Recommended Phase 2 Dose Research Articles

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.

Preliminary Results from a Phase 1b Dose De-Escalation Stage of Abnl-Marro 001: An International MDS/MPN Working Group Study

Background: Myelodysplastic/Myeloproliferative neoplasms (MDS/MPN) represent a group of rare hematologic malignancies, distinguished by their concurrent dysplastic and proliferative features. Patients with these neoplasms have an increased risk of acute leukemia transformation and often present with extramedullary and constitutional symptoms. The only approved therapies for MDS/MPNs are hydroxyurea, decitabine (oral decitabine/cedazuridine and parenteral decitabine) or azacitidine (parenteral) for pts with CMML. Given the rarity and the heterogeneity of MDS/MPNs, prospective studies focusing specifically on MDS/MPN have been uncommon, and refining treatment strategies has been difficult. ABNL-MARRO ( A Basket study of Nove l therapy for untreated MDS/MPN and Relapsed/ Refractory Overlap Syndromes) is an international cooperative effort that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides a framework for collaborative studies around the world to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response (Moyo TK et.al BMC Cancer. 2022). Methods: ABNL-MARRO 001 (AM-001) is an open-label, phase 1b/2 study testing the treatment combination of ASTX727 (days 1-5), a fixed dose oral combination pill containing 35 mg of the DNMTi decitabine (DEC) and 100 mg of the cytidine deaminase inhibitor cedazuridine (CED), together with a series of active agents in myeloid disease (see Figure 1a) for MDS/MPN. In arm A, ASTX727 is combined with itacitinib 300 mg (days 1-28), a selective JAK1 inhibitor in newly diagnosed and relapsed/refractory (R/R) pts. Here we report results from the 3+3 dose de-escalation phase 1b portion used to determine the recommended Phase 2 dose (RP2D) in arm A. Dose-limiting toxicities (DLTs) were assessed in cycle 1. Disease response was assessed by the MDS/MPN IWG response criteria (Savona et.al., Blood. 2015). Results: Seven patients were enrolled with a median age 75 (range 32-82) years with newly diagnosed (4 pts) or R/R (3 pts) MDS/MPN. Three patients had CMML, 2 had MDS/MPN-U, and 2 had refractory MDS/MPN RST. One patient was not DLT evaluable given severe disease-induced cytopenia, and was not included in the assessment (patient 4 in Figure 1b). The majority of pts experienced a treatment-emergent adverse event (TEAE) of any grade; the most common (≥30% of pts) were thrombocytopenia (50%), neutropenia (30%), and constipation (30%); 50% of pts experienced a Grade ≥3 TEAE; the most common was neutropenia (30%). No DLTs were reported, and these AEs were consistent with what has been reported in the use of ASTX727 (Savona et al. Blood. 2022). One patient achieved a CR, and two additional patients had the best overall response of optimal marrow response after receiving 6 cycles of treatment. All patients are alive with a median follow-up of 12 months (range 6-17 months). The clinical responses and time-on-treatment of all pts in phase 1b are summarized in Figure 1b. Summary/Conclusion: Based on the preliminary results of the phase 1b study, the dosing schedule of 35 mg DEC / 100 mg CED daily for 5 days in combination with itacitinib 300 mg daily for 28 days was selected as the RP2D as it balanced clinical efficacy with an acceptable and manageable safety profile. This regimen and dose are being utilized in a 28-day cycle in the ongoing global, multi-center phase 2 study (NCT04061421).

A Phase 1b Study Evaluating the Safety and Efficacy of AK117 (anti-CD47 monoclonal antibody) in Combination with Azacitidine in Patients with Treatment-Naïve Acute Myeloid Leukemia

Background: AK117 is a humanized IgG4 monoclonal antibody that specifically targets CD47, a “don't eat me” signal excessively expressed on tumor cells such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). CD47 blockade effectively stimulates macrophage-mediated phagocytosis of AML cells, and when combined with azacitidine (AZA), it synergistically enhances the activation of “eat me” signals. Here, we report the data from a Phase 1b study of AK117 plus AZA in patients with treatment-naïve AML. Methods: Patients newly diagnosed with AML who were deemed unfit for intensive chemotherapy were included in the study to receive combination therapy with AK117 and AZA. AK117 was administered intravenously (IV) following various dosing regimens (10-20 mg/kg once weekly [QW], or 30-45 mg/kg every 2 weeks [Q2W]), whereas AZA was administered subcutaneously (SC) at the standard dosage (75 mg/m 2, Day 1-7, every 4 weeks [Q4W]). The primary endpoints of the study were safety/tolerability, and composite complete remission (CCR) defined as the combination of complete remission (CR) and complete remission with incomplete hematologic recovery (CRi), based on the 2017 European Leukemia Net (ELN) response criteria. Results: As of June 9, 2023, 40 patients were enrolled (median age: 63 years, 42.5% males, 72.5% with ECOG≥1). Most patients had abnormal hematologic conditions at baseline, including decreased hemoglobin, neutrophil count, and platelet count. Specifically, 80.0% of patients had Grade ≥3 anemia, 62.5% had Grade ≥3 neutrophil count decrease, and 50.0% had Grade ≥3 platelet count decrease. For the recommended phase 2 dose (RP2D) group, treated with a combination of AK117 30 mg/kg Q2W and AZA, 22 patients were enrolled (median age: 63 years, 31.8% males, 72.7% with ECOG≥1). After a median follow-up of 6.7 months (ranging from 0.2-20.7 months), anemia (a primary adverse event associated with CD47 blocking antibodies) occurred in 32.5% (13/40) of the patients. Other commonly observed treatment-emergent adverse events (TEAEs) (≥30%) included decreased white blood cell count (70.0%), decreased lymphocyte count (62.5%), decreased platelet count (55.0%), decreased neutrophil count (52.5%), pyrexia (52.5%), constipation (40.0%), and vomiting (37.5%). The most frequently reported Grade ≥3 TEAEs (≥20%) were decreased white blood cell count (52.5%), decreased platelet count (47.5%), decreased neutrophil count (45.0%), decreased lymphocyte count (25.0%), and anemia (25.0%). One patient (2.5%) discontinued treatment due to TEAE. The efficacy of AK117 was compared at different dosages, and ultimately, 30mg/kg Q2W was chosen as the RP2D. Out of 20 evaluable patients, 11 (55%) achieved a CCR, including 9 (45%) with a CR and 2 (10%) with a CRi. Stable disease (SD) was reported in 35% of the patients. The median time to response (TTR) was 1.31 months, while the median time to CR (TTCR) was 1.84 months. The median duration of response (DoR) and duration of CR (DoCR) were not reached. Conclusions: The combination of AK117 and AZA exhibited a manageable safety profile with a low incidence of anemia, and demonstrated promising efficacy as a first-line treatment in AML patients who were unable to undergo intensive chemotherapy.

Covalent-103: A Phase 1, Open-Label, Dose-Escalation, and Dose-Expansion Study of Bmf-500, an Oral Covalent FLT3 Inhibitor, in Adults with Acute Leukemia (AL)

Background: FLT3 mutations occur in 25-35% of patients with AML and are associated with poor prognosis. FLT3 mutations are most frequently the result of an internal tandem duplication (ITD) of amino acids in the juxtamembrane region of FLT3 or point mutations in the tyrosine kinase domain (TKD). FLT3-ITD mutations are associated with increased incidence of relapse, shorter duration of remission, and decreased disease-free and overall survival. BMF-500 is a novel orally bioavailable, highly potent and selective covalent inhibitor of FLT3 including wildtype (WT), ITD, TKD, as well as a variety of additional resistance-conferring mutations such as the gatekeeper F691. BMF-500 has demonstrated high affinity for FLT3, lack of cKIT inhibition, and sustained cell-killing capacity despite drug washout (Law et al., ASH 2022 Abstract 2756). BMF-500 has shown sustained tumor regression and improved survival in both subcutaneous and disseminated xenograft models of mutant FLT3-driven AML. Study Design: COVALENT-103 (NCT05918692) is an open-label, non-randomized, multicenter, first-in-human Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of twice daily oral BMF-500 in patients with relapsed or refractory (R/R) AL, including AML, ALL, or MPAL, with or without FLT3 mutations. The trial has 2 arms that will undergo dose escalation in parallel: Arm A (without) and Arm B (with) concomitant use of a moderate or strong CYP3A4 inhibitor. Utilizing an accelerated titration design (ATD), doses of BMF-500 will be escalated in single-subject cohorts until 1 subject experiences either a Grade 2 or higher related-adverse event or dose-limiting toxicity (DLT). At that point, the cohort will switch to a classical “3 +3” design. Patients with WT FLT3 AL may be enrolled, up to a limit of 33% per arm. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts will enroll additional patients to obtain further safety and efficacy data. Patients must be refractory, relapsed or must have progressed on or following discontinuation of the most recent anti-cancer therapy or be ineligible for any approved standard of care therapies, including HSCT. Participants with FLT3-mutant AML must have received treatment with a FLT3 inhibitor approved for treatment of relapsed or refractory FLT3-mutant AML. Key inclusion criteria include ECOG PS ≤ 2, adequate organ function, and documented FLT3 mutation status. Key exclusion criteria include known CNS disease involvement, clinically significant cardiovascular disease, and WBC count >50,000/µL (uncontrollable with cytoreductive therapy). Objectives: The primary objective of the study is to evaluate safety and tolerability and to determine the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-500 oral monotherapy based on evaluation of available PK/ PD, safety and efficacy data. Secondary objectives include characterization of the pharmacodynamics and pharmacokinetics of BMF-500, and assessment of its antitumor activity per modified Cheson (2003) criteria or the NCCN Clinical Practice Guidelines (ALL Version 1.2022) as determined by the investigator. Endpoints include best overall response rate (ORR), complete remission (CRc), duration of response (DOR), relapse-free survival (RFS) and overall survival (OS). The study was initiated in July 2023 and will enroll ~110 participants at approximately 30 sites.

BMS-986393 (CC-95266), a G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)-Targeted Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from a Phase 1 Study

Introduction: Despite advances in RRMM therapy, new approaches are needed for patients (pts) that relapse. GPRC5D, an orphan receptor expressed on MM cells with limited expression in other tissues, is a promising therapeutic target for MM. Previously, we presented interim results from the dose escalation and expansion parts of CC-95266-MM-001 (NCT04674813), a phase 1, first-in-human, multicenter, open-label, dose-finding study evaluating BMS-986393 (CC-95266), a GPRC5D-targeted autologous CAR T-cell therapy, in pts with RRMM (Bal S et al. ASH 2022, P364; Bal S et al. EHA 2023, S193). Here, we present updated safety and efficacy data from the study. Methods: Eligible pts received ≥ 3 prior treatment regimens and must have received a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 therapy, and an autologous stem cell transplant (if eligible); prior BCMA-directed and CAR T-cell therapies were allowed. After screening and leukapheresis, pts received bridging therapy, if needed, and underwent lymphodepletion followed by a single infusion of BMS-986393. In dose escalation, BMS-986393 was used at doses of 25, 75, 150, 300, and 450 × 10 6 CAR T cells. In dose expansion, additional pts received 75, 150, 300, or 450 × 10 6 CAR T cells. Safety, tolerability, and determination of maximum tolerated dose and/or recommended phase 2 dose (RP2D) of BMS-986393 were primary objectives; secondary objectives included evaluation of preliminary efficacy. Results: As of May 24, 2023, 70 pts received BMS-986393 at doses of 25 (n = 6), 75 (n = 10), 150 (n = 26), 300 (n = 17), and 450 (n = 11) × 10 6 CAR T cells. 32 pts (46%) had high-risk cytogenetics (del[17p], t[4;14], and/or t[14;16]), 40 (57%) had 1q21amp, and 30 (43%) had extramedullary plasmacytomas; 32 (46%) pts had received prior BCMA-targeted therapy, including BCMA-directed CAR T-cell therapy in 25 (36%) pts. 24 (34%) pts had penta-refractory MM. Grade (G) 3/4 treatment-emergent adverse events (AEs) occurred in 64/70 (91%) pts; the most frequent were neutropenia (69%), anemia (31%), and thrombocytopenia (30%). Any-grade infections occurred in 30 (43%) pts (G 3/4 in 11 [16%] pts). Cytokine release syndrome (CRS) occurred in 59 (84%) pts (G ≥ 3 in 3 [4%] pts, with 1 [1%] G5 event); 3 (4%) pts had hemophagocytic lymphohistiocytosis, all G3. On-target off-tumor treatment-related AEs (TRAEs), all G1/2, included skin (17 [24%]) and nail (11 [16%]) TRAEs and dysgeusia/dysphagia (2 [3%]). Immune effector cell-associated neurotoxicity syndrome (ICANS)-type neurotoxicity occurred in 8 (11%) pts (G3 in 2 [3%] pts). The most frequent non-ICANS neurologic TRAEs were headache (10 [14%]), dizziness (6 [9%]), ataxia (5 [7%]), dysarthria (3 [4%]), neurotoxicity (3 [4%], including events termed cerebellar toxicity in 2 pts), and paresthesia, gait disturbance, and nystagmus (1 pt each [1%]). Aside from headache and paresthesia, incidence of the listed non-ICANS neurologic TRAEs appeared to be dose-related, and reversibility of some events was observed. Overall response rate (ORR) across doses was 86% (55/64) in efficacy-evaluable pts and 75% (21/28) in pts treated with prior BCMA-directed therapies, including CAR T cells. Complete response (CR) rate was 38% (24/64). In pts refractory to prior BCMA-directed therapies, ORR was 85% (11/13), and CR rate was 46% (6/13). Median follow-up for all treated pts was 5.9 mo (range, 0.0-24.0). At the time of data cutoff, 75% of responses (41/55) were ongoing. All 10 pts (100%) with available minimal residual disease (MRD) data and a best overall response of CR were MRD-negative (10 −5 depth) at ≥ month 3. BMS-986393 reduced soluble BCMA levels (indicative of tumor burden reduction) across all dose levels and showed a dose-dependent increase in cellular expansion. Conclusions: In this first-in-human study, BMS-986393 showed a manageable safety profile and deep and durable responses, including MRD negativity, at all tested dose levels, including in pts refractory to prior BCMA-directed therapies. CRS and ICANS-type neurotoxicity were mostly low-grade, with increased G ≥ 3 events at the 300 and 450 × 10 6 CAR T-cell doses. On-target off-tumor TRAEs, all G1/2, occurred in a minority of pts. These data support GPRC5D-directed CAR T-cell therapy with BMS-986393 as a potential treatment in RRMM, irrespective of prior BCMA-directed therapy. Dose expansion is continuing to define the RP2D. Updated data will be presented.

Preliminary Safety and Efficacy of Venetoclax and Selinexor in Combination with Chemotherapy in Pediatric and Young Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia: Selclax

Background: Survival rates for children and adolescent/young adults (AYAs) with relapsed or refractory acute myeloid leukemia (R/R AML) remain poor. Previous clinical trials have demonstrated that the selective inhibitor of nuclear export selinexor and the BCL2 inhibitor venetoclax are each safe and active when combined with chemotherapy in children with R/R AML (NCT02212561, NCT03194932). However, many patients are refractory to these combinations. Preclinical data indicate that selinexor and venetoclax are synergistic and that selinexor may abrogate resistance to venetoclax. We thus aimed to characterize the toxicity profile and explore preliminary activity of venetoclax and selinexor with chemotherapy in pediatric and AYA patients with R/R AML and report results from the dose escalation phase of the SELCLAX clinical trial (NCT04898894). Methods: SELCLAX is a Phase I and expansion cohort study of selinexor and venetoclax in combination with chemotherapy in pediatric and AYA patients with R/R AML. For the dose escalation phase, eligibility criteria included < 30 years of age, adequate organ function and performance status, primary refractory, early first relapse (< 12 months from initial diagnosis), relapsed and refractory to salvage, post-transplant relapse or second or greater relapse AML or acute leukemia of ambiguous lineage (ALAL). The primary endpoint was determination of the recommended phase 2 dose (RP2D) of venetoclax and selinexor with chemotherapy. In the dose level 1 (DL1) cohort, venetoclax was given at 360 mg/m 2 per dose (max 600 mg) on days 1-21 in combination with selinexor at 40 mg/m 2 on days 1, 8, 15. For dose level 2 (DL2), venetoclax was dosed as in DL1, and selinexor was dosed at 40 mg/m 2 twice weekly on days 1, 3, 8, 10, 15, 17. Chemotherapy (fludarabine 30 mg/m 2, cytarabine 2 g/m 2 ± granulocyte colony stimulating factor 5 mcg/kg [FLA(G)]) was given on days 16-20. Response was evaluated by blast percentage in day 8 and 15 peripheral blood and in day 15 and end-cycle bone marrow. Any patient with a two-log (100-fold) reduction in measurable residual disease (MRD) between baseline and Day 15 was designated an “exceptional responder” (ER). At the discretion of the treating physician, ER patients could continue venetoclax until day 28 with additional selinexor (DL1: day 22; DL2: day 22, 24); FLA(G) could either be omitted or given on days 30-34; omission of FLA(G) deemed a patient non-evaluable (NE) for dose-limiting toxicity (DLT). Evaluable patients were assessed for DLTs, and dosing was escalated according to a rolling-six design. Results: As of July 14, 2023, fifteen patients (aged 3-17 years) with R/R AML (n=14) or ALAL (n=1) were enrolled in the dose escalation phase ( Table 1). Nearly all patients had high-risk cytomolecular features: KMT2A-rearranged (n=5), NUP98-rearranged (n=5), -7/del(7) (n=3), or FUS::ERG (n=1). Seven patients were enrolled on DL1 (one NE, replaced); eight patients were enrolled on DL2 (two NE, replaced). In the DL1 cohort, one DLT was reported of grade 3 anorexia requiring nasogastric feeds; however, this was cofounded by a prior history of anorexia, mucositis, and poor dentition requiring extractions and restorations. At DL2, one patient experienced a hematologic DLT with failure to recover absolute neutrophil count above 500/uL and platelet count above 25,000/uL by day 43 from start of FLA(G). There were no DLTs in the other five evaluable patients in DL2 and no serious adverse events (AEs) reported. The most common Grade 3 or 4 AE was febrile neutropenia (16.7%). Of the evaluable patients, five of twelve (41.7%) achieved complete response (CR) or complete response with incomplete count recovery (CRi). One patient was an ER on Day 15 at DL2 and did not receive FLA(G); thus, this patient was not evaluable for DLT assessment. Six patients proceeded to hematopoietic cell transplant after protocol therapy, five of whom are alive to date. Conclusion: Venetoclax and selinexor with FLA(G) chemotherapy is a tolerable combination in pediatric and AYA patients with R/R AML. Early activity of this combination regimen was observed in some patients, including those with primary refractory or early first-relapsed AML. Enrollment of the dose expansion phase at DL2 is underway in two cohorts: venetoclax-naïve and venetoclax-exposed.

Anti-Btla Antibody Tifcemalimab As a Single Agent or in Combination with Toripalimab in Relapsed/Refractory Lymphomas

Background: The B- and T-lymphocyte attenuator (BTLA) is an inhibitory receptor expressed on B, T and NK cells. Using Peripheral Blood Mononuclear Cell (PBMC) derived from cancer patients, co-blockade of the BTLA and PD-1 pathways improved antigen specific T cell response compared to either blockade alone. Tifcemalimab (JS004 or TAB004) is a humanized IgG4 monoclonal antibody with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand Herpesvirus Entry Mediator (HVEM). Tifcemalimab is the first BTLA antibody to enter the clinical development stage. Here, we report the safety and efficacy of tifcemalimab as a single agent or in combination with toripalimab (anti-PD-1) in patients with relapsed/refractory (R/R) lymphoma after long term follow-up. Methods: Eligible patients with R/R lymphoma were enrolled in this open-label, multicenter phase 1 study (NCT04477772). Tifcemalimab was administered as a monotherapy at escalating doses of 1, 3 and 10 mg/kg intravenously Q3W, followed by 3 mg/kg and 200 mg monotherapy dose expansion until disease progression or intolerable toxicity. During combination dose escalation, patients received ascending doses of tifcemalimab (100mg and 200mg) plus toripalimab (240mg). Dose-limiting toxicity (DLT) was evaluated by a safety monitoring committee. Study objectives included safety, pharmacokinetics, and efficacy. Results: By the cutoff date of July 19, 2023, a total of 71 patients were enrolled, including 25 in the monotherapy and 46 in the combination cohorts. The median follow-up time was 57 weeks. The median age was 38 (range 19-70) years with 50 (70%) male patients. The median prior line of therapy was 4 with 54 (76%) progressed upon prior anti-PD-1/L1 therapy. No DLT was observed in either monotherapy or combination dose escalation. Recommended phase 2 dose (RP2D) was determined to be 200 mg tifcemalimab as monotherapy or in combination with toripalimab. Sixty-seven (94%) patients experienced treatment emergent adverse events (TEAEs), 22 (31%) of whom experienced grade 3 or above TEAEs. The most common TEAEs were COVID-19 infection (30%), anemia (30%) and Infusion related reaction (27%). Four treatment-related adverse events led to the discontinuation of the study drug. Among 25 patients receiving monotherapy, 1 PR (follicular lymphoma) and 7 SD were observed with median progression-free survival (PFS) 2.1 months. Among 46 patients receiving combination therapy, 1 CR,16 PR (ORR 37.0%) and 20 SD (DCR 80.4%) were observed and estimated median PFS was 14.7 months. Thirty-four patients with Hodgkin's Lymphoma received RP2D of combination therapy and all of them had received previous chemotherapy and anti-PD-1 or anti-PD-L1 antibody, and 12 PR (ORR 35.3%) and 17 SD (DCR 85.3%) were observed with estimated median progression-free survival was 16.2 months. Conclusions: Tifcemalimab alone or in combination with toripalimab were well tolerated in all doses evaluated. The combination regimen showed favorable safety and durable efficacy in lymphoma patients with heavily pretreatment, providing evidence for future investigation.

Dose Escalation of ISB 1342, a Novel CD38xCD3 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Introduction: ISB 1342 is a humanized CD38xCD3 bispecific T-cell engager using Ichnos proprietary Bispecific Engagement by Antibodies based on the T cell receptor (BEAT ®) platform, designed to simultaneously bind CD38 on multiple myeloma (MM) cells and CD3ε on T cells, to induce tumor killing. This mechanism of action is different from existing monospecific CD38 targeting therapies and was designed to overcome resistance to daratumumab in MM. ISB 1342 exhibits potent killing of the primary MM cells and MM cell lines with low sensitivity to daratumumab ( Pouleau B. et al. Blood 2023; 142 (3): 260-273). We report here, the updated findings from the weekly dose-escalations of intravenous (IV) and subcutaneous (SC) injections of an ongoing, single-agent phase 1 study (NCT03309111) of ISB 1342 in patients with RRMM. Methods: Adult patients with RRMM that relapsed after or were refractory to prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody; received ISB 1342 on a weekly (QW) schedule by IV or SC injection with a priming dose on the first day in 2 parallel dose-escalation schemas. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation in the QW schedule began at 0.2/0.3 mg/kg priming/treatment dose and followed a “3 + 3” design. The primary study objectives are to determine the maximum tolerated dose (MTD) and select a recommended phase 2 dose (RP2D) of ISB 1342. Secondary objectives includ evaluation of anti-myeloma activity, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of ISB 1342. Results: As of July 18, 2023, based on ongoing clinical database, 39 subjects had received weekly IV infusions of ISB 1342 in 8 dose-escalation groups from 0.2/0.3 mg/kg to 4.0/16.0 mg/kg as priming/treatment dose; and 7 additional subjects had received weekly SC injections at 2.0/8.0 mg/kg. Two different formulations have been tested in SC group. Median number of cycles administered was 2. The majority were male (57%) and white (74%); 13% were Black or African American. The median age was 69 years (range, 54-76) and the median time since diagnosis was 6.6 years (range, 2.8-22.2). The median number of prior anti-myeloma lines of therapy was 6 (range 1-12). Twenty-one (67%) subjects were considered to be triple-class refractory and 18 (48%) penta-drug refractory. Forty-one (89%) subjects experienced treatment-related adverse events (TRAEs) of any grade. Most TRAEs were grade 1-2, including infusion related reactions (37%), cytokine release syndrome (CRS, 34%, all grade 1or 2), anemia (24%), neutropenia (24%), and thrombocytopenia (17%). Five subjects in SC group (71% of SC) had injection site reaction, all grade 1 or 2. Grade 3 or higher TRAEs occurring in more than 5% of subjects were infusion related reaction (no grade 4), anemia (no grade 4), neutropenia, leukopenia. No Grade 5 TRAE was observed. After QW IV infusion, ISB 1342 serum concentration peaked at the end of infusion and then showed bi-exponential decline. ISB 1342 serum exposures increased in a dose linear fashion across the tested IV infusion dose range. The limited PK data after SC injection suggest slow presentation of ISB 1342 into the systemic circulation leading to lower C max and delayed T max relative to IV. Transient increases in serum cytokines were observed within 24 hours after ISB 1342 dosing, including IFNg, TNFa, IL-2, IL-6 and IL-10. Transient increases in T-cell activation were observed by flow cytometry at 24-48 hours after ISB 1342 dosing at 1.0 / 4.0 μg/kg and above, based on increased expression of CD69 on peripheral blood CD4+ and CD8+ T-cell populations (Figure 1). Comparison of the available data from subjects treated at 2 / 8 μg/kg (Cohort 109) indicated reduced T-cell activation following SC compared to IV administration of ISB 1342. The efficacy signals observed in Cohorts 108 and 109 are consistent with the estimates of the lower boundary of the predicted efficacious dose range using a quantitative systems pharmacology (QSP) model based on preclinical data. Updated clinical data, including response rates and safety data, will be present at the meeting. Conclusions: Treatment with ISB 1342 was well tolerated at higher dose levels evaluated. Observed CRS events were moderate. No increased risk of infection has been observed . Updated safety, efficacy, biomarker and PK data will be presented.

Beat AML S8 Group 2: Gilteritinib (GILT) in Combination with Decitabine (DEC) and Venetoclax (VEN) in Untreated FLT3 Mutated Acute Myeloid Leukemia (AML) Patients Age ≥60 with High and Low Variant Allele Frequency (VAF)

Background: GILT is a potent oral selective FLT3 kinase inhibitor ( FLT3i) approved for the treatment of patients with relapsed/refractory FLT3 mutated ( FLT3m) AML. However, the optimal combination in older, newly diagnosed (ND) FLT3m AML patients is unknown. GILT in combination with azacitidine (AZA) had higher initial response rates, but did not improve overall survival (OS), compared to placebo in the LACEWING trial (Wang et al. Blood 2021). GILT followed by decitabine (DEC) was also tested and found to be safe, but the efficacy did not meet pre-determined criteria (NCT03013998, S8 Group 1). In the interim, VEN + AZA/DEC emerged as the new standard of care for older/unfit patients with AML (DiNardo et al. NEJM 2020). Thus, the Beat AML S8 study was amended to assess the safety and efficacy of GILT in combination with DEC and VEN in newly diagnosed FLT3m AML patients aged ≥60 years (NCT03013998, S8 Group 2). Methods: The S8 Group 2 sub-study was part of the multicenter (15 sites) Beat AML Master Trial. Key eligibility criteria included ND FLT3m AML patients aged ≥60 years who are not able to receive intensive induction chemotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. A conventional 3+3 design was used to determine the recommended phase 2 dose (RP2D) of GILT+DEC+VEN. Patients were treated with GILT at three dose levels (DL). During induction, treatment consisted of GILT 120mg/day on days 1-7 then 80mg/day on days 8-28 for dose level 1 (DL1), or on days 8-21 (DL-1), or on days 8-14 (DL-2). All patients received DEC at 20mg/m 2 on days 8-12, and VEN at 400mg/day (or at 100mg/day if concomitant antifungal) on days 8-28. Patients who achieved a complete remission (CR) or CR with hematologic improvement (CRh) received GILT 80mg/day on days 1-15 (DL1) or days 1-7 (DL-1, DL-2), DEC on days 1-5 (All DLs), and VEN on days 1-15 (DL1, DL-1) or days 1-10 (DL-2) for an additional 12 consolidation cycles. The primary end point was to determine the tolerability and toxicity of GILT in combination with DEC and VEN. Secondary end point was the composite CR (CRc: CR/CRh) rate. Response was assessed using modified 2017 European LeukemiaNet (ELN) AML criteria. Results: Between 10/22/2020 and 6/13/2022, 19 patients were consented, of whom 18 started treatment and were included in the analysis. The median age was 73 and baseline patient characteristics are shown in Table 1. The first 2 patients treated at DL1 both experienced hematologic dose-limiting toxicities (DLTs) with persistently low absolute neutrophil count (ANC). Therefore, the GILT dose was de-escalated to DL-1, where 8 patients were enrolled and treated. Among the 6 evaluable patients on DL-1, DLTs occurred in 2 patients; one had hematologic DLT and the other had failure to thrive. This led to dose de-escalation to DL-2. In DL-2, 2/8 patients experienced hematologic DLTs. The protocol was then amended to include DL-3 and DL-4, but the trial was closed by the sponsor due to priority transition and enrollment was halted so further dose reductions were not evaluated. Adverse events (AEs) were mostly hematologic, and 11 patients had treatment-related adverse events (TAEs), 10 of them grade 3 or higher. Median (range) time on treatment was 6 (1-25) cycles. Most common reason for treatment discontinuation were adverse event (3, 21.4%), recurrence (2, 14.3%), stem cell transplant (2, 14.3%), and death (2, 14.3%) Nine patients achieved CR, 2 patients achieved CRh and 1 patient achieved complete remission with incomplete hematologic recovery (CRi). The CRc rate (CR/CRh) was 61.1% (11/18, 95% CI: 38.6%-83.6%). After a median follow up of 19.7 months, the median overall survival and duration of response were not reached. One-year overall survival (OS) was 71.8% (95% CI: 44.9-87.2). Conclusion: Triplet therapy of GILT+DEC+VEN inND FLT3m AML patients ≥60 years old induced a high response rate (CRc rate 61.1%), and the median OS was not reached at time of this report (median follow-up 19.7 months). The typical dose of GILT 120mg/day with DEC+VEN was associated with significant hematology toxicities, which required multiple dose level reductions. At the reduced dose (GILT 80mg/day on days 1-7), the combination therapy was generally safe and well tolerated. A Phase 2 clinical trial sponsored by Astellas of GILT+AZA+VEN as frontline treatment for ND older patients with FLT3m AML is now enrolling (NCT05520567). Funding: this study was funded by Astellas Pharma Inc.

Preliminary Safety and Efficacy of Emavusertib (CA-4948) in Acute Myeloid Leukemia Patients with FLT3 Mutation

Background Acute myeloid leukemia (AML) is a heterogenous disease and exhibits a dynamic mutational landscape as the disease progresses. Internal tandem duplication (ITD) of FLT3 is considered an acquired late-event mutation and is associated with a poor prognosis in AML. Emavusertib is a potent oral inhibitor of IRAK4 and FLT3, conferring potential efficacy advantages compared to other IRAK4 and FLT3 inhibitors. IRAK4 is upregulated during anti-FLT3- or other cytotoxic therapies, which could drive a resistance pathway of early relapse and progression (Melgar 2019; Li 2019). Presence of spliceosome mutations U2AF1 or SF3B1 results in excessive IRAK4-L and further enhance toll-like receptor pathway activation (Smith 2019). Methods The safety, clinical activity, and potential biomarkers of emavusertib in relapsed/refractory (R/R) AML and higher-risk myelodysplastic syndrome are being investigated in the ongoing open-label, Phase 1/2a TakeAim Leukemia trial (NCT04278768). Here we present preliminary safety and efficacy data in the subset of enrolled AML patients who carried FLT3 mutation (FLT3m) at baseline and were treated with emavusertib monotherapy. Patients' mutational profiles were documented based on local testing results. Results As of 12 June 2023, 10 R/R AML patients with FLT3m have been treated at initial doses of 200, 300, or 400 mg BID. There was 1 patient with FLT3-TKD and 9 patients with FLT3-ITD, of which 2 carry both FLT3-ITD and U2AF1 mutations, and 1 with both FLT3-TKD and SF3B1 mutations. The median number of prior anti-cancer therapies was 3 (range 1-6) and 7 out of 10 patients had prior exposure to gilteritinib. Two patients with prior gilteritinib exposure also received midostaurin therapy. Treatment-emergent adverse events (TEAEs) Grade ≥ 3 were reported in 7/10 (70%) patients, and the majority of Grade ≥ 3 TEAEs were reversible and manageable. No dose-limiting toxicity was reported in these 10 patients. Five of 9 response evaluable patients demonstrated more than 90% bone marrow blast reduction compared to baseline. Enrollment is being expanded in this trial at the Recommended Phase 2 Dose (RP2D) of 300 mg BID for patients with ≤ 2 prior lines of therapy. Preliminary data for the 3 response evaluable patients in this population (for whom baseline and post-treatment marrow assessments were available) include blast count reductions of 99%, 100%, and 100% and include 2 CRs and 1 morphologic leukemia-free state (MLFS), with on-treatment duration of 213 days, 225 days, and 134 days, respectively. FLT3-ITD became undetectable in both patients achieving CR. Conclusion Emavusertib has a favorable safety profile in heavily pretreated AML patients with FLT3m and demonstrated anti-cancer activity in patients with FLT3m, including patients who have progressed on prior FLT3 inhibitor. No dose-limiting myelosuppression was reported. In addition, mutational profiles are suggestive of disease-modifying activity of emavusertib. Enrollment in this trial is continuing at a dose of 300mg BID (phase 2 expansion cohort) for patients with ≤ 2 prior lines of therapy.

Clinical Outcomes of Subsequent Therapies in Patients with Relapsed/Refractory Multiple Myeloma Following Talquetamab Treatment: Analyses from the Phase 1/2 MonumenTAL-1 Study

Introduction: Talquetamab (tal) is an off-the-shelf, T-cell redirecting bispecific antibody (BsAb) targeting G protein-coupled receptor family C group 5 member D. Results from the phase 1/2 MonumenTAL-1 (NCT03399799/NCT04634552) trial showed overall response rates (ORRs) of >71%, which were durable, and a manageable safety profile with the recommended phase 2 doses (RP2Ds) of subcutaneous (SC) tal, 0.4 mg/kg weekly (QW) or 0.8 mg/kg every other week (Q2W), in patients (pts) with relapsed/refractory multiple myeloma. Data with tal also demonstrated preservation of B cells throughout treatment, contributing to relatively few severe infections. To date, there is a paucity of data describing pt outcomes after T-cell redirection therapies. Here, we report outcomes for pts who received subsequent antimyeloma therapies (SATs) after discontinuing tal in MonumenTAL-1, including pts who went on to receive subsequent T-cell redirection therapies. Methods: Pts eligible for MonumenTAL-1 were intolerant to or progressed on established therapies (phase 1) or had ≥3 prior lines of therapy (LOT), including ≥1 proteasome inhibitor (PI), ≥1 immunomodulatory drug (IMiD), and ≥1 anti-CD38 monoclonal antibody (mAb) (phase 2). Pts received step-up doses and the QW or Q2W RP2Ds of SC tal until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. Following tal discontinuation, SAT, start/end date of SAT, best response to SAT, and date of PD on SAT were recorded, if available. Data are pooled for the QW and Q2W RP2D cohorts. Response to SAT is based on investigator-reported assessment. Efficacy is presented for first SAT received post tal discontinuation. Results: As of 17 Jan, 2023, 288 pts with no prior exposure to T-cell redirection therapies received tal at the RP2Ds (0.4 mg/kg QW [n=143] or 0.8 mg/kg Q2W [n=145]). Median prior LOT was 5. In the QW and Q2W cohorts, respectively, 74.1% and 69.0% were triple-class refractory, 29.4% and 23.4% were penta-drug refractory, and 15.4% and 11.0% had prior belantamab mafodotin exposure. Overall, 135 pts received ≥1 SAT post tal discontinuation: chemotherapy-based regimens (n=60 [44.4%]), a PI-, IMiD-, or other anti-neoplastic-containing regimen (n=40 [29.6%]), anti-CD38 mAb-containing regimens (n=36 [26.7%]), BsAbs (mostly monotherapy, n=23 [17.1%]: n=18 [13.3%] anti-B-cell maturation antigen [BCMA]; n=5 [3.7%] anti-Fc receptor-like protein 5 [FcRH5]), chimeric antigen receptor T-cell (CAR-T) therapy (n=20 [14.8%]; of whom n=18 [13.3%] were reported as receiving anti-BCMA-targeting CAR-T therapy), or anti-BCMA antibody-drug conjugates (n=13 [9.6%]). Time from tal discontinuation to the start of first SAT was generally similar across all drug classes (median, 1.1 months [range, 0.1-7.4]), including T-cell redirection therapies and bridging therapy in pts receiving CAR-T therapy: 1.5 months (range, 0.1-7.4) with CAR-T, 1.7 months (range, 1.0-3.5) with anti-BCMA BsAbs, and 1.0 month (range, 1.0-2.3) with anti-FcRH5 BsAbs. Best responses for each treatment class are shown in the Table. Pts had deep responses to CAR-T therapy as the first SAT post tal discontinuation with an ORR of 66.7% (8/12) (Table). ORR was 33.3% (2/6) in pts treated with anti-BCMA BsAbs as the first SAT post tal and 66.6% (2/3) with subsequent anti-FcRH5 BsAb therapy. Conclusions: Pts from MonumenTAL-1 who discontinued tal were effectively treated with several classes of therapy. Subsequent treatment with T-cell redirection therapies appears feasible, with 25.0% of pts achieving a complete response or better with CAR-T therapy post tal. Further investigation in larger pt populations is warranted to better understand the sequencing of T-cell redirecting therapies after tal to optimize outcomes.

A Phase I/II Study to Investigate the Addition of Venetoclax to Dasatinib and Steroids in Patients with Newly Diagnosed or Relapsed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL): The Venda Trial, in Progress

Background: Acute Lymphoblastic Leukemia (ALL) is a hematologic malignancy of immature lymphocytes of either B cell or T cell origin. One particularly high -risk subset is Ph+ ALL, characterized by a translocation of chromosome 9 and 22, which generates the constitutively active BCR-ABL1 fusion tyrosine kinase capable of driving proliferation and survival of leukemic cells. Currently treatment options include multi-agent chemotherapy along with an ABL-specific tyrosine kinase inhibitor (TKI), though these regimens can lead to significant toxicity, particularly in older adults. Venetoclax is a potent and selective small molecule inhibitor of the B-cell lymphoma 2 (BCL-2) anti-apoptotic protein. Strong mechanistic and preclinical data have demonstrated strong synergistic activity between dasatinib and venetoclax I xenograft models and ex vivo patient samples, and provide an impetus to further explore the combination of BCR-ABL and BCL-2 inhibition in vivo. Based on these data, we designed a clinical trial to investigate the safety and preliminary efficacy of venetoclax in combination with the second generation TKI dasatinib in Ph+ ALL. Study Design and Methods This is an open label, Phase I/II investigator initiated trial evaluating the addition of venetoclax to dasatinib and steroids (with Rituximab in CD20+ patients). Phase I is the safety and dose-finding portion of the trial combining the BCL2 inhibitor venetoclax with dasatinib and steroids during the first 28 days of induction followed by dasatinib and venetoclax for the final 48 days of induction in newly diagnosed and relapsed Ph+ ALL and mixed phenotype acute leukemia (MPAL) patients, including patients with molecular only relapse. Primary inclusion criteria include a histologically confirmed diagnosis of Ph+ ALL or MPAL. Newly diagnosed Ph+ ALL or MPAL patients may not have received leukemia-directed therapy other than for steroids or hydrea, and relapsed patients must have not had prior dasatinib exposure. Key exclusion criteria include subjects with CML in myeloid blast crisis or Ph+ AML, ECOG < 2 and patients with a history of pleural effusions. n order to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), a Bayesian toxicity probability interval design applied to a pre-specified targeted dose limiting toxicity rate of 30%. Three dose cohorts investigating increasing doses of venetoclax will be enrolled. Once the RP2D dose has been identified, a Phase II expansion will examine preliminary efficacy of the combination. The primary endpoint is the rate of measureable residual disease (MRD) negative remission rate as assessed by both BCR-ABL RT-PCR and next generation sequencing (NGS) after induction. Secondary endpoints include relapse-free survival (RFS) and overall survival (OS). Correlative studies include BH3 profiling (measure of apoptosis) and ex vivo screening to dasatinib and venetoclax alone and in combination. Consolidation phase with blinatumomab plus dasatinib and venetoclax is planned for the cohort expansion group. Enrollment began in September 2022 and is expected to be complete by September 2025. This trial is registered at clinicaltrials.gov (NCT04872790).

Komet-008: A Phase 1 Study to Determine the Safety and Tolerability of Ziftomenib Combinations for the Treatment of KMT2A-Rearranged or NPM1-Mutant Relapsed/Refractory Acute Myeloid Leukemia

Background and Significance: Relapsed or refractory (R/R) acute myeloid leukemia (AML) with nucleophosmin 1-mutations ( NPM1-m) or KMT2A-rearrangment ( KMT2A-r) remain a high unmet need. Ziftomenib is a potent and selective inhibitor of the interaction between menin and mixed-lineage leukemia (MLL) lysine[K]-specific methyltransferase 2A ( KMT2A), which drives leukemogenesis in these subtypes. Preclinical data have demonstrated ziftomenib's ability to target multiple types of menin-dependent AML clones, and that the antitumor activity of ziftomenib and other menin inhibitors in cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models of KMT2A-r and NPM1-m AML is enhanced by the addition of FLT3 inhibitors such as gilteritinib and quizartinib. An ongoing Phase 1/2 study (KOMET-001) in R/R AML has demonstrated that ziftomenib monotherapy is safe and well tolerated and that the clinical activity at the recommended phase 2 dose (RP2D) is robust, as the rates of response were not affected by the presence of downstream co-mutations, such as FLT3 and IDH1 or IDH2. Given the monotherapy activity seen to date, the development of ziftomenib in combination with standard-of-care (SOC) chemotherapies or FLT3 inhibitors may provide increased clinical benefit for R/R AML patients with KMT2A-r or with NPM1-m with or without concurrent FLT3-mutations ( FLT3-m) and warrants further investigation. Study Design and Methods: KOMET-008 (NCT# 05735184) is an open-label, dose escalation and expansion study to determine the safety, tolerability, and preliminary efficacy of ziftomenib when combined with SOC regimens for the treatment of either NPM1-m (Arm A) or KMT2A-r (Arm B) R/R AML. Each genetically defined arm will evaluate ziftomenib in combination with various SOC treatments in separate and independent cohorts, as outlined below: Arm A:NPM1-m R/R AML Cohort A-1: Ziftomenib plus FLAG-IDACohort A-2: Ziftomenib plus LDACCohort A-3: Ziftomenib plus gilteritinib (for NPM1-m + FLT3-m R/R AML) Arm B: KMT2A-r R/R AML Cohort B-1: Ziftomenib plus FLAG-IDACohort B-2: Ziftomenib plus LDAC The Part 1a dose escalation uses a i3+3 design, followed by dose expansion/validation in Part 1b. Key eligibility criteria include adults (≥18 years) with documented NPM1-m (±co-occurring FLT3-m) or KMT2A-r R/R AML, ECOG ≤2, prior hematopoietic stem cell transplant (HSCT) allowed, if recovered and prior gilteritinib allowed. Patients who receive an HSCT during study participation will be allowed to receive ziftomenib maintenance therapy upon recovery. The primary objectives are to establish the safety and tolerability of ziftomenib when combined with SOC therapies (ie, dose limiting toxicities, AEs per CTCAE v5.0) and to identify the RP2D of ziftomenib for each SOC combination in each genetically defined cohort. Secondary endpoints include preliminary efficacy (including MRD-negative responses and number of patients able to receive stem cell transplant) and pharmacokinetics. Exploratory end points include biomarkers for efficacy and resistance and pharmacodynamic biomarkers potentially related to the activity of ziftomenib when combined with SOC treatments in adults with R/R AML with NPM1-m or KMT2A-r.

Tuspetinib Myeloid Kinase Inhibitor Safety and Efficacy As Monotherapy and Combined with Venetoclax in Phase 1/2 Trial of Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)

INTRODUCTION: Tuspetinib is a potent once daily oral myeloid kinase inhibitor of SYK, FLT3, JAK1/2, RSK1/2, mutant KIT, and TAK1-TAB1 kinases that mediate dysregulated cellular proliferation in AML. In an orthotopic mouse model of FLT3-mutant AML, tuspetinib exhibited greater antitumor activity than gilteritinib, entospletinib, venetoclax (VEN), and azacitidine (AZA) and combined favorably with VEN and AZA individually. Tuspetinib is being evaluated clinically as monotherapy (TUS) and in combination (VEN/TUS) in a global Phase 1/2 trial of patients with R/R AML. AIMS: Study objectives are to assess the safety, tolerability, and pharmacokinetics (PK) of TUS and VEN/TUS, to support selection of a recommended phase 2 dose (RP2D). METHODS: Dose escalation (Part A) and exploration (Part B) of single agent TUS have completed dosing of patients treated at 20 mg to 200 mg once daily. In dose expansion (Part C), 80 mg of TUS is administered continuously as once daily oral monotherapy in 28-day cycles, or in combination with daily VEN with a C1D15 marrow assessment and planned 28-day cycles. Treatment emergent adverse events (TEAE) and clinical responses are evaluated using CTCAE and Revised IWG criteria, respectively. RESULTS: As of May 30, 2023, 100 patients received TUS in Parts A/B (20mg to 200mg; n=77) and in Part C (n=23: TUS 120 mg (n=14) and TUS 80 mg + VEN 400 mg dose equivalent (n=9)). Patients are predominantly Asian (46%) and White (41%) with a median age of 63 (range 18 to 84); 60% FLT3 wild-type (FLT3-WT), 35% FLT3-mutated (FLT3m) of which 18 (51%) received prior FLT3 inhibitors, and 5% FLT3 undetermined. Patients received a mean of 2.6 prior lines of therapy (range 1-6) (Table 1). Sixty percent of patients have received prior venetoclax. In Parts A/B, clinical responses with TUS monotherapy (composite complete remission [CRc; including CR, CRh, CRp and CRi]; see Figure 1 for definitions), were observed at 40 mg (15.4%), 80 mg (29.4%), 120 mg (7.1%), and 160 mg (16.7%) in both FLT3-WT (n=33, CRc:15.2%,) and FLT3-mutated (n=23, CRc:21.7%) patients. Overall response rate (ORR, including CRc and PR) was 14.3% in prior VEN treated patients (n=28), 23.1% in FLT3-mutated patients with previous FLT3i treatment (n=13), and 66.7% in NPM1 and FLT3-mutated patients (n=6). Notably, responses were also seen in patients with TP53 (n=5; CRc:40%) and RAS (n=9; CRc:22.2%) mutations frequently associated with resistance to VEN and standard therapies. TUS was well tolerated, with no dose limiting toxicity (DLT) observed at doses ranging from 20 mg to 160 mg. One patient experienced a DLT (Grade 3 muscular weakness) at 200 mg which demonstrated partial improvement at the time of treatment discontinuation (9 days after AE onset). Related TEAEs of Grade ≥3 were low (10.4%) with only neutrophil count decreased and muscular weakness (n=2 each; 2.6%) reported in more than 1 patient. No treatment-related non-hematologic SAEs, deaths, or discontinuations were observed. PK exposure was linear (20 mg-160 mg). The RP2D of 80 mg was selected for TUS monotherapy. In Part C, all 9 patients receiving VEN/TUS have tolerated treatment to date and remain on study. Eight (89%) patients had prior VEN treatment. Preliminary responses have been observed at the first post-dose bone marrow assessment (C1D15), including patients with prior VEN treatment. No treatment-related SAEs or TEAEs of Grade ≥3 have been reported. Updated enrollment, safety, PK, and response data will be presented at the meeting along with findings on the association between somatic mutations and TUS sensitivity as well as results for the TUS food-effect absorption study. CONCLUSIONS: Tuspetinib was well-tolerated and delivered single agent clinical responses across four dose levels among diverse AML genotypes; with a RP2D of 80 mg chosen for future single agent studies. Although early, the VEN/TUS combination has been well tolerated with preliminary objective responses noted.

Long-Term Safety and Efficacy Results of Belantamab Mafodotin Plus Lenalidomide and Dexamethasone in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma: An Updated Part 1 Analysis from the Phase 1/2 Belard Trial

Introduction The preferred upfront treatment of transplant ineligible (TI) patients (pts) with newly diagnosed multiple myeloma (NDMM) consists of the combination of lenalidomide and dexamethasone (Rd) with a third antimyeloma agent of a different mechanism of action (e.g., proteasome inhibitors or anti-CD38 monoclonal antibodies). Belantamab mafodotin (belamaf; GSK2857916), an antibody-drug conjugate targeting BCMA, has shown efficacy in pretreated MM pts, while preclinical data demonstrate synergy between belamaf and lenalidomide, with no overlapping toxicities. Thus, there is a strong rationale for investigating the belamaf-Rd triplet in TI NDMM pts. Methods BelaRd (NCT04808037) is an open-label, phase 1/2 study conducted in Greece, aiming to enroll 66 TI NDMM pts. Eligible are adult pts with ECOG PS 0-2 and adequate organ function. Part 1 evaluates the safety/tolerability of three belamaf doses (2.5/1.9/1.4 mg/kg) plus Rd in 36 pts and establishes the recommended phase 2 dose (RP2D). In this part, belamaf is initially administered q8w and, depending on toxicity, dosing may be adjusted to q12w. Ocular exams include Snellen best corrected visual acuity (BCVA) and slit lamp corneal evaluation. Ocular symptoms are classified by CTCAE v5.0, while the Ocular Surface Disease Index (OSDI) captures dry eye disease and activities of daily living (ADL).Herein, we present updated safety and efficacy results of all Part 1 pts with an extended follow-up time (cut-off date 05/06/2023). Results Of the 36 pts [median age: 72.5 years; male: 19 (53%)] in Part 1, 29 (81%) are still on treatment, while 7 (19%) have discontinued [6 pts due to belamaf-unrelated fatal events: (COVID-19: 1/1/2; Pneumonia: 1/1/0, for cohorts 2.5/1.9/1.4 respectively); 1 pt withdrew consent]. The median belamaf administrations and number of cycles reached were 6/7/7 and 20.0/22.5/20.0, for the respective cohorts. The most common (≥10% of pts) non-ocular ≥ Gr3 treatment-emergent adverse events were fatigue (21 pts, 58%; [7 (58%)/7 (58%)/7 (58%)]), diarrhoea (8 pts, 22%; 2 (17%)/3 (25%)/3 (25%)]), rash (6 pts, 17%; [2 (17%)/2 (17%)/2 (17%)]), COVID-19 (5 pts, 14%; [2 (17%)/1 (8%)/2 (17%)]) and insomnia (4 pts, 11%; 0/4 (33%)/0]) , while no ≥Gr3 thrombocytopenias and infusion-related reactions were reported. Regarding ≥Gr3 infections other than COVID-19, pneumonia was reported for 3 (8%) pts [1/1/1 (8%)] and lower respiratory tract infection for 1 (3%) pt [0/0/1(8%)]. Regarding ocular adverse events (OAEs), among 216/244/201 BCVA assessments in cohorts 2.5/1.9/1.4, a meaningful BCVA decline (BCVA <20/50) with at least 3 lines drop in the better seeing eye, was observed in 21 (10%)/24 (10%)/17 (8%), while BCVA ≤20/200 with at least 3 lines drop in the better seeing eye was noted in only 2 (1%)/3 (1%)/8 (4%), with a median time to resolution of 1 month. Across all cohorts, the most frequently reported ≥Gr 3 ocular symptom was decreased vision (26/665, 4%), while ≥Gr3 keratopathy was noted in <2% of assessments. Regarding OSDI, from 202/234/196 responses received, the number of “all/most” of the time worst responses in the ocular symptoms category were 6 (3%)/6 (3%)/8 (4%), while the respective proportions in the ADL category were 6 (3%)/4 (2%)/3 (2%). The overall response rate was 100% across all cohorts: More specifically CR or better was achieved by 7 (58%)/6 (50%)/6 (50%), VGPR by 3 (25%)/5 (42%)/3 (25%) and PR by 2 (17%)/1 (8%)/3 (25%) pts in cohorts 2.5/1.9/1.4, with a median time to first response of 1 month. Finally, at a median follow-up of 20.3 months, no disease progression was observed, median PFS and median time to progression were not reached ( Figure 1) and responses continue to deepen across all cohorts. Conclusions Over an extended follow-up period, the belamaf-Rd triplet has proven a safe and effective combination for the upfront treatment of TI NDMM pts, with no long-term safety signals. Furthermore, the extended dosing schedule for belamaf had a minimal impact in vision-related functioning, as very low rates of meaningful BCVA decline and “most/all” OSDI responses were noted across all cohorts, with a rapid time to resolution. Meanwhile, a very promising clinical activity is observed, with rapid, deep and durable responses across all dose levels. Consequently, after validation with bigger pt numbers, this novel combination may well be a very attractive frontline option for this vulnerable and difficult-to-treat pt population.

Immuno-PRISM: A Randomized Phase II Platform Study of Bispecific Antibodies in High-Risk Smoldering Myeloma

Background: B-cell Maturation antigen-directed immunotherapies have demonstrated significant efficacy in relapsed and refractory multiple myeloma (RRMM), with recent approval of the bispecific antibody teclistamab (TEC) . However, the use of immunotherapy in high-risk smoldering myeloma (HR-SMM) has not been examined to date. We hypothesized that bispecific antibody therapy would have greater benefit in HR-SMM due to this population having a more intact immune system, lower disease burden and may therefore have a higher efficacy and less toxicity compared to RRMM. Based on previous studies of lenalidomide and dexamethasone demonstrating benefit in HR-SMM, the Immuno-PRISM trial is studying various bispecific antibodies against a control arm of lenalidomide and dexamethasone. Herein, we report our first results of TEC in HR-SMM. Methods: This is a multiple arm, randomized, phase II, platform study evaluating TEC vs lenalidomide and dexamethasone in HR-SMM. Eligibility criteria included HR-SMM per Mayo 2018 “20-2-20” model, total IMWG risk score of 9 or greater, and other previously established high-risk criteria including PETHEMA criteria, evolving-type SMM, and high-risk FISH abnormalities. This study has an initial, safety run-in cohort of 6 patients treated with TEC. All patients receive 2 step-up doses of subcutaneous TEC. In the safety run-in, patients receive a dose lower than the recommended phase 2 dose (RP2D) of TEC. If no dose limiting toxicities (DLTs) are observed, the next cohort receives the RP2D of TEC. Once safety run-in is complete, the randomized trial begins with 2:1 randomization to TEC (30 patients) vs control arm of lenalidomide and dexamethasone (15 patients). Treatment duration is for 24 cycles. All eligible patients undergo stem cell collection after 4 cycles of therapy. The primary objective is complete response rate. Secondary objectives include PFS, ORR, MRD negativity rates, safety, pharmacokinetics of TEC, and safety. Exploratory objectives include mass spectrometry quantification of M protein, molecular evolution of tumor cells, and immune biomarkers of response. Results: At the time of data cut off, 19 patients have been enrolled to study with median follow up of 6 months. The median age is 59 years old (range 35-73) with 9 females (47%) and 10 males ( 53%). Sixty-four percent of patients that had evaluable FISH results had high-risk abnormalities as follows: 1q gain (7 pts), t(4;14) 1 patient. No DLTs were observed in the safety run-in cohort and patients are now enrolling into the randomized portion of trial. In the TEC-cohort (12 patients), grade 3 or greater hematologic toxicities were neutropenia (4 patients, resolved) and thrombocytopenia (1 patient, resolved). Grade 3 or greater non-hematologic toxicities were ALT increased in 3 patients (grade 3, resolved) and pancreatitis in 1 patient (grade 3, resolved). Infections occurred in 9 patients but only 1 patient had grade 3 infection (sinusitis). Remainder of the infections were low grade and were mostly upper respiratory infections (6 patients). One patient had grade 2 uveitis. CRS occurred in 75% of patients (all grade 1 except 2 patients with grade 2 CRS requiring tocilizumab, all resolved). No patients experienced ICANS with no delayed neurotoxicity observed. All patients treated with TEC are receiving IVIG with mean IgG level at start of IVIG treatment of 418 mg/dL, with 64% of patients achieving normalization of IgG values within two IVIG doses. In the TEC- treated cohorts (12 patients), the ORR is 100% with 42% achieving a CR, 25% VGPR, 33% PR. Four patients with high risk FISH receiving TEC have achieved a CR within 5 cycles.In control arm of lenalidomide and dexamethasone (3 patients), the ORR is 66% without any complete responses to date. Of the 8 evaluable patients treated with TEC, the MRD negative rate at 10 -6 is 100%, including 2 patients with VGPR-MRD negative disease. Average time to MRD negativity observed among evaluable patients was 4.25 cycles. No patients have progressed on treatment. Stem cell collection was successful in all eligible patients with an average stem cell yield of 9.06 x 10 6CD34+ cells/kg. Conclusions: TEC in HR-SMM demonstrates significant activity with 100% ORR with MRD-negative disease in 100% of evaluable patients to date, and overall significantly improved safety profile compared to RRMM.

Initial Dose Escalation of ISB 1442, a Novel CD38 Biparatopic x CD47 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Introduction: ISB 1442 is a fully human bispecific, biparatopic antibody that targets CD38 and CD47, generated using Ichnos' Bispecific Engagement by Antibodies based on the T cell receptor (BEAT ®) platform. ISB 1442 is designed to kill CD38-expressing tumor cells through multiple mechanisms of action including blocking CD47-signal regulatory protein alpha (SIRPα) axis to increase several antibody effector functions: antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) through optimized architecture, affinity to targets, and Fc engineering. ISB 1442 has 2 Fab domains binding to distinct CD38 epitopes that do not compete functionally with daratumumab. ISB 1442 is expected to have optimized tolerability with low potential for adverse effects on red blood cells (RBC) such as hemagglutination, platelet aggregation and RBC depletion (Sammicheli at al., ASH 2021, Blood (2021) 138 (Supplement 1): 73). We report here initial findings from the early dose-escalation portion of an ongoing, multi-center, open-label, single-agent phase 1/2 study (NCT05427812) of ISB 1442 in patients with RRMM. Methods: Adult patients with relapsed refractory multiple myeloma (RRMM) to prior therapies, including a proteasome inhibitors (PIs), an immunomodulatory drugs (IMiDs), and an anti-CD38 antibodies received subcutaneous (SC) doses of ISB 1442 weekly (QW) in 28-day cycles. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation began at 6 mg dose with single patient accelerated titration phase for the first 3 cohorts, followed by a standard titration phase with a “3 + 3” design. The primary study objective for phase 1 is to assess the safety and tolerability to determine the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D) of ISB 1442. For phase 2 the primary study objective is to evaluate efficacy of ISB 1442. Secondary objectives include evaluation of pharmacokinetics (PK) and immunogenicity of ISB 1442. Exploratory objectives include assessment of minimal residual disease (MRD), assessment of cellular biomarkers in blood and bone marrow, and soluble factors in blood, and their correlation with efficacy, safety and other clinical endpoints of interest. Results: As of July 18, 2023, based on preliminary data from ongoing clinical database, 10 subjects had received once weekly SC injections of ISB 1442 in 4 dose-escalation groups from 6 mg to 150 mg. The majority were male (60%) and white (90%). The median age was 67 years (range 57-79). The median number of prior anti-myeloma lines of therapy was 6 (range 3-7); 70% were exposed to 5 drugs (2PIs, 2IMiDs, and CD38). The median number of ISB 1442 cycles was 1(range 1-2). Eight subjects (80%) experienced treatment-related adverse events (TRAEs), all were grade 1 or 2: cytokine release syndrome (CRS) (50%), injection site reactions (injection site erythema 20%, injection site bruising 10%), anemia (10%, 1 subject, grade 2) (Table 1). No grade 5 TRAE was observed. Following QW SC injection, ISB 1442 was slowly absorbed into the systemic circulation with T max generally occurring on day 2 of dosing. The ISB 1442 serum concentrations generally remained quantifiable over the entire dosing duration from 20 mg and above. The available PK data suggest an approximately dose-linear increase in serum concentration up to DL 3 (60 mg), followed by a supra-proportional increase in serum levels in subjects treated at DL 4 (150 mg). To date, 5 subjects treated at DL4 (150 mg) have experienced clinical symptoms of CRS (Grade 1-2) following the first dose of ISB 1442. Assessment of a panel of 63 soluble factors (including multiple cytokines, chemokines and growth factors) in the peripheral blood revealed that several subjects at DL3-4 exhibited transient increases (>10-fold) in macrophage inflammatory protein-1b (MIP-1b/CCL4) within 24h after treatment with ISB 1442, consistent with a macrophage-associated mechanism of action. Conclusions: Treatment with ISB 1442 was well tolerated at the dose levels evaluated. The observed clinical CRS events were moderate and potentially related to macrophage activation following ISB 1442 administration. Updated clinical, biomarker and PK data will be presented for this ongoing study.

A Phase 1, First-in-Human, Dose Escalation and Dose-Expansion Study of a BCMAxCD38xCD3 Targeting Trispecific Antibody ISB 2001 in Subjects with Relapsed/Refractory Multiple Myeloma

Background Despite advances, multiple myeloma (MM) remains an incurable disease and resistance mechanisms are emerging. ISB 2001 has been designed to overcome those resistance mechanisms inherent to current MM therapies such as monoclonal antibodies (e.g. daratumumab), BCMA-targeted therapies, proteasome inhibitors(PIs), or immunomodulatory drugs(IMiDs). ISB 2001 is a first in class Trispecific T cell engager (TCE) that redirects cytotoxic T cells to BCMA and/or CD38 expressing myeloma cells. Simultaneous targeting of the two tumor associated antigens (TAA) may increase binding to tumor cells through avidity even with heterogeneous or low expression of the targeted TAA (BCMA or CD38). Therefore, it may overcome tumor escape mechanisms associated with low tumor antigenic expression inherent to current MM targeted therapies. Preclinically, ISB 2001 has demonstrated improved activity when compared to other BCMA or CD38 targeted molecules either alone or in combination across different MM models (M. Pihlgren et al., Blood. 140, 858-859 (2022), M. Pihlgren et al., Cancer Res. 83, 2970-2970 (2023)). Study design and methods This first-in-human, multicenter, open label Phase 1 study is assessing the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of ISB 2001 in relapsed/refractory multiple myeloma (RRMM) patients. This study will enroll subjects treated with prior IMiDs, PIs, and anti-CD38 therapies, or intolerant of, established therapies known to provide benefit (prior BCMA therapies, or prior transplantation and cellular therapies allowed).be conducted in two parts (Part 1: Dose escalation and Part 2: Dose expansion) (Figure 1). Criteria for enrollment in this study include patients with RRMM with measurable disease who have been treated with an anti-CD38 antibody, IMiDs, PIs either in combination or as a single agent, and /or intolerant of established therapies known to provide clinical benefit. ISB 2001 is being administered weekly by subcutaneous (SC) injection in 28-day cycles, with two step-up doses on cycle 1 day 1 (C1D1) and C1D4 before administering the full dose on C1D8. The first-in-human dose was derived by integrating both in vitro and in vivo preclinical data benchmarked to teclistamab utilizing a quantitative systems pharmacology (QSP) model guided approach. The fractionated step-up dosing before administering the full dose on C1D8 was included in every cohort preemptively to minimize the potential cytokine release syndrome (CRS) risk. The study will follow a rapid titration single patient dose escalation design until the completion of cohort 3 or until one of the safety conversion criteria are met, whichever comes first, after which the design will be converted to a conventional 3+3 dose escalation. The primary outcome measure is the number of DLTs during the first 28 days after the first study treatment (ie, Cycle 1) in each cohort. Once a potential safe and efficacious dose range is identified, the Part 2 expansion will start enrollment in two arms at two putative recommended Part 2 doses with 1:1 randomization with at least 20 patients per arm (FDA Project Optimus). The primary objective of Part 2 is to confirm safety and to select the recommended Phase 2 dose (RP2D). Secondary endpoints include PK parameters, immunogenicity incidence, ORR, CRR and DOR based on IMWG criteria. Exploratory endpoints include levels of cytokines, chemokines, sCD38, sBCMA, APRIL and BAFF in peripheral blood, immunophenotyping in peripheral blood and bone marrow, and MRD negative rate. Approximately 40 patients will be enrolled in Part 1 at sites in Australia, France and the United States. A total of approximately 40 evaluable patients will be enrolled in Part 2. The study is currently open for enrollment (Clinicaltrials.gov identifier: NCT05862012).

Efficacy and Safety of Less Frequent/Lower Intensity Dosing of Talquetamab in Patients with Relapsed/Refractory Multiple Myeloma: Results from the Phase 1/2 MonumenTAL-1 Study

Introduction: Talquetamab (tal) is an off-the-shelf, T-cell redirecting bispecific antibody targeting G protein-coupled receptor family C group 5 member D (GPRC5D) and CD3. Results from the phase 1/2 MonumenTAL-1 (NCT03399799/NCT04634552) trial showed overall response rates (ORRs) of >71% and a manageable safety profile with the recommended phase 2 doses (RP2Ds) of subcutaneous tal (0.4 mg/kg weekly [QW] or 0.8 mg/kg every other week [Q2W]) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). The impact of reducing dose intensity with bispecifics on safety and efficacy is an area of clinical interest. We report safety and efficacy in pts from MonumenTAL-1 who switched to less frequent or reduced dosing with tal. Methods: In phase 1, pts were intolerant to or progressed on established therapies and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. In phase 2, pts had received ≥3 prior lines of therapy, including ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 monoclonal antibody, and had an ECOG PS of 0-2. Phase 1 included 2 prospectively designed cohorts: (A) a reduced dosing cohort in which pts treated with tal 0.8 mg/kg Q2W were permitted to switch to 0.4 mg/kg Q2W at the next cycle following a confirmed partial response or better (≥PR), and (B) a less frequent dosing cohort in which pts treated with tal 0.8 mg/kg Q2W were permitted to switch to 0.8 mg/kg monthly (Q4W) at the next cycle following a confirmed ≥PR. Results for these phase 1 prospective cohorts are pooled. Supportive analyses were also performed based on pts in phases 1/2 who received the RP2Ds and switched to reduced dosing based on meeting response criteria or to mitigate treatment-emergent adverse events (TEAEs). Dose reduction could be achieved by reducing dose frequency or by reducing dose. ORRs were assessed per IMWG criteria. TEAEs were graded per CTCAE v4.03. Results: In total, 45 pts switched to reduced intensity dosing. As of June 20, 2023, 24 pts were included in the prospective cohorts, with a median follow-up of 9.7 months. In total, 9/12 pts achieved a ≥PR and switched from 0.8 mg/kg Q2W to 0.4 mg/kg Q2W dosing, and 10/12 pts achieved a ≥PR and switched from Q2W to 0.8 mg/kg Q4W dosing. Generally, pts switched to reduced intensity dosing during cycles 3-5. Following the change in dosing, responses deepened in 11/19 pts and were maintained in 5/19 pts; 3/19 pts had disease progression. At 6 months post switch, an estimated 88.9% of responders maintained a response. Oral-related TEAEs, reported in 16/19 (84.2%) pts, improved or resolved in 4 pts 1-6 months after switching to reduced intensity dosing. Nail-related TEAEs, reported in 7/19 (36.8%) pts, improved or resolved in 2 pts after 3-4 months. Skin-related TEAEs, reported in 8/19 (42.1%) pts, resolved in 3 pts after 1-3 months. Overall, improvement or resolution of oral-, nail-, and skin-related TEAEs was observed over time in some pts in the prospective reduced and less frequent dosing cohorts. No pts discontinued tal due to these TEAEs. As of January 17, 2023, supportive phase 1/2 analyses included 20 pts who switched from tal 0.4 mg/kg QW to a reduced dose (TEAE mitigation, n=16; response, n=3; both, n=1), and 6 pts who switched from tal 0.8 mg/kg Q2W to a reduced dose (TEAE mitigation, n=4; response, n=2). In pts who switched from tal 0.4 mg/kg to a reduced dose, an estimated 84.2% and 78.9% of responders maintained a response at 9 and 12 months, respectively. In pts who switched from tal 0.8 mg/kg Q2W to a reduced dose, an estimated 100% and 80.0% of responders maintained a response at 9 and 12 months, respectively. Conclusions: Most pts who switched to reduced intensity dosing in MonumenTAL-1 deepened or maintained responses to tal. GPRC5D-associated TEAEs generally improved over time in the prospectively design cohorts. Overall, reduced or less frequent tal dosing may help to mitigate these TEAEs while maintaining response. Further analyses on the impact of reduced or less frequent tal dosing on clinical outcomes are warranted.

Takeaim Lymphoma: An Open-Label, Dose Escalation and Expansion Trial of Emavusertib (CA-4948) in Combination with Ibrutinib in Patients with Relapsed or Refractory Hematologic Malignancies

Background: Emavusertib (CA-4948) is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. Additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4) is also present in emavusertib. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation ofnuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. Emavusertib has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) (Nowakowski 2020). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. Emavusertib crossed the blood-brain barrier in a murine PDX model of PCNS lymphoma, blocked the activated IRAK4 pathway, and induced tumor response and prolonged survival (von Roemeling 2022). In combination with Bruton tyrosine kinase (BTK) inhibitors, emavusertib showed in vitro synergy and re-sensitization of resistant cell lines, overcoming BTK resistance (Guidetti 2023a and 2023b). In vivo synergy in B-cell NHL was also demonstrated. Adaptive chemotherapy treatment resistance through IRAK4 upregulation and activation was also described in other disease models (Melgar 2019, Li 2019). This abstract presents preliminary efficacy and safety data of emavusertib + ibrutinib in R/R NHL patients. Aim:Assessment of safety and clinical activity of emavusertib in combination with ibrutinib. Methods: This is an ongoing open-label trial (NCT03328078) of emavusertib as monotherapy and in combination with ibrutinib. Part A1 - completed; dose escalation of emavusertib as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing (Nowakowski 2020). Part A2 - completed; dose escalation of emavusertib in combination with ibrutinib at 420 and 560 mg QD (Joffe 2022). Part B - ongoing; an expansion cohort of PCNSL patients with resistance to prior BTK inhibitors for additional safety and efficacy related to exposure: emavusertib at 100 or 200 mg BID + ibrutinib at 560 mg QD in 28-Day cycles. Results:As of 19 July 2023, 18 heavily pretreated NHL (including five PCNSL) patients received emavusertib at 100, 200, or 300 mg BID in combination with full ibrutinib doses per label. Median age was 63.5 years (range 50-92). Median number of prior lines of anti-cancer therapies was 3 (range 1-10). Eleven of 18 patients failed prior BTK inhibitors. Median treatment duration was 95.5 days (21-587 days), suggesting acceptable safety and tolerability. No DLTs were observed at the 200 mg BID dose level, and two reversible DLTs (stomatitis and syncope) were observed at the 300 mg BID dose level. The preliminary efficacy data of 16 evaluable patients in combination with ibrutinib showed 5 CRs (2 MCL, 3 PCNSL) and 1 PR (1 CLL). All 3 PCNSL patients with CR were previously treated with BTK inhibitors. Conclusion: The combination ofemavusertib plus ibrutinib (ema+ibr) is well tolerated with an acceptable long-term safety profile and promising efficacy, showing several objective responses in heavily pretreated and/or BTK inhibitor resistant patients. Emavusertib may have the potential to overcome BTK inhibitor resistance and the combination of ema+ibr has the potential to show increased anti-cancer activity compared to ibrutinib monotherapy.