Related Treatment-emergent Adverse Events Research Articles

CTIM-08. FIRST IN HUMAN STUDY OF THE MRNA-BASED CANCER VACCINE CVGBM IN PATIENTS (PTS) WITH NEWLY-DIAGNOSED AND SURGICALLY RESECTED MGMT-UNMETHYLATED GLIOBLASTOMA (GBM): FIRST RESULTS FROM THE DOSE ESCALATION PHASE

Abstract INTRODUCTION CVGBM is an investigational therapeutic mRNA-based vaccine encoding 8 epitopes derived from tumor associated antigens with potential relevance in GBM. This is an ongoing, first-in-human study evaluating the safety of CVGBM in pts with newly-diagnosed MGMT-unmethylated GBM. METHODS HLA-A*02:01-positive pts with newly-diagnosed MGMT-unmethylated GBM (CNS WHO Grade [Gr] 4) who had a gross total or partial resection and completed radiotherapy ± concomitant temozolomide received CVGBM on Days 1, 8, 15, 29, 43, 57 and 71 + 6 optional doses at 6-week intervals. Primary endpoints are safety, tolerability and dose-limiting toxicities (DLTs). Immunogenicity is an exploratory endpoint. RESULTS As of 29/2/2024, 16 pts were enrolled in the dose-escalation part (Part A); 3 each in DL 1 (12 µg), DL 2 (25 µg), and DL 3 (50 µg), and 7 in DL 4 (100 µg). For all cohorts, mean time on study from 1st dose to last visit was 4.5 months (min: 1.5; max: 8). 109 doses were administered (mean: 6.8 doses per pt). All pts completed the 2-week DLT evaluation period without DLTs. Of 156 treatment-emergent adverse events (TEAEs), the majority (73%) were CTCAE Gr 1 (21% Gr 2, 6% Gr 3). The most common related TEAEs were chills (n=13), pyrexia (n=12), headache (n=12), fatigue (n=11) and malaise (n=5), mostly of mild to moderate severity. 7 pts had 9 ≥ Gr 3 AEs assessed as potentially related to CVGBM by the investigators outside the DLT period (cerebral edema [n=2], leukoencephalopathy, pseudoprogression with cerebral edema, structural epilepsy, ataxia, hypertension, malaise and fever [1 of each]), evenly distributed across cohorts. First immunogenicity data are planned to be presented. CONCLUSIONS CVGBM was generally well tolerated with an acceptable safety profile. The highest tolerated dose was not reached. Based on all available safety data, the selected dose for trial expansion was 100 µg. Previously presented at ESMO 2024, “FPN (Final Publication Number): 4400, Ghazaleh Tabatabai et al. - Reused with permission.

Efficacy and Safety of Valbenazine in Elderly and Nonelderly Japanese Patients With Tardive Dyskinesia: A Post Hoc Analysis of the J-KINECT Study.

The efficacy and safety of valbenazine, a selective vesicular monoamine transporter 2 inhibitor, has been confirmed for treatment of tardive dyskinesia (TD) in patients aged ≥65 years in non-Asian clinical trials; however, data are lacking in elderly Asian patients. This post hoc analysis of J-KINECT aimed to evaluate the efficacy and safety of valbenazine in elderly Japanese patients with TD. J-KINECT was a randomized, double-blind, placebo-controlled study with a 6-week double-blind, placebo-controlled period; 42-week double-blind, valbenazine extension period; and 4-week posttreatment observation period. Outcomes were summarized by age (≥65 years [elderly] and <65 [nonelderly]) and treatment group. The safety analysis set included 100 and 153 patients aged ≥65 and <65 years, respectively (intention-to-treat set: 98 and 151 patients, respectively). In the elderly group, the difference versus placebo in least-squares mean change from baseline in the Abnormal Involuntary Movement Scale total score at week 6 was -3.1 (95% confidence interval: -4.5, -1.7) and -5.5 (-7.0, -3.9) with valbenazine 40 and 80 mg, respectively; in the nonelderly group, respective differences were -1.5 (-2.6, -0.4) and -2.5 (-3.6, -1.3). Both age groups showed improvement in Clinical Global Impression of Change-Tardive Dyskinesia scores with valbenazine. The incidence of treatment-emergent adverse events (TEAEs) leading to treatment discontinuation was higher in the elderly versus nonelderly group. There was no trend toward higher incidences of TEAEs or related TEAEs in the elderly group. The findings suggest that valbenazine may be used effectively and safely as a treatment for TD, even in elderly patients.

Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors

BackgroundJNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors.MethodsAdult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS).ResultsOverall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry.ConclusionJNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels.Trial registration number ClinicalTrials.gov (No. NCT04991740).

Efficacy and safety of erdafitinib in pediatric patients with advanced solid tumors and FGFR alterations in the phase 2 RAGNAR trial.

10002 Background: Erdafitinib is an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved in the US for adult patients (pts) with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations, as determined by an FDA-approved companion diagnostic test, whose disease has progressed on or after ≥1 line of prior systemic therapy. Primary analysis of the RAGNAR study Broad Panel Cohort demonstrated tumor agnostic efficacy in pts with solid tumors harboring predefined FGFR mutations or fusions (Pant 2023). Here we report on Final Analysis of efficacy and safety results from the Pediatric Cohort of the RAGNAR study. Methods: Pediatric pts ≥6 years with advanced solid tumors and any FGFR mutation, fusion, or tandem duplication received oral erdafitinib. Starting doses were 8 mg, 5 mg, and 3 mg daily for ages &gt; 15 years, 12 to &lt; 15 years, and 6 to &lt; 12 years, respectively, in 21-day cycles with possible individualized up-titration based on serum phosphate and adverse events (AEs). The primary endpoint was objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 or Response Assessment in Neuro-Oncology [RANO]) by independent review committee (IRC). Secondary endpoints included ORR by investigator, duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Results: 11 pts (median age 13 years; range, 6-16; 64% female) received erdafitinib. Median follow-up was 9.7 months at data cutoff. Histologies included low-grade glioma (LGG-6 pts); high-grade glioma (HGG-3 pts); soft tissue sarcoma (1 pt), and temporal neurocytoma (TNEURO-1 pt). 7, 1, and 3 pts had FGFR1, FGFR2, and FGFR3 alterations, respectively. 6, 4, and 1 pts had FGFR fusions, mutations, and tandem duplication, respectively. Pts had a median of 1 prior line of systemic treatment; 6 (55%) had prior radiotherapy. At data cutoff, 1 of 3 pts (33%) with HGG and an FGFR1-TACC1 fusion achieved a partial response based on investigator assessment with a response duration of 19.8 months. Investigator-assessed objective responses were not observed in the other tumor types. DCR and CBR were 100% in pts with LGG and 67% in pts with HGG. Most common treatment-emergent adverse events (TEAEs) included hyperphosphatemia (64%), diarrhea (64%), pain in extremity (45%), alanine transaminase increased (36%), nausea (36%), and onycholysis (27%). No central serous retinopathy events occurred; related serious adverse events (SAEs) occurred in 4 (36%) pts, including 1 SAE of epiphysiolysis; there were no related TEAEs leading to death. Conclusions: In this small pediatric population comprising primarily refractory HGG and LGG with any FGFR alteration, erdafitinib demonstrated limited objective responses but promising disease control with acceptable safety. Clinical trial information: NCT04083976 .

FCN-159, a MEK1/2 inhibitor, in patients with advanced melanoma harboring NRAS or NF1mutations: A phase 1B dose-expansion study.

3095 Background: In phase 1A dose-escalation study, preliminary anti-tumor activity of FCN-159 was observed in advanced melanoma patients harboring NRAS mutations (ORR: 19.0%, mPFS: 3.8 months) with tolerable safety profile, which was posted during AACR 2022 (No.: 22-LB-7398-AACR). Here, we report the results from phase 1B dose-expansion study in advanced NRAS- or NF1-mutant melanoma patients at RP2D predetermined at 12 mg. Methods: This open-label, dose-expansion, phase 1B study (NCT03932253) consists of two cohorts, which enrolled patients with unresectable stage III/IV melanoma harboring NRAS or NF1 mutations, respectively. Patients received FCN-159 orally at 12 mg once daily (QD) continuously in 28-day cycles. The primary endpoint was anti-tumor activity. Results: As of July 17, 2023, 46 patients (32 patients with NRASmutations in Cohort 1 and 14 patients with NF1mutations in Cohort 2) were enrolled and received 12 mg FCN-159 QD. The median follow-up time was 8.6 months. Among 25 patients who failed in previous anti-PD-1 therapy in Cohort 1, 6 had confirmed partial responses (ORR, 24.0%; 95% confidence interval [CI], 9.4–45.1). Median DOR was 6.5 months (95% CI, 2.7–NE). Median progression-free survival (mPFS) was 3.6 months (95% CI, 1.8–5.5). Among 14 patients in Cohort 2, 1 had PR (ORR, 7.1%; 95% CI, 0.2-33.9) and mPFS was 2.8 months (95% CI, 1.8-5.5) (Table). Grade≥3 FCN-159-related treatment-emergent adverse events (TEAEs) were reported in 10 (21.7%) patients in both cohorts; the most common was blood creatine phosphokinase increased (13.0%). FCN-159–related serious AEs (SAEs) were reported in 3 (6.5%) patients, which were edema lower limb, cellulitis and pneumonia. Two (4.3%) patients discontinued treatment due to FCN-159 related TEAEs, including serous retinal detachment and herpes zoster. No FCN-159-related TEAEs led to death. Conclusions: FCN-159 showed encouraging efficacy data with well tolerated safety profile in patients with NRAS-mutant advanced melanoma, especially those who failed in previous anti-PD-1 therapy. Clinical trial information: NCT03932253 . [Table: see text]

Abstract PO2-04-13: TWT-203: PHASE 1b/2 STUDY OF CFI-402257 AS MONOTHERAPY IN ADVANCED SOLID TUMORS AND IN COMBINATION WITH FULVESTRANT IN PATIENTS WITH ER+/HER2- ADVANCED BREAST CANCER AFTER PROGRESSION ON PRIOR CDK4/6 INHIBITORS AND ENDOCRINE THERAPY

Abstract Background: TTK (Threonine Tyrosine Kinase also known as Monopolar spindle 1), is a dual-specificity serine-threonine kinase critical for anaphase promoting complex inhibition at the spindle assembly checkpoint and is required for chromosome alignment and error correction. TTK inhibition results in premature mitosis exiting with unattached chromosomes potentially leading to aneuploidy and cell death. High TTK tumor levels correlate with worse prognosis and contribute to the survival and proliferation of aneuploid cells. CFI-402257, a potent and selective inhibitor of TTK, inhibits the growth of a variety of human cancer-derived cell lines. A first-in-human phase 1 study of CFI-402257 (NCT02792465) demonstrated a tolerable safety profile when enrolled as a monotherapy in solid tumors, and in combination with fulvestrant in hormone receptor positive, HER2 negative (HR+/HER2-) breast cancer1. The dose for expansion was 168 mg, dose limiting toxicity was dose-dependent neutropenia which was manageable and reversible. Investigator-confirmed partial responses (cPR) were observed in 5 pts (8%) with 32 (50.8%) exhibiting disease control. In the HR+/HER2- breast cancer population previously treated with cyclin dependent kinase 4/6 inhibitors (CDK4/6i) and aromatase inhibitors (N=25), there were 4 cPR’s with a median duration of response of 223 days, with responses emerging after 2 cycles of therapy. Responses were observed with CFI-402257 as a single agent and in combination with fulvestrant. Based on these data, study TWT-203 will focus on advanced solid tumors for dose confirmation then focus on advanced HR+/HER2- breast cancers in combination with an approved endocrine therapy. Methods: In TWT-203 study, safety and clinical activity of CFI-402257 monotherapy will be evaluated in patients (pts) with advanced solid tumors (Part A) or in combination with fulvestrant in pts with HR+/HER2- advanced breast cancer (Part B). Part A will confirm the RP2D using a 3+3 design with a starting dose of 126 mg daily. Part B evaluates CFI-402257 in combination with fulvestrant in pts with HR+/HER2- advanced breast cancer following progression on prior CDK4/6i and endocrine therapy. Efficacy endpoints include overall response rate and disease control rate. Safety endpoints include incidence of treatment emergent adverse events. Exploratory objectives include characterization of protein and molecular alterations relevant to the cell cycle and CFI-402257 response. Results: At data cutoff of 11 May 2023, 14 pts were enrolled. All received monotherapy treatment. Median treatment duration was 2.1 months (range, 0.2-7.3+). Median age was 67 years (57-76). Median number of prior regimens was 3.5 (2-12). Tumor types enrolled were colorectal (n=6, 43%), breast (3, 21%), and endometrial, hepatocellular, leiomyosarcoma, pancreatic, and sarcoma (1 each, 7%). 4 dose levels, from 126 to 252 mg, were studied. Most pts (12, 86%) experienced ≥1 treatment emergent adverse event (TEAE). More than half of pts (8, 57%) experienced ≥1 treatment related TEAE. Most common TEAEs were fatigue (5, 36%) and nausea (4, 29%). 5 pts (36%) experienced TEAEs grade ≥3, most common were fatigue, neutrophil count decrease, white blood cell count decrease (2 pts each, 14.3%). 1 pt (7%) experienced a serious adverse event (hematuria), not related to study therapy. No patients discontinued treatment due to TEAE. All pts who ended treatment were due to disease progression (8, 57%). No grade 5 TEAEs occurred. No dose limiting toxicities were reported. Disease control rate (CR, PR, or SD ≥ 6 weeks from baseline) was 54.5% (6 pts/11): all achieved SD. 3 of the 6 pts remain on study. Conclusion: CFI-402257 is a potent inhibitor of TTK. It is well tolerated with manageable TEAEs, no dose limiting or treatment limiting toxicities, and no treatment related deaths. Dose expansion in the patient population of interest will commence. 1. John Hilton et al. Cancer Res 2023;83(5 Suppl): P6-10-13. Citation Format: Justin Call, Muralidhar Beeram, Alexander I. Spira, Mark Bray, Dih-Yih Chen, Long Kwei, Emily Roberts-Thomson, Trisha Denny, Roger Sidhu, Robert Wesolowski. TWT-203: PHASE 1b/2 STUDY OF CFI-402257 AS MONOTHERAPY IN ADVANCED SOLID TUMORS AND IN COMBINATION WITH FULVESTRANT IN PATIENTS WITH ER+/HER2- ADVANCED BREAST CANCER AFTER PROGRESSION ON PRIOR CDK4/6 INHIBITORS AND ENDOCRINE THERAPY [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-13.

RESILIENT Part 2: A Randomized, Open-Label Phase III Study of Liposomal Irinotecan Versus Topotecan in Adults With Relapsed Small Cell Lung Cancer.

The phase III RESILIENT trial compared second-line liposomal irinotecan with topotecan in patients with small cell lung cancer (SCLC). Patients with SCLC and progression on or after first-line platinum-based chemotherapy were randomly assigned (1:1) to intravenous (IV) liposomal irinotecan (70 mg/m2 every 2 weeks in a 6-week cycle) or IV topotecan (1.5 mg/m2 daily for 5 consecutive days, every 3 weeks in a 6-week cycle). The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) and objective response rate (ORR). Among 461 randomly assigned patients, 229 received liposomal irinotecan and 232 received topotecan. The median follow-up was 18.4 months. The median OS was 7.9 months with liposomal irinotecan versus 8.3 months with topotecan (hazard ratio [HR], 1.11 [95% CI, 0.90 to 1.37]; P = .31). The median PFS per blinded independent central review (BICR) was 4.0 months with liposomal irinotecan and 3.3 months with topotecan (HR, 0.96 [95% CI, 0.77 to 1.20]; nominal P = .71); ORR per BICR was 44.1% (95% CI, 37.6 to 50.8) and 21.6% (16.4 to 27.4), respectively. Overall, 42.0% and 83.4% of patients receiving liposomal irinotecan and topotecan, respectively, experienced grade ≥3 related treatment-emergent adverse events (TEAEs). The most common grade ≥3 related TEAEs were diarrhea (13.7%), neutropenia (8.0%), and decreased neutrophil count (4.4%) with liposomal irinotecan and neutropenia (51.6%), anemia (30.9%), and leukopenia (29.1%) with topotecan. Liposomal irinotecan and topotecan demonstrated similar median OS and PFS in patients with relapsed SCLC. Although the primary end point of OS was not met, liposomal irinotecan demonstrated a higher ORR than topotecan. The safety profile of liposomal irinotecan was consistent with its known safety profile; no new safety concerns emerged.

A Phase 1 Open-Label Study to Assess the Tolerability, Safety, and Immunogenicity of Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 20% in Healthy Adults

PurposeHyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 20% will allow reduced infusion volumes and frequency versus existing subcutaneous therapies such as fSCIG 10% and conventional subcutaneous immunoglobulin 20%, respectively. We assessed the tolerability, safety, and immunogenicity of warmed and unwarmed fSCIG 20%.MethodsThis phase 1, single-dose, open-label, three-arm study enrolled healthy adults aged 19–50 years (inclusive) at a single US center (NCT05059977). Post-screening, participants received a single fSCIG 20% dose comprising recombinant human hyaluronidase and varying doses of in-line warmed or unwarmed immunoglobulin G (IgG) during a 4-day treatment period in a sentinel and sequential dosing design (treatment arm 1, warmed IgG 20% 0.4 g/kg; treatment arm 2, warmed IgG 20% 1.0 g/kg; treatment arm 3, unwarmed IgG 20% 1.0 g/kg). Participants were followed for 12 (± 1) weeks post-infusion. The primary endpoint was tolerability (“tolerable” infusions were not interrupted, stopped, or reduced in rate owing to fSCIG 20%-related treatment-emergent adverse events (TEAEs)). Secondary endpoints included occurrence of TEAEs.ResultsOverall, 24 participants were included, 8 per treatment arm (mean age 39.0 years, 54.2% men). All participants tolerated the infusions. All TEAEs were mild (107 events, in all participants), and all participants experienced fSCIG 20%-related (105 events) and local (102 events) TEAEs. Infusion site erythema and infusion site swelling were most frequently reported. No serious TEAEs occurred, and no participants discontinued the study owing to TEAEs.ConclusionfSCIG 20% was well-tolerated with a favorable safety profile in healthy adults. Future studies will evaluate fSCIG 20% in primary immunodeficiency diseases.Trial registration number (ClinicalTrials.gov): NCT05059977 (registered 28 September 2021).

Importance of Long-Acting Injectable Antipsychotic Preparation, Administration, and Injection Site Tolerability: A Focus on Paliperidone Palmitate Once-Every-6-Months Formulation

Purpose. This post hoc analysis assessed the importance of proper paliperidone palmitate (PP) dose preparation prior to administration and evaluated injection site reactions after dorsogluteal injection of PP once-every-6-months (PP6M) and once-every-3-months (PP3M) formulations from a double-blind (DB) noninferiority study. Design and Methods. Clinically stable patients receiving moderate/high doses of PP once-monthly (PP1M) (156 mg/mL; 234 mg/1.5 mL) or PP3M (546 mg/1.75 mL; 819 mg/2.63 mL) were randomly assigned 2:1 to corresponding dorsogluteal injections of PP6M (1092 mg/3.5 mL; 1560 mg/5 mL) or PP3M (546 mg/1.75 mL; 819 mg/2.63 mL) during a 12-month DB phase. Patients receiving PP6M injections received alternating matching placebo injections every 3 months between active doses to maintain blinding. Prior to administration, each PP formulation was prepared per specific instructions to ensure complete resuspension of the medication. Findings. Of 895 PP6M injections, one of two incomplete injections was possibly related to insufficient shaking before administration; neither resulted in an adverse reaction. After dorsogluteal administration, 59 of 478 patients who received PP6M (12.3%) and 11 of 224 patients who received PP3M (4.9%) reported an injection site–related treatment-emergent adverse event (TEAE), with pain being the most commonly reported (7.7% and 4.0%, respectively). Patient-reported pain decreased from baseline to end point in both groups. During the DB phase, injection site-related TEAEs associated with PP6M injections up to 5 mL and PP3M injections up to 2.63 mL were mild to moderate in severity; none were reported as serious, resulted in treatment discontinuation, or required dermatological consultation. Practice Implications. These results inform provider and patient expectations of PP6M administration and reinforce the importance of proper PP dose preparation and administration; future work could assess safety data from real-world clinical practice. This trial is registered with NCT03345342.

Strategies to Develop Anti-KIR Mab Lacutamab in Patients with Peripheral T-Cell Lymphoma: Preliminary Monotherapy Clinical Data and Pre-Clinical Combinability Data

Peripheral T-cell Lymphoma (PTCL) is a heterogeneous group of aggressive T-cell lymphomas associated with poor prognosis. Many patients with PTCL do not respond or relapse despite responding to first line systemic therapy. Despite the common use of chemotherapies, there is no universally accepted standard of care. This highlights an urgent and significant need for innovative treatment strategies that incorporate novel mechanisms of action, particularly for patients with relapsed or refractory (R/R) PTCL. One such novel target is KIR3DL2, a killer immunoglobulin-like receptor that is expressed across different subtypes of T-cell lymphomas including approximately 50% of PTCL patients. Lacutamab is a first-in-class monoclonal antibody designed to specifically deplete KIR3DL2-expressing cells through antibody-dependent cell-cytotoxicity (ADCC) and antibody-dependent cell-phagocytosis (ADCP). It is being developed as a novel treatment for patients with R/R PTCL as a single agent or in combination. In previous trials in patients with R/R cutaneous T-cell lymphoma (CTCL), lacutamab showed acceptable safety profile with no dose limiting toxicities and promising activity. Here we provide preclinical combination data supporting anti-tumor activity and rationale for the exploration of lacutamab in combination with approved and novel therapies in patients with PTCL and we present preliminary monotherapy data from an ongoing Phase 1b study in PTCL. To further develop novel-lacutamab combinations, the combinability of lacutamab with therapies used in R/R or frontline PTCL e.g., pralatrexate or CHOP, respectively, was tested. Pralatrexate is an antineoplastic folate analog approved for the treatment of R/R PTCL. In vitro, pralatrexate was shown to induce KIR3DL2 upregulation on several tumor cell lines with endogenous or forced KIR3DL2 expression and to enhance lacutamab-induced ADCC by NK cells. Importantly, the combination of lacutamab with pralatrexate in vivo delayed tumor growth (Figure 1A) and improved survival (Figure 1B) compared to each monotherapy. CHOP-based chemotherapy is a standard of care in the frontline treatment of PTCL subtypes. In a preclinical in vivo human tumor model, lacutamab in combination with CHOP was shown to reduce tumor growth compared with CHOP or lacutamab alone. An ongoing multi-center, open-label, Phase Ib trial (NCT05321147) evaluate the safety and efficacy of lacutamab monotherapy in patients with KIR3DL2-expressing R/R PTCL who have received at least one prior line of systemic therapy. Lacutamab 750 mg is administered as an intravenous infusion weekly x 5 weeks, every 2 weeks x 10 then every 4 weeks until disease progression or unacceptable toxicity. The primary objective was to assess the safety and tolerability of lacutamab in R/R PTCL. Secondary objectives were to assess clinical activity and to characterize the pharmacokinetics and immunogenicity of lacutamab. At the data cut-off, 10 patients were treated with lacutamab. Median age was 71.0 years (range: 61-77), median prior lines of therapies was 3 (range: 1-5), and median follow-up was 1.9 months (m) (range: 0.5-8.8 m). The majority (90%) of treatment-emergent adverse events (TEAEs) were of grade 1-2 severity, grade ≥3 related TEAEs were observed in 2 (20%) patients: 1 with serum sickness, and 1 with aspartate aminotransferase elevation. No serious TEAEs were observed and none of the patients discontinued study drug due to TEAE. Overall, preliminary Phase 1b data in patients with R/R PTCL confirm the acceptable safety profile of lacutamab monotherapy. The preclinical activity profile improves when assessed in combination. These data inform the future development of lacutamab to provide additional therapeutic options that may improve outcomes for PTCL patients, including those who relapse or are refractory to available therapies. A Phase 2 study evaluating the combination of lacutamab with GemOx is ongoing (NCT04984837) based on pre-clinical observations that GemOx improves lacutamab-induced ADCC by NK cells.

Initial Report of Part B Phase 1/2 Efficacy and Safety Results for Bruton Tyrosine Kinase Inhibitor Rilzabrutinib in Patients with Relapsed Immune Thrombocytopenia

Introduction: Rilzabrutinib is a potent oral, reversible Bruton tyrosine kinase inhibitor that can treat hematological autoimmune diseases through multiple putative mechanisms of action: (1) inhibition of B-cell activation, (2) interruption of antibody-coated cell phagocytosis by FcϒR in spleen and liver, and (3) induce sustained anti-inflammatory effects (Langrish J Immunol 2021). Preliminary evidence showed that rilzabrutinib treatment resulted in rapid and durable platelet responses with a favorable safety profile in previously treated patients with immune thrombocytopenia (ITP) as studied in part A of a phase 1/2 clinical study (LUNA 2; Kuter N Engl J Med 2022). This abstract summarizes the results of part B that focused on the durability of response with rilzabrutinib in relapsed ITP patients. Methods: Part B of the multicenter, open-label, phase 1/2 study evaluated the efficacy and safety of rilzabrutinib 400 mg bid in patients with relapsed ITP (NCT03395210). Adult patients aged 18-80 y were eligible with ≥2 baseline platelet counts &amp;lt;30x10 9/L no less than 7 days apart in the 15 days before the first dose. Eligible patients were required to have a past response (achievement of platelet count ≥50x10 9/L) to intravenous immunoglobulin (IVIg)/anti-D or corticosteroid (CS) that was not sustained and failed ≥1 other ITP therapy (that was not IVIg or CS). Stable doses of concomitant CS/thrombopoietin receptor agonists (TPO-RA) were allowed with rilzabrutinib. The primary endpoints for part B were safety and durable platelet response defined as platelet counts ≥50x10 9/L on ≥8 of the last 12 weeks of rilzabrutinib without rescue medication. Patients completing 24 weeks of rilzabrutinib with platelet counts ≥50x10 9/L or ≥30x10 9/L and doubling from baseline in ≥4 of the last 8 weeks of treatment without rescue medication could continue rilzabrutinib in the long-term extension (LTE) period. Results: At baseline, 26 enrolled patients had a median age of 57 y (range, 20-75), 62% were female, and median baseline platelet count was 13x10 9/L (range, 2-24x10 9/L). Patients had a median duration of ITP of 10.3 y (range, 0.7-48.2) and had received a median of 6 prior unique ITP therapies (range, 3-19; 46% splenectomy). Seventeen patients (65%) received concomitant non-rescue CS and/or TPO-RA. Nine patients (35%; 95% CI, 17%-56%) achieved the primary endpoint of durable platelet response. Approximately 25% of patients achieved platelet counts ≥50x10 9/L by day 15 of rilzabrutinib treatment (Figure 1A). In 16 patients who achieved platelet counts ≥50x10 9/L, median time to first platelet count ≥50x10 9/L was 15 days (range, 7-134). Median platelet counts for all patients (responders and non-responders) increased over time, exceeding the platelet count thresholds of 30x10 9/L at day 57 and 50x10 9/L at day 120 (Figure 1B). The mean number of weeks with platelet counts ≥50x10 9/L and/or ≥30x10 9/L and doubling from baseline was both 9.3 weeks (SD, 10.1). Three patients (12%) received rescue medication in the main treatment period. Fifteen patients (58%) completed 24 weeks of rilzabrutinib and 11 (42%) entered the LTE. Over the main treatment period, the median duration of treatment was 167 days (range, 7-169). Sixteen patients (62%) had ≥1 related treatment-emergent adverse event (AE), including 35% diarrhea, 23% headache, and 15% nausea. Most AEs were grade 1 or 2; there was 1 treatment-related AE of grade 3 blood creatinine phosphokinase increase. There was no treatment-related grade ≥2 bleeding/thrombotic events or infections, serious AEs, or deaths. Conclusion: Part B study results were consistent with part A. Rilzabrutinib demonstrated rapid, stable, and durable platelet responses in patients with relapsed ITP, with a favorable safety profile in part B.

Safety and Efficacy of Relmacabtagene Autoleucel (relma-cel) in Adults with Relapsed/Refractory Mantle Cell Lymphoma (r/r MCL): Updated Results from a Phase II Open-Label Study in China

Background: Mantle cell lymphoma (MCL), an aggressive subtype of B-cell non-Hodgkin lymphoma, predominantly affects elderly males. Poor overall response rates (ORR) and high rates of recurrence are observed for those patients after discontinuation or failure from Bruton 's tyrosine kinase inhibitors (BTKi), with median overall survival (OS) of 6~10 months. A phase II open label study (NCT04718883) for relma-cel reported the first efficacy and safety data in 11 Chinese patients with relapsed/refractory Mantle Cell Lymphoma (r/r MCL) in ASH 2022. This abstract provides the updated data based upon 56 patients. The study is still ongoing. Methods: The study enrolled patients with confirmed diagnosis of MCL, relapsed or refractory after at least 2 lines of prior therapies including anti-CD20 antibody, anthracycline or bendamustine, andBTKi. After lymphodepleting chemotherapy, patients received relma-cel (100×10 6 CAR+ Tcells). Bridging therapy was allowed. Primary endpoint was ORR at month 3 assessed by investigator, and secondary endpoints included complete response rate (CRR) at month 3, duration of response (DoR), progression-free survival (PFS), OS, pharmacokinetics (PK), pharmacodynamics (PD) and safety. Results: As of June 30, 2023, 66 patients enrolled and receivedleukapheresis. Relma-cel was administered in 56 patients (78.6% males; median age of 59.5 years). 42 patients had tumor assessment at month 3 or discontinued treatment due to death, disease progression before evaluation. The study population had poor prognostic factors at baseline: Age: 19 (33.9%) ≥ 65 years oldPathology: 13 (23.2%) with blastoid and 6 (10.7%) with pleomorphic variants30 (53.6%) with extranodal lesions, 4 (7.1%) with gastrointestinal involvement; 28 (50.0%) with spleen involvement, 17 (30.4%) with bone marrow involvementMCL International Prognostic Index (MIPI) score ≥ 4: 27 (48.2%)High tumor burden: 17 (30.4%) had bulky disease ≥ 5 cm Over 65% patients received ≥ 3 lines of prior therapies, including 25.0% patients received ≥ 5 lines. Almost all patients failed to BTKi (29 [51.8%] relapsed and 25 [44.6%] refractory). Seven (12.5%) patients relapsed after hematopoietic stem cell transplantation (HSCT). Twenty-six (46.4%) patients underwent bridging therapy. At month 3, of the 42 efficacy-assessable patients, 27 (64.29%) reached objective responses (OR), and 23 (54. 76%) achieved complete response (CR). Best ORR was 78.57% and best CRR was 66.67%. Based on the safety analysis set of 56 patients, 52 (92.86%) patients had treatment emergent adverse events (TEAE), including 44 (78.57%) with treatment related TEAE of grade ≥ 3. Twenty-five (44.64%) patients had serious adverse events (SAE), and 13 (23.21%) with treatment related SAE. Thirty-one (55.36%) patients had cytokine release syndrome (CRS), 3 (5.36%) with grade ≥ 3. Six (10.71%) patients had neurotoxicities (NT), 4 (7.14%) with grade ≥ 3. Twenty-seven (48.21%) patients had infections, 15 (26.79%) with grade ≥ 3. Forty-seven (83.93%) patients had prolonged cytopenia, 38 (67.86%) with grade ≥ 3. Eighteen (32.1%) deaths occurred, 6 (10.7%) died from disease progression, 8 (14.3%) due to AE, 2 (3.6%) died from treatment related AE, 4 (7.2%) from other reasons or unknown causes. Conclusions: In this phase II study, relma-cel continually demonstrated high response rates (best ORR: 78.57%; best CRR: 66.67%) and good tolerability in patients with r/r MCL.

Abstract 13840: Safety Outcomes From a First-in-Human Study of a Novel Investigational Monoclonal Antibody, REGN5381, an Agonist to the Natriuretic Peptide Receptor 1

Introduction: Natriuretic peptides (NPs) regulate vascular volume and tone via the membrane-bound guanylate cyclase, natriuretic peptide receptor 1 (NPR1). Activation of this pathway is known to lower systemic and venous blood pressure (BP) and effect natriuresis and diuresis. Previous recombinant NP infusions for heart failure were limited by their duration of effects. REGN5381, a novel investigational NPR1 agonist monoclonal antibody, showed sustained hemodynamic effects in animal models. Here, we report safety and pharmacodynamic (PD) outcomes from a phase 1, first-in-human study of REGN5381. Hypothesis: REGN5381 is sufficienty well tolerated in healthy humans to warrant continued clinical investigation. Aim: To assess the safety, tolerability, and REGN5381 PD in normotensive humans. Methods: This double-blind, single-ascending dose study (NCT04506645), randomized healthy adults aged 18-55 years (6:2) to receive a single intravenous dose of REGN5381 or placebo. Participants received a fixed-sodium and fluid diet and remained 4 days in the clinic for non-invasive hemodynamics monitoring and safety assessment. Results: A total of 48 participants were enrolled; 12 were randomized to placebo and 6 to each of 6 REGN5381 dose levels (total n=36). Eight (66.7%) participants in the placebo and 24 (66.7%) in the total REGN5381 group reported ≥1 treatment-emergent adverse event (TEAE), with no obvious relationship to dose level. Four (33.3%) participants in the placebo and 15 (41.7%) in the total REGN5381 group reported ≥1 study drug related TEAE, with no obvious relationship to dose level. Common TEAEs (experienced by &gt;10% of participants in the total group) were postural dizziness (placebo: 2 [16.7]%; total REGN5381: 6 [16.7]%) and headache (placebo: 5 [41.7%]; total REGN5381: 4 [11.1%]). Pyuria and orthostatic hypotension were reported in 4 (11.1%) participants in the total group, but none in the placebo group. No serious or severe TEAEs or deaths were reported in any dose groups. Participants treated with the highest dose saw a 7-11 mmHg reduction of systolic BP that was sustained over 72 hours (the full duration of inpatient monitoring). Conclusion: A single dose of REGN5381 is generally well-tolerated and provides sustained hemodynamic effects.

A Phase 1a/b Trial of Luxeptinib (CG-806) in Patients with Relapsed/Refractory B-Cell Malignancies or Acute Myeloid Leukemia and Evaluation of New G3 Formulation

INTRODUCTION: Luxeptinib (CG-806; LUX) is an orally active noncovalent kinase inhibitor of Bruton's tyrosine kinase (BTK), wild type and mutant forms of Fms-like tyrosine kinase 3 (FLT3) (including the internal tandem duplicates (ITD), tyrosine kinase domain (TKD), and F691L mutant forms), and growth receptors like KIT, CSF1R, PDGFRα, and TRKs. In prior studies, LUX has been shown to suppress aberrant proliferative signaling in B cell malignancies and acute myeloid leukemia (AML) via regulation of BTK, LYN, SYK, AKT, ERK, and MAPK. LUX is cytotoxic to primary AML cells insensitive to other FLT3 inhibitors and to malignant B-cells insensitive to ibrutinib, at pM and nM concentrations, respectively. AIMS: The primary objectives of these studies are to assess the safety, tolerability, and pharmacokinetics (PK) of LUX and determine recommended phase 2 doses for relapsed or refractory (R/R) AML and B cell malignancy patients. METHODS: In two studies (NCT04477291; NCT03893682), LUX (original formulation, G1) was administered continuously as oral capsules BID in 28-day cycles of ascending cohorts (relapsed or refractory de novo, secondary, or therapy-related AML or higher risk myelodysplastic syndrome (MDS), and relapsed and refractory for B cell lymphoma and chronic lymphocytic/small lymphocytic leukemia). A novel generation 3 (G3) formulation of LUX designed to increase bioavailability was tested at a single-dose (sub-study) for relative bioavailability (RBA), followed by continuous dosing in subsequent R/R AML patients. RESULTS: In the B-cell study (as of 15 th May 2023), LUX has been administered to 36 patients at dose levels from 150 mg to 900 mg BID in patients with a median of 3 lines of prior treatment, with 47.2% having received a BTK-inhibitor. Only one (2.8%) patient had a DLT of hypertension and 14 (38.9%) experienced at least one drug related ≥Grade3 treatment emergent adverse event (TEAE). Two patients (900 mg) are currently on study with no DLT and no ≥Grade 3 related TEAEs. A Follicular lymphoma patient is at cycle 28, and achieved a best response as partial response (PR) with a decrease in lesion size of 76.2%; an SLL patient is at cycle 13, and achieved stable disease (SD) showing a decrease in lesion size of 43.1% (Figure A). The overall best response achieved among the 17 patients who have been on treatment for more than 12 weeks are stable disease (SD) (n=11), partial response (PR) (n=3), minor response (n=2) and complete response (CR) (n=1). As of 5 th June 2023, in the AML trial, a total of 40 patients (16 (40%) FLT3-ITD, 21 (52.5%) FLT3-WT, 2 (5.0%) FLT3-TKD, and 1 (2.5%) unknown mutations) with a median of 3 prior treatments (range, 1 - 10) have been treated with LUX G1 formulation at dose levels from 450 mg - 900 mg BID (n=34) or with 50 mg BID of G3 formulation (n=6). Four (10%) experienced drug related SAE and 7 (17.5%) had a drug related grade ≥3 TEAEs. The most common related TEAEs were lymphocyte count decrease, platelet count decrease, and anemia (n=2; 5% patients each). One (2.5%) patient at 450 mg dose, reported complete remission without minimum residual disease (CRmrd) and remained on study for 56 weeks. In the RBA sub-study, G3 (50 mg) produced comparable exposures to G1 (450-900 mg range) (Figure B) and was, therefore, selected as the starting dose for use in the R/R AML study. Six patients were treated with a continuous dosing of 50 mg BID G3; with plasma levels of 274 ng/mL and 195 ng/mL LUX observed by the end of C1D15 and C1D22 respectively. No drug related Grade ≥3 TEAEs or DLTs were observed in 50 mg BID G3 LUX treated patients; with no new safety signals observed for the G3 formulation. Based on these findings and expected exposures for higher dose levels, the cohort safety review committee has approved escalation of G3 dosing to 200 mg BID at which dosing is ongoing. CONCLUSIONS: LUX has a favorable safety profile in patients at all tested dose levels, for multiple cycles, for both studies. Antitumor activity was observed in a heavily pretreated relapsed AML patient and in multiple B-NHL subtypes and CLL/SLL patients including several with prior ibrutinib exposure. Continuous dosing of patients with R/R AML and Higher-Risk MDS with the G3 formulation is ongoing; with updated clinical data (200 mg dose level) to be presented at the meeting.

Phase 1 dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of FCN-159 in adults with neurofibromatosis type 1-related unresectable plexiform neurofibromas

BackgroundSurgery is a common treatment strategy for patients with neurofibromatosis type 1 (NF1)-related plexiform neurofibroma (PN) and has limited efficacy. FCN-159 is a novel anti-tumorigenic drug via selective inhibition of MEK1/2. This study assesses the safety and efficacy of FCN-159 in patients with NF1-related PN.MethodsThis is a multicenter, open-label, single-arm, phase I dose-escalation study. Patients with NF1-related PN that was non-resectable or unsuitable for surgery were enrolled; they received FCN-159 monotherapy daily in 28-day cycles.ResultsNineteen adults were enrolled in the study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. Among patients included in dose-limiting toxicity (DLT) analysis, DLTs (grade 3 folliculitis) were reported in 1 of 8 patients (16.7%) receiving 8 mg and 3 of 3 (100%) patients receiving 12 mg. The maximum tolerated dose was determined to be 8 mg. FCN-159-related treatment-emergent adverse events (TEAEs) were observed in 19 patients (100%); most of which were grade 1 or 2. Nine (47.4%) patients reported grade 3 study-drug–related TEAEs across all dose levels, including four experiencing paronychia and five experiencing folliculitis. Of the 16 patients analyzed, all (100%) had reduced tumor size and six (37.5%) achieved partial responses; the largest reduction in tumor size was 84.2%. The pharmacokinetic profile was approximately linear between 4 and 12 mg, and the half-life supported once daily dosing.ConclusionsFCN-159 was well tolerated up to 8 mg daily with manageable adverse events and showed promising anti-tumorigenic activity in patients with NF1-related PN, warranting further investigation in this indication.Trial registrationClinicalTrials.gov, NCT04954001. Registered 08 July 2021.

Integrated safety analysis of phase 3 studies for investigational microbiome therapeutic, SER-109, in recurrent CDI

Background:Clostridioides difficile infection (CDI) often recurs in patients aged ≥65 years and those with comorbidities. Clinical trials often exclude patients with history of immunosuppression, malignancy, renal insufficiency, or other comorbidities. In a phase 3 trial (ECOSPOR III), SER-109 was superior to placebo in reducing recurrent CDI (rCDI) risk at week 8 and was well tolerated. We report integrated safety data for SER-109 in a broad patient population through week 24 from phase 3 studies: ECOSPOR III and ECOSPOR IV. Methods: ECOSPOR III was a double-blind, placebo-controlled trial conducted in participants with ≥2 CDI recurrences randomized 1:1 to placebo or SER-109. ECOSPOR IV was an open-label, single-arm study conducted in 263 patients with rCDI enrolled in 2 cohorts: (1) rollover participants from ECOSPOR III with on-study recurrence and (2) participants with ≥1 CDI recurrence, inclusive of the current episode. In both studies, the investigational product was administered as 4 oral capsules over 3 days. Treatment-emergent adverse events (TEAEs) were collected through week 8; serious TEAEs and TEAEs of special interest (ie, bacteremia, abscess, meningitis) were collected through week 24. Results: In total, 349 participants received SER-109 in ECOSPOR III and/or ECOSPOR IV (mean age 64.2; 68.8% female). Chronic diseases included cardiac disease (31.2%), immunocompromised or immunosuppressed (21.2%), diabetes (18.9% ), and renal impairment or failure (13.2%). Overall, 221 (63.3%) of 349 participants who received SER-109 experienced TEAEs through week 24. Most were mild to moderate and gastrointestinal. The most common (&gt;5% of participants) treatment related TEAEs were flatulence, abdominal pain and distension, decreased appetite, constipation, nausea, fatigue, and diarrhea. No participants experienced a treatment-related TEAE leading to study withdrawal. Invasive infections were observed in 28 participants (8%); those with identified pathogens were unrelated to SER-109 species, and all were deemed unrelated to treatment by the investigators. There were 11 deaths (3.2%) and 48 participants (13.8%) with serious TEAEs, none of which were deemed treatment related. There were no clinically important differences in the safety profile across subgroups of sex, race, prior antibiotic regimen, or number of CDI recurrences. No safety signals were observed in participants with renal impairment or failure, diabetes, cardiac disease, or immunocompromised or immunosuppressed individuals. Conclusions: In this integrated analysis of phase 3 trials, SER-109, an investigational microbiome therapeutic, was well tolerated in this vulnerable patient population with prevalent comorbidities. No infections, nor those with identified pathogens, were attributed to SER-109 or product species. This safety profile might be expected because this purified product is composed of spore-forming Firmicutes normally abundant in the healthy microbiome.Financial support: This study was funded by Seres Therapeutics.Disclosures: None

Interim Analysis of STS101 Nasal Safety Data From the Phase 3 Open-Label ASCEND Migraine Study (P13-12.006)

<h3>Objective:</h3> To assess the long-term nasal safety and tolerability of STS101 in the acute treatment of migraine. <h3>Background:</h3> STS101 (dihydroergotamine nasal powder) is a novel investigational product with rapid and easy nasal delivery. The ASCEND study assesses the safety and tolerability of STS101 5.2 mg in the acute treatment of migraine with/without aura over 12 months. <h3>Design/Methods:</h3> ASCEND (NCT04406649) is a multi-center, multiple-dose, open-label study in adults (18–65 years) with migraine. Participants self-administered STS101 for ≤2 doses/24 hours and ≤12 doses/month for acute treatment of migraines for 12 months. This interim analysis included participants exclusively using the STS101 incorporating the second-generation nasal delivery device planned for commercialization. Nasal safety assessments included nasal treatment-emergent adverse events (TEAEs), subjective assessments of nasal irritation, and a smell test (SIT). Objective nasal assessments were done by trained study personnel on a 4-point severity scale to document nasal erythema, edema, rhinorrhea, bleeding, and nasal mucosa ulcerations. <h3>Results:</h3> This population included 344 subjects who treated 5,571 attacks with 6,918 doses of STS101 and was 40.4±10.9 years old (mean±SD), 85.8% female, and 87.5% Caucasian. Overall, 97 subjects (28.2%) reported nasal/local TEAEs; 8 of 344 subjects (2.9%) discontinued the study due to nasal/local TEAEs including nasal burning/discomfort (5), nasal bleeding (1), rhinitis (1), and throat tightness (1). Most frequently reported nasal/local related TEAEs were nasal discomfort (38 [11.0%] subjects; 338 [6.1%] attacks), dysgeusia (26 [7.6%]; 154 [2.8%]), and nasal congestion (14 [4.4%]; 198 [3.6%]). At 12 months, 99.5%, 95.4%, 93.5%, and 94.4% of subjects had no nasal bleeding/ulceration, edema, erythema, or rhinorrhea, respectively. No clinically relevant findings were seen from nasal examinations, subjective nasal irritation assessments, or smell tests. <h3>Conclusions:</h3> Nasal safety data from 5,571 treated attacks demonstrate the safety and tolerability of STS101 for the acute treatment of migraine. <b>Disclosure:</b> Dr. Spierings has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Manistee. Dr. Spierings has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Lundbeck. Dr. Spierings has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Lilly. Dr. Spierings has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Abbvie. Detlef Albrecht has received personal compensation for serving as an employee of Satsuma. Detlef Albrecht has stock in Satsuma. Dr. Rapoport has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for AbbVie, Amgen, Biohaven, Cala Health, Satsuma, Teva Pharmaceutical Industries, Theranica, Xoc and Zosano. Dr. Rapoport has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for AbbVie, Amgen, Biohaven, Lundbeck and Teva Pharmaceutical Industries. Dr. Rapoport has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Reviews.

Interim Analysis of Long-Term Safety and Tolerability Data of STS101 From the Phase 3 Open-Label ASCEND Study (P13-12.004)

Interim Analysis of Long-Term Safety and Tolerability Data of STS101 From the Phase 3 Open-Label ASCEND Study (P13-12.004)

5589320 FOLLOW-UP RESULTS OF A PHASE 2 STUDY ASSESSING THE SAFETY AND EFFICACY OF MITAPIVAT TREATMENT, AN ORAL PYRUVATE KINASE ACTIVATOR, FOR UP TO 60 WEEKS IN SUBJECTS WITH SICKLE CELL DISEASE

Background: Sickle cell disease (SCD) is a devastating red blood cell (RBC) disorder. The root cause of SCD is polymerization of sickle hemoglobin (HbS) upon deoxygenation, resulting in poorly deformable sickled RBCs with shortened lifespan. 2,3-diphosphyglycerate (2,3-DPG), a glycolytic intermediate in RBCs, promotes deoxygenation by lowering hemoglobin (Hb)-oxygen affinity. Mitapivat (AG-348) is an oral allosteric activator of pyruvate kinase (PK), a key enzyme in RBC glycolysis generating adenosine triphosphate (ATP) and reducing 2,3-DPG levels. Aims: To report follow-up data of the safety and efficacy of mitapivat treatment in subjects with SCD (ESTIMATE study; www.trialregister.nl NL8517; EudraCT 2019-003438-18). Methods: The ESTIMATE study is a phase 2, investigator initiated, open-label study. Subjects ≥16 years with SCD (HbSS, HbS/β0 or HbS/β+), 1-10 vaso-occlusive crises (VOCs) in the prior year and/or prior SCD-related complications, a Hb level >6.1 g/dL and ≤11.1 g/dL, and no chronic transfusions are eligible and treated with mitapivat after obtaining informed content. In the 8-week dose finding period, initial dosing is 20 mg twice daily, escalated to max. 100 mg twice daily, and followed by an up to 52-week fixed dose extension period (FDEP). Primary endpoints are safety, based on adverse events (AEs), and efficacy of mitapivat treatment on RBC sickling (Point of Sickling (PoS), oxygen gradient ektacytometry). Key secondary endpoints are changes in Hb level, markers of hemolysis, ATP/2,3-DPG levels, and Hb-oxygen affinity (p50, Hemox Analyzer). Results: Until Jan. 2022, 9 subjects were treated with mitapivat. Baseline characteristics were: median age 22 years (range 16-59 years), 6/9 (67%) female, and 6/9 (67%) used hydroxyurea. 7/9 (78%) had HbSS, 1/9 (11%) had HbS/β0, and 1/9 (11%) had HbS/β+. One subject with a non-treatment related serious AE (SAE) of a urinary tract infection (grade 4), was lost to follow-up shortly after first dosing. No other SAEs or treatment-emergent AEs (TEAEs) grade ≥3 occurred. The remaining 8 subjects had a median treatment duration of 38 weeks (range 11-60 weeks). 6/8 (75%) took 100 mg mitapivat twice daily in the FDEP, and 2/8 (25%) took 50 mg mitapivat twice daily after a single dose reduction because of progressive transaminase increase. The most common TEAEs were (n>2 subjects): ALT or AST increase (both 5/9, 56%; all grade 1), and headache (4/9, 44%; grade 1-2). Three VOCs occurred: one related to excessive alcohol consumption with no need for hospitalization, and two in subjects with documented noncompliance the week before hospitalization. Mean annual VOC rate and SCD-related hospital admission days were, respectively, 1.5±1.3 and 5.9±7.1 days at baseline, and reduced to 0.5±0.7 and 1.6±3.1 days when weighting cases by follow-up duration (p=0.021 and p=0.134, respectively). Table 1 summarizes mean changes in parameters of primary and key secondary endpoints of scheduled visits in the FDEP compared to baseline. Hb level significantly increased, accompanied by a decrease in markers of hemolysis (absolute reticulocyte count, total bilirubin, lactate dehydrogenase). Mean PoS decreased, and p50, 2,3-DPG level and ATP/2,3-DPG ratio significantly improved. Conclusion: Treatment with mitapivat for up to 60 weeks in subjects with SCD showed no treatment related TEAEs grade ≥3. Improvements in anemia, markers of hemolysis, oxygen affinity, 2,3-DPG level and ATP/2,3-DPG ratio were seen.

Abstract P1-04-12: Systemic immune response to a Phase I/II trial of Durvalumab concomitant with neoadjuvant chemotherapy in early stage TNBC

Abstract Background Peripheral blood cells and secreted products are important regulators of the systemic immune response. Circulating cytokines have been shown to predict severity of immune-related toxicity in melanoma patients that received combination anti-PD-1-based immunotherapy. In this study, we evaluated 38 serum cytokines and the peripheral blood t cell receptor (TCR) immune repertoire of 66 patients with TNBC for associations with pCR, treatment phase (PRE; POST), and immune related treatment emergent adverse events (TEAEs). Methods Serum and peripheral blood buffy coats were collected at pre-treatment (week 0) and at post-treatment (~ week 24). MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panel was run in duplicate and read on the Luminex platform. Genomic DNA was isolated using QIAGEN Kits per manufacturer’s instructions. TCR immune repertoire profiling was performed using the Immunoseq at Adaptive Biotechnologies. Statistical analysis was performed in R. P-values &amp;lt; 0.05 for serum cytokines and P-values &amp;lt; 0.05 for TCR were considered significant. Results Pielou’s diversity index showed no difference between patient groups for TCR (P&amp;gt;0.319). Baseline samples had increased sCD40L, EGF, and IL-10 in patients with RD compared to pCR (P&amp;lt; 0.05). Baseline samples had decreased FGF2 and IFN gamma in patients with immune related TEAEs compared to those with no immune related TEAEs (P&amp;lt; 0.05). Comparison of Pre- vs Post-treatment revealed that EGF, MIP1 alpha, IL-1 alpha, IL-8, and MDC were increased in patients with pCR compared to those with RD. Comparison of Pre- vs. Post- also revealed increased levels of cytokines (EGF, IL-7, IFN gamma, GM-CSF) in samples in patients with immune related TEAEs (P&amp;lt; 0.05) compared to those patients without immune-related TEAEs. It also revealed that there was an increase in a subset of cytokines (IL-7, IL-4, MCP3, and IL-1 alpha) in patients that presented with serious immune related TEAEs (P&amp;lt; 0.05) compared to those patients without serious immune-related TEAEs. Conclusions There are subsets of circulating inflammatory cytokines that may be associated with treatment emergent adverse events in patients with TNBC treated with Durvalumab concomitant with standard of care chemotherapy. Citation Format: Kim Blenman, Michal Marczyk, Julia Foldi, Vignesh Gunasekharan, Andrea L.M. Silber, Lajos Pusztai. Systemic immune response to a Phase I/II trial of Durvalumab concomitant with neoadjuvant chemotherapy in early stage TNBC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-12.