( Figure). A gain-of-function EZH2 mutation was identified in 1 pt with FL, and this pt achieved a partial response. Median time to response overall was 3.7 (range 1.9-10.1) months (mo) and estimated median DOR for the 9 responding pts was 18.4 mo (95% CI, 5.3 mo to not reached). Among all pts who received valemetostat 200 mg/d with pharmacokinetic (PK) data available (n = 74), mean [standard deviation; SD] maximum plasma concentration (C max) on cycle 1 day 1 was 2140 [1620] ng/mL, with a median time to C max (T max) of 3.9 (range 0.2-27.8) h and a mean [SD] AUC tau of 17,500 [21,400] ng × h/mL. Conclusions: Valemetostat demonstrated encouraging clinical activity in pts with R/R B-NHLs. The safety profile of valemetostat was acceptable; cytopenias were common but manageable and did not require Tx discontinuation between 150-300 mg/d. Clinical responses were durable, with a median DOR of > 1.5 y. Results for pts in this trial with R/R T-NHLs are presented in another abstract (Jacobsen et al.) at this congress. Ongoing trials of valemetostat in pts with R/R B-NHLs include a phase 2 monotherapy trial in France and Belgium (NCT04842877) and a phase 1/2 trial of valemetostat plus rituximab and lenalidomide (R 2) in the US (NCT05683171).

Valemetostat for Relapsed or Refractory Peripheral T-Cell Lymphomas: Primary Results from a Phase 1 Trial

Introduction: Treatment (Tx) options for T-cell non-Hodgkin lymphomas (T-NHLs) are limited and prognosis is too often poor for patients (pts) with relapsed or refractory (R/R) disease. Enhancer of zeste homolog (EZH)2 and EZH1 are methyltransferases that catalyze trimethylation of histone H3 at lysine 27 (H3K27me3); this repressive transcriptional profile is broadly associated with gene silencing. Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1 that prevents H3K27me3 and increases expression of genes involved in immune function ( SLA, PAG1) that can be silenced by H3K27me3. Valemetostat was approved in Japan for the Tx of R/R adult T-cell leukemia/lymphoma (ATLL) in 2022. The clinical activity of valemetostat in pts with R/R NHLs was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT02732275) trial. Interim data were reported previously. Here we report primary outcomes for pts in J101 with R/R T-NHLs treated with valemetostat. Methods: This open-label, multicenter study was conducted in Japan and the United States (US). Eligible pts were ≥ 18 (US) or ≥ 20 (Japan) years (y) of age and relapsed from, refractory to, or ineligible for standard therapies. The trial included a dose-escalation phase (Japan only) followed by a dose-expansion phase (Japan & US). Enrollment in the expansion phase was limited to pts with R/R peripheral T-cell lymphoma (PTCL) or ATLL. Pts received valemetostat once daily in continuous 28-day (d) Tx cycles at 150-300 mg/d in the escalation phase and 200 mg/d in the expansion phase until disease progression or intolerance. Key endpoints for the dose-escalation and dose-expansion cohorts were safety and PK parameters. Preliminary efficacy assessment included objective response rate (ORR), complete response (CR) rate, duration of response (DOR), and progression-free survival (PFS). DOR and PFS were estimated using Kaplan-Meier methods. Results for PTCL and ATLL are reported separately. Results: At the primary data cutoff (Dec 31, 2022), 71 pts were included in the efficacy and safety analyses; 57 with PTCL and 14 with ATLL. Median age at baseline was 68.0 (range 26-83) y in the PTCL group and 66.5 (37-78) y in the ATLL group, and median prior therapies were 2.0 (1-8) and 2.5 (1-8), respectively; 16 (28%; 14 autologous, 2 allogeneic) pts with PTCL and 2 (14%, both allogeneic) with ATLL had previously undergone transplant. The most common PTCL subtypes were PTCL, not otherwise specified (PTCL, NOS; n = 26, 46%) and angioimmunoblastic T-cell lymphoma (AITL; n = 23, 40%). Tx was ongoing for 8 (11%) pts at data cutoff. All 71 pts included at data cutoff experienced ≥ 1 Tx-emergent adverse event; 59 (83%) pts had a Tx-related adverse event (TRAE). The most common all-grade TRAEs were cytopenias, dysgeusia, and alopecia; the most frequent grade ≥ 3 TRAEs were decreased neutrophil (17%), lymphocyte (11%), and platelet (14%) counts ( Table 1). TRAEs led to Tx discontinuation for 4 (6%) pts (1 each: acute myeloid leukemia, myelodysplastic syndrome, colitis, and acute kidney injury), dose reduction for 5 (7%) pts, and Tx interruption for 18 (25%) pts. The ORR was 55% (30/55) in the PTCL group and 64% (9/14) in the ATLL group, with CR rates of 31% (17/55) and 29% (4/14), respectively; within the PTCL group, the ORR among evaluable pts was 50% (13/26) for PTCL, NOS and 64% (14/22) for AITL ( Table 2). Median times to response were 1.8 (range 1.0-5.6) months (mo) in the PTCL group and 1.9 (1.7-19.4) mo in the ATLL group. Median DOR was 21.9 mo (95% confidence interval [CI], 10.2 mo to not reached [NR]) in the PTCL group (median follow-up 16.4 mo) and 21.2 (95% CI, 1.4 to 38.7) mo in the ATLL group (median follow-up 23.0 mo). Median PFS was 7.7 and 4.1 mo, respectively (median follow-up 18.2 mo and NR). Conclusions: Valemetostat was well tolerated and showed encouraging clinical activity in pts with R/R T-NHLs. Cytopenias were common but could usually be managed without Tx discontinuation. Valemetostat induced durable responses, with median DOR of > 1.5 y in both the PTCL and ATLL groups. Results for pts in this trial with R/R B-NHLs (Izutsu et al) and from a phase 2 trial in R/R T-NHLs (Horwitz et al) are reported separately.

Integrative Analysis of the Tumor and Microenvironment to Model the Molecular Heterogeneity Underlying the Response to Cevostamab in Relapsed/Refractory Multiple Myeloma

Background: Cevostamab is an FcRH5xCD3 bispecific antibody that facilitates T-cell directed killing of myeloma cells and has shown promising activity and a favorable safety profile as monotherapy in patients with relapsed/refractory multiple myeloma (RRMM) in the ongoing Phase I GO39775 trial (NCT03275103; Trudel et al. ASH 2021). We performed an integrative analysis of peripheral blood (PB) and bone marrow aspirate (BMA) samples collected at baseline from patients in GO39775 to understand the heterogeneity of patients with RRMM and potential correlations with clinical outcome. Methods: PB and BMA samples were collected at baseline from 100 patients in GO39775. Patients who had less than 25% missingness in any data layer were selected from the single-step (3.6/90-252mg dose levels [n=49] and 3.6/90mg tocilizumab premedication group [n=14; Trudel et al. ASH 2022]) and double-step (0.3-1.2/3.6-7.2/60-160mg dose levels [n=37]) dose-escalation and dose-expansion cohorts. To characterize immune cells, samples were profiled at a central laboratory by 8-color flow cytometry. Cytokine profiling was performed on baseline plasma samples via electrochemiluminescence and digital ELISA. Serum B-cell maturation antigen (sBCMA) levels were quantified using hybrid immunoaffinity capture by liquid chromatography with tandem mass spectrometry. For the unbiased integrative analysis, a Similarity Network Fusion algorithm was applied to preprocessed flow cytometry data from PB and BMA samples, and to baseline characteristics including demographics, prior therapies, and selected clinical laboratory analytes. Data were imputed in samples with less than 25% missingness using a random forest algorithm. Results: Initial findings from unsupervised machine learning-based integrative clustering analysis of baseline samples from multiple immunological and clinical data types revealed three patient subpopulations with unique biological features, illustrating the molecular heterogeneity of patients with RRMM. Each cluster was characterized by distinct patterns of immune cell proportions and activation states. Interestingly, these immunologically defined clusters also corresponded to clinical outcomes. Cluster 1 had the strongest response to cevostamab, followed by Cluster 2 and Cluster 3. Conclusions: Our novel, unbiased, machine learning, integrative clustering approach not only revealed unique molecular subtypes that illustrate the heterogeneity of patients with RRMM, but also identified immunological features associated with potentially reduced response to cevostamab therapy, which could provide direction for future research.

Tolerability and Clinical Activity of Novel First in Class Oral Agent, Inobrodib (CCS1477), in Combination with Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma

Background Inobrodib (CCS1477) is a first in class potent, selective, and orally bioavailable inhibitor of the bromodomains of p300 and CBP, two closely related histone acetyltransferases with oncogenic roles in hematological malignancies. Inobrodib exhibits potent anti-tumor cell activity in a range of hematological cell lines, including multiple myeloma, and demonstrates additive/synergistic activity with pomalidomide. Aims: We report preliminary safety (primary objective) and efficacy (secondary) data for inobrodib in combination with pomalidomide (pom) and dexamethasone (dex) from relapsed/refractory multiple myeloma (RRMM) patients treated in the Phase I/IIa trial (NCT04068597). Methods : Eligible patients (pts) had confirmed RRMM and had exhausted available or suitable standard of care treatment options. Two dose escalation combination cohorts were completed; pts received inobrodib at doses of 25 mg or 35 mg bidaily on a 4 days on/3 days off intermittent schedule, as well as standard dosing of pom and dex in 28-day cycles. Adverse events were graded by CTCAE v5.0. Responses were investigator assessed per IMWG. Results: Initial dose escalation cohorts enrolled 15 RRMM pts with a median age of 71 yrs (range 41-80). Median prior lines of therapy was 5 (range 3-9). Median follow-up was 56 days (range 13-189), with a median number of 3 cycles received (range 1-7). Almost all patients were pomalidomide-refractory (13/15, 87%), 13/13 (100%, 2 pts data missing) were triple class refractory and 3 pts (20%) received prior BCMA therapy. At the data cut-off (5 th June 2023), Grade (gr) 3 /4 treatment-emergent adverse events (TEAEs) were reported in 11 of 15 (73%) pts. Over half of the patients remain on treatment and all but three remain in follow-up for survival analysis. Of these three patients, two died due to disease progression and one due to an unrelated cardiac event at the end of cycle 2. The most frequent gr 3/4 events were infections (41.1%). The majority of the other gr 3/4 TEAE were hematological and seen in 5 of 13 (38.5%) pts; neutropenia (23.5%) thrombocytopenia (5.9%, all gr 3) and anemia (11.8%, all gr 3). Seven of 15 (47%) pts experienced TEAEs considered related to inobrodib; all events were gr 1/2 apart from a single patient with gr 3 electrolyte abnormalities. No DLTs were noted; two pts (13%) discontinued due to related events. The majority of patients 13/15 (87%) showed signs of activity with disease markers decreasing over time. At the point of data cut off, 7/15 (47%) heavily pre-treated patients achieved confirmed responses (MR or better) per IMWG criteria; 2 VGPR, 3 PR and 2 MR. Of note, two further patients, who initially received inobrodib monotherapy but progressed were transferred into the pom-dex combination cohort and subsequently achieved objective responses (VGPR and PR). Summary: The first in class agent inobrodib in combination with pom-dex shows promising early efficacy in heavily pre-treated, including pom-refractory, RRMM patients. The combination is tolerable, with the most common events being infections, as expected in this patient population. Dose optimisation continues as part of this study with expansion arms in an earlier setting planned.

RADT-38. DOSE ESCALATED RADIOTHERAPY IS ASSOCIATED WITH IMPROVED OUTCOMES FOR HIGH GRADE MENINGIOMA

Abstract BACKGROUND The optimal modern radiotherapy (RT) approach after surgery for atypical and malignant meningioma is unclear. We present results of dose-escalation. METHODS Consecutive patients with histopathologic grade 2 or 3 meningioma treated with RT were reviewed. A dose-escalation cohort [≥ 66Gy equivalent dose in 2 Gy fractions using an a/b = 10 (EQD2)], was compared to a standard dose cohort (< 66Gy). Outcomes were progression-free survival (PFS), cause-specific survival (CSS), overall survival (OS), local failure (LF) and radiation necrosis. RESULTS 118 patients (111 Grade 2, 94.1%) were identified; 54/118 (45.8%) received dose-escalation and 64/118 (54.2%) standard dose. Median follow-up was 45.4 months (IQR: 24.0 - 80.0 months) and median OS was 9.7 years (Q1: 4.6 years, Q3: not reached). All dose-escalated patients had residual disease vs. 65.6% in the standard dose cohort (p < 0.001). PFS at 3-, 4- and 5-years in the dose-escalated vs. standard dose cohort were 78.9%, 72.2% and 64.6% vs. 57.2%, 49.1% and 40.8%, respectively, (p = 0.030). On multivariable (MVA) analysis, dose-escalation (HR: 0.544,p = 0.042) was associated with improved PFS, whereas ≥ 2 surgeries (HR: 1.989, p = 0.035) and older age (HR: 1.035, p < 0.001) were associated with worse PFS. The cumulative risk of LF was reduced with dose-escalation (p = 0.016). MVA confirmed dose-escalation protective for LF (HR: 0.483, p = 0.019), whereas ≥ 2 surgeries prior to RT predicted for LF (HR: 2.145, p = 0.008). A trend was observed for improved CSS and OS in the dose-escalation cohort (p < 0.1). Seven patients (5.9%) developed symptomatic radiation necrosis (RN) with no significant difference between the two cohorts. CONCLUSIONS Dose-escalated radiotherapy with ≥ 66Gy for high grade meningioma is associated with improved local control and PFS with an acceptable risk of RN.

CTNI-23. SINGLE CELL TRANSCRIPTOMICS, PHARMACOKINETICS, AND PHARMACODYNAMICS OF COMBINED CDK4/6 AND MTOR INHIBITION IN A PHASE 0 TRIAL OF RECURRENT HIGH-GRADE GLIOMA

Abstract Adult High-grade gliomas (HGGs) often exhibit deregulation of RB-CDK4/6 and mTOR signaling pathways. This study investigated tumor single cell transcriptomics, pharmacokinetics, and pharmacodynamics immediately following combined CDK4/6 (ribociclib) and mTOR (everolimus) inhibition in recurrent HGG. 24 patients with recurrent gliomas harboring RB+, CDKN2A/B deletion or CDK4/6 amplification, and PTEN loss or PIK3CA mutations were enrolled in a phase 0 trial. Patients received ribociclib treatment for 5 days before surgery, including six who received ribociclib (400mg QD) plus everolimus (2.5mg QD), and six dose-escalation cohorts (n = 3 each) reaching ribociclib 600mg QD plus everolimus 70mg QW. No dose-limiting toxicities were observed. Validated LC-MS/MS methods determined total and unbound drug concentrations. Preoperative MRI revealed a marked decrease in gadolinium-enhancement in all patients. In gadolinium-nonenhancing tumor regions, the median unbound concentration of ribociclib was 561 nM, while no unbound everolimus concentrations were detected. Ribociclib’s pharmacodynamic effects in surgical specimens were compared with matched archival tissue using IHC. Across IDH-wild-type tumors, there was significant decrease in MIB1 levels between the matched archival and surgical specimens (p < 0.05) suggesting drug-associated cell cycle inhibition. Single nuclei RNAseq (snRNA) analyses were performed on 17 IDH-wild-type recurrent samples treated with ribociclib plus everolimus and 29 IDH-wild-type recurrences treated with standard therapies. Cellular state analysis based on snRNAseq data demonstrated a decreased neural progenitor-like (NPC-like) malignant cell state compared with standard therapies (p < 0.01), indicating inhibition of the CDK4-driven neural progenitor-like cell state. This observation was validated using snRNA and patient-derived glioma cell lines exposed to ribociclib, showing a consistent decrease in NPC-like proportions and cycling cells (p < 0.05). This study highlights the value of integrating pharmacokinetics/pharmacodynamics and snRNA data to assess treatment effects in phase 0 surgical tissues. These findings support further development of ribociclib, but not everolimus, for the treatment of glioma patients.

INNV-14. INTERIM REPORT OF A PHASE 1/2 STUDY OF SONODYNAMIC THERAPY (SDT) USING AMINOLEVULINIC ACID (ALA) AND LOW-INTENSITY FOCUSED ULTRASOUND IN PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Abstract BACKGROUND DIPGs are devastating pediatric brain tumors with limited treatment options, poor prognosis, and survival of 9-11 months. Preclinical studies demonstrate that performing SDT through MR-guided focused ultrasound (MRgFUS) activates ALA metabolite, protoporphyrin IX (PpIX), leading to tumor cell death and prolonging survival in rodent glioma models through generation of reactive oxygen species and lipoperoxidation, without affecting normal tissue. MEDTHODS: Herein we report preliminary data from an ongoing first-in-child dose-escalation trial of ALA-SDT post-radiation therapy in children ≥ 5 years with DIPG. The trial aims to evaluate the safety and tolerability of ALA-SDT, determine the recommended-phase-2-dose and assess preliminary efficacy and pharmacokinetics (PK) of ALA administered intravenously. RESULTS The first study cohort completed enrollment of 3 subjects. Six hours prior to SDT, patients received an infusion of ALA (SONALA-001) at a dose of 5 mg/kg, followed by sonication with 200J. The first subject was treated in 2 sessions: each to half of the pons 30 days apart. Two subsequent subjects had the entire pons treated in a single session. No dose-limiting toxicity (DLT) or related adverse event grade ≥ 3 were observed. For SONALA-001, the Cmax occurred at the end of infusion, followed by rapid clearance (15.7 mL/min/kg), with a plasma half-life of < 1 hour, indicating rapid distribution (5530 ml/kg). For PpIX, the Cmax occurred 6 hours post-dose and declined with a longer mean half-life of 3.8 hours. Both Cmax and AUCall demonstrate circulating PpIX and systemic exposure were significantly lower than for ALA. CONCLUSION SDT signals an innovative and well-tolerated approach for patients with DIPG in our first study cohort. As expected, the PK for SONALA-001 demonstrate rapid infusion and clearance, whereas for PpIX, the PK are consistent with formation of a metabolite. Clinical trial enrollment is ongoing and dose-escalation cohorts will provide additional PK and safety data.

Sonrotoclax (BGB-11417) in Combination with Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma with t(11;14): Safety, Efficacy, and Determination of Recommended Phase 2 Dose

Background: B-cell lymphoma-2 (BCL2) family proteins represent attractive therapeutic targets as they play an important role in MM cell survival. In patients with relapsed/refractory (R/R) MM harboring t(11;14) for whom multiple prior lines of therapy failed, single-agent venetoclax, a first generation BCL2 inhibitor, demonstrated antimyeloma activity (Kumar S, et al. Blood. 2017). Dexamethasone, a long-standing mainstay of treatment for MM, increases the expression of both BCL2 and Bim. This results in a greater dependency on BCL2 for tumor survival, ultimately increasing the sensitivity to a BCL2 inhibitor. Sonrotoclax (BGB-11417) is a BH3 mimetic that binds and inhibits BCL2 with potency >10x that of venetoclax in biochemical assays. BGB-11417-105 (NCT04973605) is an ongoing phase 1b/2 trial designed to evaluate safety and efficacy of sonrotoclax as monotherapy, in combination with dexamethasone, or in combination with dexamethasone plus carfilzomib in patients with R/R MM harboring the t(11;14). Here, we report preliminary data from the sonrotoclax plus dexamethasone dose-escalation (DE) cohorts. Methods: Eligible patients have R/R MM that is t(11;14) positive by fluorescence in situ hybridization (per central assessment) who have received 1-7 prior lines of therapy for MM with previous exposure to a proteasome inhibitor and an IMiD agent. In dose escalation, patients received 80, 160, 320, or 640 mg of sonrotoclax daily with 40 mg of dexamethasone weekly until intolerability, disease progression, or death. The primary objectives in the DE cohorts were to assess the overall safety/tolerability profile as well as determine the maximum tolerated dose (MTD)/maximum assessed dose (MAD) and establish the recommended phase 2 dose (RP2D). AEs were reported per CTCAEs v5.0; safety was assessed by a safety monitoring committee (SMC) after a 21-day dose-limiting toxicity (DLT) window for each cohort and was guided by a modified toxicity probability interval method (mTPI-2). Disease responses were assessed per International Myeloma Working Group 2016 criteria. Results: As of May 26, 2023, 19 patients have been enrolled in the 80-, 160-, and 320-mg (n=3 each) and 640-mg (n=10 patients) dose-escalation cohorts. The median age was 68 years (range, 52-81 years). The median prior lines of therapy was 4 (range, 1-12) and 11 patients (58%) failed on a prior anti-CD38 antibody. The most common AEs (>20% of all patients) were insomnia (n=9; 47%), fatigue (n=6; 32%), nausea (n=5; 26%), and arthralgia (n=4; 21%); none of which were severity grade ≥3. Three patients (16%) experienced grade ≥3 treatment-emergent AEs (TEAEs). One patient (33%) in the 160-mg cohort had grade 3 increases in liver enzymes and diarrhea; one patient (10%) in the 640-mg cohort had a grade 3 decrease lymphocyte count and hypokalemia; and one patient (10%) in the 640-mg cohort had grade 3 cataracts and retinal detachment. Three patients experienced COVID-19 (grade 1-2, n=2; grade ≥3, n=1). Three patients experienced TEAEs that led to treatment discontinuation (COVID-19, cancer pain, hematuria; n=1 each). No patient, across all dose levels tested, experienced a DLTs; thus, sonrotoclax 640 mg daily was the determined to be the MAD and the RP2D in combination with dexamethasone. Four patients (21%) died while on study; however, no deaths were determined by the investigators to be associated with study treatment. One patient died from COVID-19 while receiving study therapy; three additional patients died ≥50 days after treatment discontinuation (COVID, progressive disease, and unknown causes, n=1 each). With a median treatment duration of 120 days (range, 30-526), ORR was 58%; 11 patients had a PR or better (n=6, PR; n=2, very good PR; n=2, CR; n=1, stringent CR [sCR]; Figure). The ORR for the 640-mg cohort was 70% (n=3, PR; n=2 VGPR; n=1, CR; n=1, sCR). Nine patients remained on treatment; the longest duration of response was 483 days (20 cycles) which, at data cutoff, was still ongoing. Conclusion: Sonrotoclax plus dexamethasone was generally well tolerated in patients with R/R MM harboring t(11;14) at doses up to 640 mg, and initial safety and efficacy results are promising. The SMC has recommended 640 mg in combination with dexamethasone as the RP2D. Recruitment is ongoing for the sonrotoclax in combination with dexamethasone and carfilzomib dose-finding arms and the sonrotoclax plus dexamethasone indication expansion cohort.

Phase I / II Study on Infusion of Alloreactive or Ex Vivo il-15 Stimulated Natural Killer Cells after Haploidentical Stem Cell Transplantation in Pediatric Patients with Acute Leukemia (PHINK): A Study of the Spanish Hematopoietic Stem Cell Transplantation Group (GETH)

Background: Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a highly complicated but effective procedure for high-risk pediatric leukemia in the absence of an HLA-identical donor. Post-transplant relapse is the main problem for patient survival. According to literature, Natural Killer (NK) cells play a potent role as inducers of the graft-versus-leukemia (GvL) effect in haplo-HSCT. The presence of alloreactive NK cells correlates with a lower relapse rate, improved engraftment, decreasing graft-versus-recipient disease (GvHD) and viral infection risk. In the absence of donor-recipient NK cell alloreactivity, other NK cell activation strategies are necessary. We propose a phase I/II clinical trial with dose escalation, multicenter, framed in the GETH, to determine dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of a single infusion of alloreactive NK cells (Allo-NK) or NK cells stimulated ex vivo with IL-15 (IL15-NK) after haplo-HSCT in pediatric patients with high-risk leukemias. Methods: Eighteen pediatric patients with high-risk leukemia were recruited between September 16, 2020, and May 12, 2023, at 5 hospitals in Spain, Hospital Universitario La Paz, Hospital Universitario Gregorio Marañón, Hospital Universitario Niño Jesús, Hospital Universitario Central of Asturias and Hospital Santa Creu and Sant Pau. Patients were stratified in 2 treatment groups: Allo-NK (n=9) or IL15-NK (n=9), depending on the KIR disparity between donor and recipient. Our phase I/II clinical trial presents a dose-escalation design (3+3). The treatment cohorts are divided into cohort 1 (up to 2x10 7 cells/kg), cohort 2 (2-5x10 7 cells/kg) and cohort 3 (5-10x10 7 cells/kg). We have monitored infections reactivation, as well as, chimerism and engraftment after transplantation. In Allo-NK group, the KIR clone that provides alloreactivity in the NK cell was also tracked. The phenotypic profile and functional capacity of NK cells present in the patient up to 360 days after transplantation have also been analyzed. Results: Nine patients (4 in Allo-NK and 5 in IL-15NK) were included in cohort 1, 7 patients (4 in Allo-NK and 3 in IL-15NK) in cohort 2 and 2 patients (1 in Allo-NK and 1 in IL-15NK) in cohort 3. We were unable to complete the dose escalation design initially proposed due to the high weight of some patients and the unavailability of ex vivo expanded NK cells. In IL15-NK group patients presented a higher prevalence of B-ALL (p=0.018) and had received a previous transplant (p=0.082). NK cell infusions of IL15-NK group showed higher expression of CD25 and CD69 receptors and higher functional capacity. In the Allo-NK group, the most prevalent KIR-reactive clone was KIR2DL1 (55.6%). We also observed a tendency for KIR2DL1 alloreactive clone to increase from 30 (8,18%) to 360 (25,63%) days after transplantation. Regarding clinical outcomes in 2 study arms, the incidence of severe (Grades III-IV) acute GvHD was 22.2% and severe chronic GvHD was only observed in 1 (5.6%) patient (Table 1). The incidence any infection or endothelial vascular complications were 72% and 33% respectively. No statistical differences were observed in GvHD, infections and endothelial vascular complications. We found 2 relapses, 1 in each study arm (11.1%). Five patients died, 1 (5.6%) because of disease progression and 4 (22.2%) because transplant related complications (TRM) (Table 1). Dividing patients into the 3 dose-escalation cohorts, we found no significant differences between cohorts in the primary clinical outcomes analysed. One-years overall survival (OS) and disease-free survival (DFS) was 72.22% (CI95% 51.93-100) and GvHD-free/relapse-free survival (GRSF) was 64.1% (CI95% 44.62-92.1), finding no significant differences between either 2 study arms or the 3 dose-escalation cohorts. Regarding the analysis of the NK phenotype, we observed a tendency to increase the expression of CD16 and CD57 receptors between 30 to 360 days after transplantation in both groups. Conclusions: Two study arms shows similar data respect to clinical outcome. Patients infused with IL-15-stimulated NK cells showed similar toxicity to the alloreactive NK group. According to dose escalation, we observed no association between increased toxicity and increased number of infused NK cells. We were unfortunately unable to complete cohort 3 because of the cells/kg ratio in some patients.

A Phase 1 Study of the Oral CDK9 Inhibitor Voruciclib in Relapsed/Refractory (R/R) B-Cell Lymphoma (NHL) or Acute Myeloid Leukemia (AML)

Background: The anti-apoptotic protein Mcl-1 contributes to the pathophysiology of certain B-cell malignancies and AML, and dependence on Mcl-1 is associated with resistance to venetoclax. Efforts to target Mcl-1 through direct inhibition have faced challenges due to cardiovascular toxicities. Voruciclib, a potent oral CDK9 inhibitor (CDK9i), was shown to indirectly downregulate Mcl-1 protein levels and synergize with venetoclax in preclinical models in lymphoid and myeloid malignancies. In solid tumors, voruciclib maximum tolerated dose (MTD) was defined as 350 mg with continuous daily dosing, and 600 mg when used on days 1-14 on a 21-day cycle. This phase 1 study is the first to evaluate the safety, dose-limiting toxicities (DLT), preliminary efficacy, pharmacokinetics, and pharmacodynamics of voruciclib in R/R hematologic malignancies (NCT03547115). Methods: Patients (pts) with relapsed B-cell NHL, CLL, or AML aged ≥18 years who had ECOG performance status ≤1, disease progression after standard therapies, adequate hepatic and renal function, and no prior CDK9i were eligible. The study followed a 3+3 design and DLTs were assessed in Cycle 1. Voruciclib was administered daily continuously at a starting dose of 50 mg on a 28-day cycle (Cohort I). After 2 DLTs were observed at 100 mg in AML pts, dosing was changed to daily on days 1-14 on a 28-day cycle (Cohort II). Also, pts with prior allogeneic transplant were excluded and dose escalation (100, 150, 200 mg) proceeded separately in AML and B-cell malignancies. Disease response was assessed by investigators using the Lugano, 2008 iwCLL, and 2017 ELN criteria. Results: 40 pts were enrolled: 21 AML, 19 NHL (9 DLBCL, 3 CLL, 3 MCL, 3 FL and 1 MZL). Cohort I enrolled 16 pts, 8 each at 50 mg and 100 mg. Cohort II enrolled 24 pts (17 AML and 7 B-cell malignancies), including 6 at 100 mg, 7 at 150 mg, and 11 at 200 mg. Dose escalation in Cohort II did not reach the MTD and was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition. Median age was 70 years (range 40-90), 72.5% of pts were ≥65 years, and 77.5% had ECOG performance status = 1. Pts had a median of 3 prior therapies (range, 1-8). Median duration on drug was 5 weeks (range 1-22). Drug-related serious adverse events (AEs) were reported in Cohort I only. Two pts with AML had a DLT of Grade (Gr) 3 interstitial pneumonitis at 100 mg; both had had allogeneic transplant and active graft versus host disease, one of whom also had a concurrent Gr 3 differentiation syndrome. One pt with DLBCL at 50 mg had Gr 3 hypoxemic respiratory failure in Cycle 4. In Cohort II, no DLTs were observed and there were no non-hematologic Gr 3-5 drug-related AEs. In the overall population, the most common AEs were diarrhea (30%), nausea (25%), anemia (22.5%), fatigue (22.5%), constipation (17.5%), dizziness (15%) and dyspnea (15%) [Table 1). One pt with AML had Gr 3 hyperbilirubinemia. There was no evidence of drug-related neutropenia in pts with NHL. No significant cardiovascular AEs were observed. One pt with AML in Cohort I achieved a morphologic leukemia-free state. At 200 mg, 5 of 10 AML pts (50%) had stable disease. Voruciclib pharmacokinetics was dose proportional, mean accumulation ratio was 2.4, mean T max was 4 hours, and at 200 mg, steady state C max was 925 ng/mL and mean C trough was 442 ng/mL (~1 microM). Analysis of Mcl-1 protein expression in normal lymphocytes by flow cytometry showed a trend of decrease in on-treatment samples compared to pre-treatment. Consistent with this, RNA-Seq analysis of 3 paired CLL samples confirmed rapid (after 6 hours) downregulation of Mcl-1 mRNA transcript in the malignant B-cells. Furthermore, scRNA-Seq analysis of 2 longitudinal AML samples demonstrated downregulation of MYC transcriptional program and oxidative phosphorylation in circulating AML blasts, both evident 24 hours after start of voruciclib and ongoing at C1D15. Conclusions: Voruciclib at doses up to 200 mg administered on 14 consecutive days on a 28-day cycle was well tolerated, with no DLTs observed, and no cardiovascular toxicities. There was no significant myelosuppression in pts with B-cell malignancies. As the safety profile suggested non-overlapping toxicities with venetoclax, the study is now evaluating voruciclib in combination with venetoclax in pts with R/R AML to exploit dual inhibition of Bcl-2 and Mcl-1.

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

A Phase I Study of CD19-Targeted 19(T2)28z1xx CAR T Cells in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Background: Autologous CD19 CAR T cell therapies have demonstrated favorable clinical responses in relapsed or refractory (R/R) diffuse large B-cell lymphomas (DLBCL), but only a subset of patients (pts) experience durable remissions. We hypothesized that the redundancy of CD28 and CD3ζ signaling in a CAR design incorporating all 3 CD3ζ immunoreceptor tyrosine-based activation motifs (ITAMs) might negatively affect T cell differentiation and promote exhaustion. Therefore, we created a new CD19 CAR construct with calibrated CAR activation potential by mutating 2 of the 3 ITAMs, termed 1XX, and hypothesized that a 1XX CAR would afford durable responses at lower dose and fewer toxicities compared to CARs comprising 3 ITAMs. We previously presented the data from the dose-escalation portion of the phase I clinical trial of 19(T2)28z-1XX CAR T cells in DLBCL (Park J et al. ASH 2022). We have now completed accrual and report the updated results from both dose escalation and expansion portion of the study with a longer follow-up (NCT04464200). Methods: This is a single-center, phase I, dose-escalation and expansion trial of 19(T2)28z1XX CAR T cells in adult pts with R/R DLBCL conducted at Memorial Sloan Kettering Cancer Center. Pts received fludarabine and cyclophosphamide lymphodepleting chemotherapy followed by a single infusion of CAR T cells. There were 4 dose levels in the dose escalation cohort: dose level (DL) 1 (25x10 6), DL2 (50x10 6), DL3 (100x10 6) and DL4 (200x10 6 CAR T cells). The primary objective of the trial was to evaluate safety and tolerability and determine the recommended phase 2 dose. Key secondary objectives include assessment of overall response and complete response rates. Results: 28 pts have been enrolled and treated; 16 pts on the dose escalation and 12 pts on the dose expansion phase of the study. Median age was 62 (range, 48-86). 20 pts (71%) had primary refractory disease, 3 pts (11%) had prior autologous HSCT, and 2 pts (7%) had prior autologous CD19 CAR T therapy. In the dose-escalation phase (n=16), 15 pts experienced grade 1-2 CRS (94%) and no pt experienced ≥grade 3 CRS. Two pts (13%) experienced ICANS: 1 pt with grade 1 and 1 pt with grade 3 (Table 1). Eight pts received tocilizumab and 5 pts received corticosteroid. Complete response (CR) was observed in 11 of 16 pts (69%) and partial remission (PR) in 1 pt (6%) with overall response rate (ORR) of 75%. Responses were seen across all dose levels (Table 1). The lowest dose (DL1: 25x10 6) was selected for dose-expansion based on exposure-response analysis and 12 additional pts were treated at that dose level. In a pooled analysis of 16 pts who received DL1 dose (4 in dose escalation and 12 in dose expansion), 12 pts and 1 pt experienced grade 1-2 (75%) and grade 3 CRS (6%), respectively. Only 1 pt experienced ICANS (6%) at grade 3 (same pt who had grade 3 CRS), which was reversible and transient (Table 1). 11 pts received tocilizumab and 9 pts received corticosteroids. Twelve pts achieved CR (75%) and 2 pts (12%) PR with the best ORR of 87% (Table 1). A lower metabolic tumor volume (MTV) at screening but not at post-bridging was associated with a higher likelihood of achieving CR (p=0.039). With a median follow-up of 345 days (range, 33-1024), 4 pts experienced relapse (1 CR and 3 PR pts) and 16 pts have ongoing CR > 6 months (Figure 1). While CAR T cell persistence analysis is ongoing, 5 pts have CAR T cells detected beyond one year in ongoing CR including a patient treated at DL1 with detectable CAR T cells at 2 years. Conclusions: Treatment with 19(T2)28z1XX CAR T cells was shown to be safe with durable remissions with low rates of severe CRS (4%) and ICANS (7%). The overall CR rate of 71% is encouraging and appears durable with the majority of CR patients in ongoing remission > 6 months at a median follow-up of 345 days and with persisting CAR T cells. With more patients treated at DL1 with a longer follow-up, the study demonstrates a high efficacy of 19(T2)28z1XX CAR T cells at a dose significantly lower (25x10 6) than those of approved CD19 CAR T cells (100-300x10 6) and support that the 1XX single ITAM signaling domain may lead to enhanced efficacy of CD19 CARs and allow infusion of a lower T cell dose with favorable toxicity profiles.

Duvelisib for Cytokine Release Syndrome Prophylaxis during CD19-Targeted CAR T Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of patients with advanced non-Hodgkin lymphoma (NHL). However, treatment toxicity, including cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS), can be significant. Effective prophylactic strategies may reduce the frequency and/or severity of CAR T cell therapy while also expanding the pool of patients eligible for such therapy. Duvelisib is an oral inhibitor of the gamma and delta isoforms of phosphoinositide 3-kinases (PI3K), which is an active therapy for CLL/NHL with an established safety profile. In addition, prior work from our group and others has demonstrated that PI3K inhibition can prevent CRS in an in vitro model (Amatya et al. ASH 2022) and can enhance antitumor cytotoxicity of CAR-T cells. Consequently, we performed a trial of duvelisib for CRS prophylaxis in patients undergoing standard-of-care (SoC) CAR T-cell therapy for NHL (NCT05044039). This was a phase I trial with a 3 + 3 dose escalation and two-arm dose expansion phase. The trial enrolled patients with NHL eligible for SoC CAR T-cell therapy and adequate organ function. Herein, we report data from the dose escalation cohort and the first dose expansion cohort, treated with duvelisib BID from day -2 to +28. The primary outcome was safety and tolerability. Secondary outcomes included the incidence and severity of CRS and ICANS, overall response rate (ORR), and progression-free survival (PFS). 17 patients are included in this analysis, including 6 patients in dose escalation and 11 of 14 planned patients in dose expansion cohort A, with full enrollment of cohort A expected prior to presentation. Median age was 68 years (range: 28 - 79) and 53% were male. Diagnoses included DLBCL (n = 13), MCL (2), FL (1) and PBMCL (1). For CAR-T cell therapy, patients received axi-cel (10), liso-cel (4), brexu-cel (2) and tisa-cel (1). 3 patients were enrolled on dose level 1 (15 mg BID) and 3 patients were enrolled on dose level 2 (25 mg BID). No patients experienced a dose-limiting toxicity (DLT) during dose escalation and consequently, 25 mg BID was selected as the recommended dose for expansion. 75 adverse events (AEs) were considered possibly (73) or probably (2) related to duvelisib by study investigators, including 14 severe (grade ≥3) AEs. The most common AEs were blood count abnormalities (41), liver function test abnormalities (12), fatigue (8) and nausea (6). The majority of severe AEs were cytopenias (13) and one patient had grade 3 hypokalemia. 13 patients (77%) had AEs attributed to duvelisib, including 6 patients (35%) with severe AEs. 76% of patients (13/17) experienced CRS at a median of 5 days following cell infusion (range 2 - 9) (Figure 1A). In 71% of patients (12/17), the onset of CRS was after day 3. Most were grade 1 (65%) and no patients experienced severe (grade 3 - 4) CRS. The median duration of CRS was 1 day (range: 1 - 7). ICANS occurred in 41% of patients (7/17) at a median of 7 days (range 4 - 10) and 12% of patients experienced severe (grade 3-4) ICANS. The median duration of ICANS was 5.5 days (range: 4 - 11 days). Toclizumab was given to 65% of patients for treatment of CRS and 53% received steroids for CRS and/or ICANS. All 17 patients were evaluable for disease response. At day +30, the overall response rate (ORR) was 71% (12/17) with 47% achieving complete response (CR) rate. At day +100, the ORR was 64% (9/14) with 50% CR. Best response was CR in 71% of patients and stable disease in 18% of patients. No patients had progressive disease (PD) as best response. CAR T cell expansion by flow cytometry was robust at all dose levels, consistent with prior reports (Figure 1B). With a median follow up of 93 days (range: 28 - 406), 53% of patients were alive and in remission. PD occurred in 6/17 (35%) patients with a median time to progression of 89 days (range: 28 - 182). Three patients enrolled on the study have died. One died from disease progression on day +266. Two died in remission from neutropenic sepsis (day +50) and vaping-induced lung injury (day +144). Data from this ongoing phase I study suggests that duvelisib with SoC CAR T-cell therapy is safe and tolerable. Preliminary data from this study suggest that the addition of duvelisib to CAR T-cell therapy may prevent grade 3-4 CRS and also delay the onset of CRS. Although limited follow-up is available, the depth and duration of response is similar to published data for CAR T-cells in this setting.

Safety Results of a Phase I Study of Zandelisib + R-CHOP in Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL)

Introduction: Emerging data have identified distinct genetic subtypes of DLBCL based on the diverse oncogenic molecular drivers with varying clinical outcomes when treated with standard R-CHOP. Relapse post frontline treatment could be curbed by integrating novel agents upfront. The phosphatidylinositol 3 kinase (PI3K) signalling pathway contributes to the oncogenesesis of both germinal center derived and activated B-cell (ABC) DLBCL subtypes (Wright, et al Cancer Cell, 2020). Zandelisib, a highly selective oral PI3Kδ inhibitor has proven efficacy in B cell lymphoma with a favorable toxicity profile when administered in intermittent dosing schedule (Pagel, et al Lancet Oncol 2022). We conducted a phase I/2 trial to evaluate the safety and efficacy of zandelisib in combination with R-CHOP chemotherapy in newly diagnosed DLBCL. The study enrollment was closed in 12/2022 after the development of zandelisib was discontinued. We present the results of the phase I (P1) trial. Methods: In this investigator-initiated trial, patients (pts) with untreated DLBCL with ECOG performance status (PS) ≤ 2, adequate bone marrow (BM) and organ function were enrolled from 08/2021-12/2022 at Cleveland Clinic (NCT04517435). ECOG PS 3 was allowed if it was attributed to the lymphoma diagnosis. The study was supported by the MEI Pharma. The P1 study had 2 dose escalation cohorts in combination with standard doses of R-CHOP every 21 days for 6 cycles; zandelisib was dosed 60 mg daily on days 1-4 in cohort 1 and daily on days 1-7 in cohort 2. If the 3 subjects in dose level 1 (D1) did not experience any dose limiting toxicity (DLT) during cycle 1 (C1), pts were enrolled into D2. In phase 2 (P2), a cycle of R-CHOP prior to the study treatment was allowed, if clinically deemed. All pts received pneumocystis jirovecii (PJP) and viral prophylaxis. Disease response was assessed after C3 and C6. Primary end point for P1 was to assess safety and tolerability of the combination and to determine recommended P2 dose (RP2D) of zandelisib. Pts who received at least 1 cycle of study treatment were included in the safety analysis. Primary objective of P2 is progression free survival (PFS) at 1 year. Pt and disease characteristics were analyzed using descriptive statistics. Results: We enrolled a total of 13 pts (P1: 9 and P2: 4) in the study prior to termination. The median age was 67 (range 46-79) years, with majority being female (53.8%), with an ECOG PS of 0-2 (100%). Most pts had stage III-IV disease 10/13 (77%), IPI ≥3 in 8/15 (62%), elevated LDH 9/13 pts (69%), and extranodal involvement 7/13 (54%). 3 pts had BM involvement. DLBCL was germinal center (GC) subtype in 77% of the pts. FISH studies revealed translocations in BCL2 (46%), BCL6 (8%) and c-myc (0%). There was no DLT observed in cohort 1 and zandelisib 60 mg daily on D1-7 was the RP2D. 12 of 13 enrolled pts completed 6 cycles of the study regimen prior to study closure. Of the 12 evaluable pts, the ORR was 100% with 9 pts (75%) achieving CR and 3 PR (25%). No pt experienced disease progression prior to study closing. Median time from treatment start to response was 165 (range 48-189) days. The most common adverse events were diarrhea (38%), neutropenia and anemia (31% each), fatigue, constipation, leukopenia and thrombocytopenia (23% each). Other AEs include colitis, nausea, hypoalbuminemia and hypokalemia (15% each). Of the 2 pts who developed colitis, 1 pt had G1 colitis which resolved, while the other pt discontinued the study after 2 cycles due to G3 colitis and bowel obstruction. Another pt experienced G3 jejunal perforation after completing cycle 6. Other G≥3 AE observed were neutropenia and leukopenia each (23% each), lung infection and lymphopenia (8% each). All pts were alive at the time of study closure. Conclusion: In this phase 1/II study, encouraging efficacy was observed with zandelisib + R-CHOP, but this should be interpreted with caution as the study was incomplete. There is a potential signal for increased gastrointestinal toxicity (one G3 colitis, one G3 bowel perforation) in this small sample size and larger prospective trials are needed to further assess the toxicity profile of the combination of oral PI3K inhibitors with R-CHOP.

A Phase 1 Cohort Dose Escalation and Expansion Trial to Determine the Safety, Tolerance, Maximum Tolerated Dose, and Preliminary Antineoplastic Activity of IKS03 in Patients with Advanced B-Cell Non-Hodgkin Lymphomas (NHL)

Background: IKS03 is an antibody-drug conjugate (ADC) comprising an anti-CD19 antibody conjugated with novel ConjuALL technology to a highly potent proprietary DNA-crosslinking pyrrolobenzodiazepine (PBD) prodrug payload for the treatment of CD19-positive hematologic malignancies. Both the payload and the linker of IKS03 incorporate an innovative tumor-selective chemistry that takes advantage of the overexpression of beta glucuronidase in cancer cells compared to most normal tissues. Payload release and activation require cleavage of glucuronide moieties that are incorporated into the linker payload structure providing improvements in both efficacy and safety compared to traditional ADC formats. This “glucuronide trigger” is stable while in circulation with minimal to no systemic payload release from the ADC. Following binding and internalization of IKS03 into a CD19-positive cancer cell, beta glucuronidase can release the active PBD payload leading to cell death. Normal tissues without CD19 expression and/or with low levels of the beta glucuronidase enzyme have limited ADC uptake, are less able to process IKS03 and are differentially spared. In preclinical studies, IKS03 demonstrated significant in vivo efficacy with complete tumor regressions in CD19-positive diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) xenograft models at single doses of 0.1 to 1 mg/kg. IKS03 demonstrated greater activity than the clinical benchmark ADC loncastuximab tesirine. IKS03 is also highly effective in patient-derived xenograft models that contain some of the genetic alterations commonly found in relapsed/refractory NHL patients. Results from toxicology studies in cynomologus monkey suggest a manageable safety profile at single doses, well above those required for in vivo activity. Pharmacokinetics are favorable with a mean total ADC half-life of 8 days and undetectable levels of the active PBD payload in circulation confirming targeted delivery of the payload. Study Design and Methods: This Phase 1 multicenter, open label, non-randomized study of IKS03 will consist of two parts: dose-escalation (Part I) and dose-expansion (Part II) together enrolling approximately 140 adult patients with relapsed or refractory B-cell NHL after at least two prior lines of systemic therapy. Patients will receive repeat doses of study drug by IV infusion on Day 1 of each 21-day cycle, until disease progression, unacceptable toxicity, or another withdrawal criterion is met. Key exclusion criteria include: active central nervous system involvement with NHL; clinically significant cardiovascular, pulmonary or hepatic disease; or receipt of other CD19-directed therapy within 3 months. Part I dose escalation will enroll patients with confirmed CD19-positive, measurable or non-measurable advanced B-cell NHL. Eligible subtypes include DLBCL, MCL, FL, high-grade B-cell, and marginal zone lymphoma as per WHO 2016 classification. Patients with Burkitt's lymphoma, Waldenström macroglobulinemia, and chronic lymphocytic leukemia are excluded. In Part 1, the primary objective is establishment of the recommended Phase 2 dose (RP2D) by evaluation of safety, tolerability and the maximum tolerated dose (MTD) of IKS03. Dose escalation will follow a 3+3 design. A two cycle Dose-Limiting Toxicity (DLT) assessment period will be observed, and dose-escalation decisions will be guided by a study safety committee. Dose escalation increments will be adjusted based on occurrence of protocol-specified DLTs as well as overall tolerability. Secondary objectives include characterization of immunogenicity and pharmacokinetic (PK) profile of IKS03. Exploratory objectives include preliminary antineoplastic activity per Lugano criteria (Cheson et al, JCO 2014) and evaluation of pharmacodynamic markers. Part II will further evaluate the antineoplastic activity of IKS03 at the RP2D in expansion cohorts of patients with selected NHL subtypes and with measurable disease. Sample size will be determined for each subtype using a Simon Two-Stage design. Secondary objectives include further evaluation of safety, tolerability, immunogenicity and PK profile of IKS03 as well as confirmation of the RP2D. Clinical trial information: NCT05365659.

Low-Dose Venetoclax-Dexamethasone in t(11;14) Positive Relapsed and Refractory Multiple Myeloma; Interim Results from the Ongoing, Danish, Investigator-Initiated, Open Label, Phase 2 Victoria Study

Background Venetoclax (VEN) is an oral BCL-2 inhibitor that is effective for the treatment of multiple myeloma (MM) with t(11;14), expressing high levels of BCL-2. In a previous phase 1 study, VEN was given to 66 patients [30 with t(11;14)] with relapsed and refractory MM (RRMM) at 300, 600, 900 or 1200 mg in dose-escalation cohorts and 1200 mg in the expansion cohort, without reaching a maximum tolerated dose; the overall response rate (ORR) in t(11;14) positive patients was 40% (Kumar et al. 2017). Later, in a phase 1-2 study, 800 mg VEN with 40/20 mg weekly dexamethasone (DEX) was explored in 51 patients with RRMM and t(11;14) with an overall response rate (ORR) of 48-60% (Kaufman et al. 2021). Here, we report the interim results of an ongoing, Danish, investigator-initiated, open label, phase 2 study which is testing the safety and efficacy of low-dose VEN-DEX in RRMM. Methods Patients with RRMM, at least one prior line of therapy and t(11;14) were included in the study between 1 st July 2020 and data cutoff in 31 st July 2022. VEN was administered orally, once daily at a dose of 400 mg. DEX was administered orally, once weekly at a dose of 20 mg. Treatment continued until progressive disease or unacceptable toxicity. After discontinuation of treatment, patients were followed for 24 months. The primary endpoint of the study was ORR, key secondary endpoints were progression-free survival (PFS) and overall survival (OS). Grade three or higher adverse events (AE) were recorded. Results Patient characteristics At the time of data cutoff in July 2023, twenty-six patients were included in the study. The median (IQR) age was 74 (63-82) years. The median time from diagnosis was 4 (1-7) years. The median (IQR) number of prior lines of therapy was 3 (2-5). 46% of patients were males. At screening, 56% had anemia, 7% had renal failure, 15% had hypercalcemia according to the CRAB criteria. Performance status was 0 in 40% and 1-2 in 60% of patients. 47% of patients had ISS I, 19% had ISS II, 33% had ISS III. Besides t(11;14), present in all patients, 7% of patients had high-risk cytogenetic abnormalities, defined as the presence of t(4;14), t(14;16) or del(17p). 55% of patients had been treated with high dose melphalan and autologous stem cell transplantation, 92% had been exposed to an IMiD, 96% to a proteasome inhibitor, 70% to daratumumab. 29% were triple class-refractory, 15% were penta-drug refractory. Safety One patient had a grade 4 ventricular ulcer, besides this there were no grade 4 or 5 AEs. The most frequent grade 3 AE was infection, detected in 9 (35%) patients. Of these, there were 3 cases of pneumonia, 3 cases of COVID-19, 1 case of influenza, 1 case of gastroenteritis, and 1 case of fever of unknown focus. Other grade 3 AEs related to venetoclax were dehydration in 2 patients, thrombocytopenia in 1 patient, and nausea in 1 patient. The dose of venetoclax was reduced in 3 patients, to 200 mg daily in each case. Efficacy Ten of 25 evaluable patients had partial response or better, resulting in an ORR of 40% (Figure 1A). Four percent of patients achieved stringent complete response, 16% very good partial response and 20% partial response. In subgroup analysis, worse responses were observed in patients with creatinine >177 µmol/L (n=2), high-risk cytogenetics (n=2), triple-class refractory (n=7) and penta-drug refractory (n=3) disease. In responding patients, the median duration of response (DOR) was not reached. The estimated percentage of patients still responding to therapy was 74% after one year and 55% after two years. The median (95% CI) PFS in the intention-to treat population was 5.5 (3.7; not available) months (Figure 1B). Median OS was not reached. The estimated percentage of patients still alive was 90% after one year. Conclusion: Based on this interim analysis, low-dose VEN-DEX in patients with RRMM and t(11;14) has a convenient safety profile and an efficacy comparable to previously tested VEN and VEN-DEX regimens with higher VEN doses. Updated results will be presented at the meeting.

Dexamethasone is Associated with a Lower Incidence and Severity of Cytokine Release Syndrome Compared with Other Corticosteroid Regimens When Given as Premedication for Glofitamab Monotherapy in Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Background: Glofitamab, a CD20xCD3 T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format, induced frequent and durable complete responses (CRs) with a manageable safety profile in pivotal expansion cohorts of an ongoing Phase I/II study (NCT03075696) in patients (pts) with R/R LBCL (Dickinson et al. NEJM 2022, Falchi et al. ASCO 2023). Cytokine release syndrome (CRS) is a potentially life-threatening toxicity caused by immune activation that can be triggered non-specifically by T-cell engaging therapies. As previously reported, corticosteroid (steroid) premedication was required to prevent or mitigate CRS in pts treated with glofitamab. Dexamethasone (Dex) was mandated in one expansion cohort to assess if this could reduce the rate and severity of CRS versus other steroids. Here, we report data from the dose-escalation and expansion cohorts in pts with R/R LBCL who received Dex only versus non-Dex premedication. Methods: Pts with R/R LBCL (diffuse LBCL not otherwise specified [DLBCL NOS], high-grade B-cell lymphoma [HGBCL], primary mediastinal LBCL [PMBCL], or LBCL arising from follicular lymphoma [trFL]) and ≥2 prior therapies received 1000mg obinutuzumab pretreatment (Gpt) 7 days prior to the first glofitamab dose. IV glofitamab was administered with step-up dosing during Cycle (C) 1 (Day 8, 2.5mg; Day 15, 10mg) followed by the target dose (30mg) on Day 1 of C2-12 (21-day cycles; 8.4 months). Steroid premedication (80mg IV methylprednisolone, or equivalent dose of prednisone [100mg] or prednisolone [100mg], or 20mg IV Dex) was given at least 60 minutes prior to Gpt and each glofitamab dose. Responses were assessed using Lugano criteria (Cheson et al. JCO 2014). CRS events were graded by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of May 1, 2023, 145 pts with R/R LBCL had received glofitamab, including 33 (22.8%) pts (DLBCL NOS, n=24 [72.7%]; HGBCL, n=2 [6.1%]; trFL, n=7 [21.2%]) who received Dex premedication before each glofitamab dose (Dex only cohort) and 112 (77.2%) pts (DLBCL NOS, n=81 [72.3%]; HGBCL, n=5 [4.5%]; PMBCL, n=6 [5.4%]; trFL, n=20 [17.9%]) who had not received Dex premedication before each glofitamab dose (non-Dex cohort). In the Dex only and non-Dex cohorts, median age was 73.0 years (range: 27-86) and 66.0 years (range: 21-90), and 26/33 (78.8%) pts and 83/112 (74.1%) pts had Ann Arbor stage III/IV disease, respectively. Median number of prior therapies was 3.0 for both cohorts. Ten (30.3%) and 37 (33.0%) pts had previously received chimeric antigen receptor T-cell therapy, and 6 (18.3%) and 22 (19.6%) pts had received autologous stem cell transplant in the Dex only and non-Dex cohorts, respectively. Median number of glofitamab cycles was 5.0 in both cohorts. CRS of any grade occurred in 48.5% of pts in the Dex only cohort and 73.2% of pts in the non-Dex cohort, and CRS leading to serious adverse events occurred in 5 (15.2%) and 27 (24.1%) pts, respectively. In both cohorts, CRS events were mostly low grade and primarily occurred during C1 (Table; Figure). Recurring Grade (Gr) ≥2 CRS was not observed in the Dex only cohort and 6 (5.4%) pts had recurring Gr ≥2 CRS in the non-Dex cohort. Median time to CRS onset and median time to resolution were similar in the two cohorts. Treatment discontinuation rate was lower in the Dex only cohort (n=21, 63.6%) versus the non-Dex cohort (n=80, 71.4%), mainly due to progressive disease (Dex only cohort, n=12 [36.4%]; non-Dex cohort, n=52 [46.4%]). In the DLBCL NOS and trFL population, the best overall response assessed by Independent Review Committee was similar between the Dex only (n=31) and non-Dex (n=101) cohorts, with CR reported in 14 (45.2%) and 44 (43.6%) pts, and 12 (38.7%) and 34 (33.7%) pts remaining in CR at data cutoff, respectively. The estimated event-free rate among complete responders at 12 months after the first CR was 83.1% (95% CI: 61.5-100.0) in the Dex only cohort and 77% (95% CI: 63.8-90.2) in the non-Dex cohort. Conclusions: The incidence, severity, and seriousness of CRS after glofitamab administration in pts with R/R LBCL were numerically lower with Dex premedication versus premedication with other steroid regimens. Response rates in the Dex only cohort were similar to those reported in the non-Dex cohort. We therefore propose Dex as the steroid of choice for premedication to prevent or mitigate CRS in pts with LBCL treated with glofitamab monotherapy, considering its half-life and potency.