Dose Cohorts Research Articles

Abstract LB407: Propranolol may enhance long term survivorship in a subset of dogs with hemangiosarcoma when combined with doxorubicin chemotherapy

Abstract Angiosarcomas are rare (fewer than 300 cases each year), highly aggressive sarcomas of blood vessel-forming cells with an unfavorable prognosis. We and others have previously reported that propranolol, a beta adrenergic receptor antagonist commonly used to treat heart disease and anxiety, increased the overall survival of patients with advanced angiosarcoma when used alone or incorporated into chemotherapy regimens. Treatment of angiosarcoma has been hampered by the relative lack of suitable models to analyze molecular responses to treatment. To overcome this hurdle and understand the vulnerability of angiosarcoma to propranolol, we capitalized on the similar morphological and clinical characteristics between human angiosarcoma and canine hemangiosarcoma, which occurs in thousands of dogs each year. The objectives for the PRO-DOX clinical trial were to assess tolerability and clinical benefit of propranolol in dogs with hemangiosarcoma when given as an adjunct to chemotherapy. We conducted a phase I study using a continuous reassessment model with three dose cohorts (0.8, 1.0, and 1.3 mg/kg PO q 8 hrs) in dogs diagnosed with stage 1 or stage 2 splenic hemangiosarcoma. Following splenectomy, propranolol was onboarded using a dose escalation strategy over 12 days prior to the start of doxorubicin (30 mg/m2 intravenously every three weeks, five rounds). Twenty dogs were enrolled and distributed across the dose cohorts based on the study design. One dog in the highest cohort experienced acute hypotension after six months on propranolol, which resolved with dose reduction. Although a statistically significant survival benefit was not seen in this study when compared to historic controls, a subset of dogs (n=8 or 40%) exceeded the expected survival of 4-6 months. Notably, three dogs diagnosed at or below age five survived over two years. Gene expression analysis of tumors obtained from the short-, mid-, and long-term survivors revealed sets of genes associated with immune responses (e.g. lymphocyte activation, positive regulation of T cell activation), antigen processing, cell adhesion, and mitochondrial metabolism in the long-term survivor group. Our findings suggest that age (< 6 years) may predict a favorable outcome, and immune mediated responses differ between the short and long-term survivors. Ongoing experiments seek to define the specific molecular properties and immune responses contributing to these outcomes, with potential implications for human angiosarcoma. Citation Format: Erin B. Dickerson, Jeremy Chacón, Brian D. Husbands, Michael S. Henson, Jaime F. Modiano, Kathleen M. Stuebner, Amber Winter, Sara Pracht, Andrea Chehadeh, Kelly Bergsrud, Caitlin Feiock, Julia Medland, Heather Scavello, Pascale C. Salah, Jennifer Mahoney, Michael O. Childress, David R. Brown, Antonella Borgatti. Propranolol may enhance long term survivorship in a subset of dogs with hemangiosarcoma when combined with doxorubicin chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB407.

Abstract CT193: Phase 1 clinical trial evaluating the safety, tolerability, and immunogenicity of AST-021p, a novel cancer vaccine targeting HSP90-derived epitopes in advanced solid tumor patients (CornerStone-002)

Abstract Background: AST-021p is an "off-the-shelf" therapeutic cancer vaccine composed of two peptides, AST-021p4 and AST-021p5, derived from MHC class II-specific epitopes of Hunam HSP90 protein. Both peptides serve as antigenic determinants for HSP90 and act as a tumor-associated antigen (TAA) inducing activation of type 1 helper T cells (Th1). Th1 cell immunologically elicited by AST-021p secrete cytokines, including IFN-γ, and activate local antigen presenting cells (APC) enhancing cross priming at the tumor site. This immunological activity, through the mechanism of cross priming, sequentially leads to the activation of cytotoxic T cells and epitope spreading. In preclinical studies using the MMTV neu gene overexpressing mouse model, the administration of the HSP90 peptide vaccine, AST-021p, significantly inhibited tumor growth. Based on these scientific rationales, The first-in-human (FIH) study was conducted to evaluate the safety, tolerability, and immunogenicity of AST-021p in advanced solid tumor patients have no treatment option. Methods: Phase 1 study (CornerStone-002, NCT No.: 04864418) was conducted on patients with recurrent or metastatic solid tumors for whom applicable standard treatment options were unavailable (patient enrollment period: June 9, 2021, to June 14, 2023). Four-dose cohorts of AST-021p (Cohort 1: 1.2mg, Cohort 2: 2.4mg, Cohort 3: 3.6mg, Cohort 4: 4.8mg) received three vaccinations at 2-week intervals (Priming immunization) followed by boosting immunization with 4-week interval based on PI's discretion. Enrolling one patient initially in the lowest dose cohort, Cohort 1 (1.2mg), dose escalation occurred sequentially after confirming safety and tolerability. Subsequently, each dose cohort (Cohort 2: 2.4mg, Cohort 3: 3.6mg, Cohort 4: 4.8mg) enrolled six patients each for vaccination. Antigen-specific immune response was assessed by IFNγ ELISPOT using PBMCs from the subjects at baseline, 4 weeks, and 8 weeks. Results: During the study period, a total of 22 patients were enrolled (Cohort 1: 1, Cohort 2: 6, Cohort 3: 8, Cohort 4: 7). The median age of the patients was 66, with a gender distribution of 14 males and 8 females. Among the 22 patients, 20 completed the priming immunization with 3 vaccinations, and 7 of them proceeded with the boosting immunization. A total of 75 adverse events were reported in 21 patients (95.5%). Adverse drug reactions (ADRs) occurred in 15 patients (68.2%), accounting for 92 cases. The most common ADR was injection site reaction (ISR), observed in 15 patients (68.2%), with 35 cases and all reactions were graded as 1 or 2. Serious adverse events (SAEs), including gastrointestinal hemorrhage, vomiting, and aspiration, were observed in 3 patients (13.6%), totaling 3 cases. However, these events were unrelated to AST-021p. Conclusions: This study, as the first-in-human (FIH) administration of the AST-021p, demonstrated safety and tolerability across all four dose groups. Plus, optimal immunogenic dose (OID) and recommended phase 2 dose (RP2D) were confirmed based on AST-021p-specific immunogenicity and safety. Citation Format: Eun Joo Kang, Kyoungmin Lee, In Ho Kim, Ju Won Kim, Jwa Hoon Kim, Soohyeon Lee, Jiwon Lee, Kabsoo Shin, Sejun Park, Joori Kim, Hyun Won Shin, Kyong Hwa Park. Phase 1 clinical trial evaluating the safety, tolerability, and immunogenicity of AST-021p, a novel cancer vaccine targeting HSP90-derived epitopes in advanced solid tumor patients (CornerStone-002) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT193.

Abstract LB236: Metabolically armed CD19 CAR-T cells for safe and effective treatment of relapsed or refractory CD19+ B cell hematological malignancies at extremely low doses

Abstract Background: The undeniable success of CD19 CAR-T cell therapy in managing relapsed or refractory (r/r) B-cell hematological malignancies, such as diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL), underscores its significance. Despite the favorable complete remission (CR) rates of around 50% for r/r DLBCL and up to 90% for r/r B-ALL, a notable challenge persists as more than half of patients experiencing CR after CD19 CAR-T cells treatment encounter relapse within a year, attributed to inadequate CAR-T persistence in both indications. Urgent attention is required to devise innovative strategies to overcome these challenges. Recently, we developed metabolically armed CD19 CAR-T cells expressing IL-10 can enhance OXPHOS metabolism, proliferation, and persistence of CAR-T cells in vivo. Significantly, these IL-10-expressing CAR-T cells trigger stem-like memory responses in various lymphoid organs, leading to robust tumor eradication and durable protection. Motivated by these promising findings, an open-label, single arm, investigator-initiated trial (IIT, ClinicalTrials.gov identifier: NCT05715606, NCT05747157) was conducted to assess the safety and efficacy of newly developed metabolically armed IL-10-expressing CD19 CAR-T (product name: Meta10-19 infusion) for treating patients with r/r DLBCL or r/r B-ALL. Method: From Feb 2023 to Dec 2023, this IIT clinical trial evaluated Meta10-19 infusion in adult patients with r/r DLBCL or r/r B-ALL. The patients were recruited and treated at the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China. Patients in 3 dose cohorts (2.0 × 104, 5.0 × 104, or 1.0 × 105 CAR-T cells/kg, corresponding to 1%, 2.5%, or 5% doses of commercialized CAR-T infusion) underwent lymphodepleting chemotherapy with cyclophosphamide and fludarabine before Meta10-19 infusion. The primary endpoint was the incidence of dose-limiting toxicities. The secondary endpoint was the response and survival. Results: The treatment with Meta10-19 infusion has successfully induced CR in all 12 cases of r/r DLBCL (n=6) or r/r B-ALL (n=6), as evaluated by PET-CT scan, NMR spectroscopy or minimal residual disease assessment of bone marrow. No server cytokine storm syndrome or neurotoxicity was observed. All treated patients achieved CR at 3 months post treatment, with the first patient maintaining continuous remission up to 9 months until now. Notably, these metabolically armed CD19 CAR-T cells demonstrated efficacy even for patients with bulky mass (≥7.5 cm) of DLBCL at extremely low infusion dose (1~5% doses of commercialized CAR-T). Conclusion: Preliminary findings suggest that Meta10-19 infusion exhibits promising breakthrough efficacy and safety profile, and active enrollment is ongoing to validate the initial results. Citation Format: Yugang Guo, Qianwen Xu, Lei Xue, Erling Chen, Chonglin Liu, Min Gao, Youjia Li, Jingjing Ren, Jinping Li, Li Tang, Xingbing Wang. Metabolically armed CD19 CAR-T cells for safe and effective treatment of relapsed or refractory CD19+ B cell hematological malignancies at extremely low doses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB236.

Abstract CT001: Linvoseltamab, a B-cell maturation antigen-targeted T-cell-engaging bispecific antibody, induces deep and durable responses in patients with relapsed or refractory multiple myeloma including difficult-to-treat subgroups

Abstract Background We report pivotal results from the registrational filing data cut-off (DCO) of the 200 mg dose used in the LINKER-MM1 (NCT03761108) clinical trial, testing the safety and efficacy of linvoseltamab (a B-cell maturation antigen × CD3 antibody [Ab]) as treatment for relapsed/refractory multiple myeloma (RRMM). Methods Eligible patients had RRMM that either progressed on/after ≥3 lines of therapy that included a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 Ab or that was ≥double- (Phase 1) or triple- (Phase 2) class (PI/IMiD/anti-CD38 Ab) refractory. Phase 2 patients received intravenous linvoseltamab once a week through week 14, then once every 2 weeks (Q2W). Phase 2 patients achieving ≥very good partial response (VGPR) who have received treatment for ≥24 weeks transitioned to Q4W dosing. Primary endpoint was objective response rate (ORR) per Independent Review Committee (IRC). Secondary endpoints included duration of response (DOR), progression free survival (PFS), overall survival (OS), and safety. Results At DCO of Sep 8, 2023, median duration of follow-up for the 117 patients enrolled into the 200 mg dosing cohorts (phase 1+2) was 11.1 months (interquartile range 2.9-14.1). Median age was 70 years (26% ≥75), 17% were African American, 18% had International Staging System (ISS) stage III disease, 16% had extramedullary (excluding paramedullary) plasmacytomas (EMPs) ≥2 cm, 39% had high-risk cytogenetics, and 82% were ≥triple-class refractory. Linvoseltamab induced high rates of deep responses with an ORR of 71% including ≥complete response (CR) rate of 46%. Among all patients with ≥CR, 39% were documented minimal residual disease negative. These frequent and deep responses were observed across prespecified high-risk subgroups including patients with ISS stage III (ORR 62%; ≥CR 43%), and EMPs (ORR 53%; ≥CR 26%). Kaplan-Meier (KM) estimated median DOR was not reached (NR); estimated probability of ongoing response at 12 months was 78% (95% confidence interval [CI] 65-86). KM estimated PFS and OS were NR; and probability of PFS and OS at 12 months were 69% (95% CI 58-77) and 75% (65-82), respectively. The most common treatment emergent adverse event (TEAE) was cytokine release syndrome (CRS; any grade [Gr] 46%, Gr2 10%, Gr3 1%, Gr≥4 0%), which occurred mostly during step-up dosing of linvoseltamab with a median time to onset of 11 hours. Other common TEAEs were neutropenia (any Gr 41%, Gr 3-4 40%), anemia (39%, 31%), cough (36%, 0%), and diarrhea (35%, 2%). Infections occurred in 73% (Gr 3-4 34%) of patients. The frequency and severity of infections decreased after 6 months coincident with Q4W dosing. Conclusions Linvoseltamab induced high rates of deep and durable responses in patients with RRMM including those in high-risk subgroups. Linvoseltamab is associated with a generally predictable timing of CRS, and the Q4W response adapted schedule in patients with ≥VGPR may provide a substantial benefit for patient convenience and is associated with a reduced infection rate. Citation Format: Sundar Jagannath, Joshua Richter, Madhav V. Dhodapkar, James E. Hoffman, Hans C. Lee, Attaya Suvannasankha, Mansi R. Shah, Suzanne Lentzsch, Jeffrey A. Zonder, Rachid Baz, Joseph J. Maly, Swathi Namburi, Ka Lung Wu, Matthew Pianko, Rebecca Silbermann, Chang-Ki Min, Marie-Christiane Vekemans, Markus Munder, Ja Min Byun, Joaquín Martínez Lopez, Michelle DeVeaux, Dhruti Chokshi, Anita Boyapati, Anasuya Hazra, Karen Rodriguez Lorenc, Glenn S. Kroog, Yariv Houvras, Naresh Bumma. Linvoseltamab, a B-cell maturation antigen-targeted T-cell-engaging bispecific antibody, induces deep and durable responses in patients with relapsed or refractory multiple myeloma including difficult-to-treat subgroups [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT001.

Abstract CT083: A first-in-human phase 1/2a study of a novel anti-PAUF monoclonal antibody PBP1510 in patients with advanced/metastatic pancreatic cancer

Abstract Background Pancreatic Adenocarcinoma Up-regulated Factor (PAUF) is a protein overexpressed in pancreatic cancer but not in non-cancerous tissues and plays an important role in carcinogenesis and metastasis. PBP1510 is a first-in-class, anti-PAUF humanized immunoglobulin G1 monoclonal antibody developed for treatment of pancreatic cancer. PBP1510 demonstrated promising pancreatic cancer growth inhibition efficacies in in vivo patient-derived xenograft studies and is being evaluated in humans for the first time in the ongoing PAUF-I study. Methods PAUF-I (NCT05141149) is an open-label, multi-center, Phase 1/2a study in advanced/metastatic pancreatic cancer patients. Eligible patients must have a tumor that has progressed on standard chemotherapy, with at least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status score of 0 or 1, a life expectancy of ≥ 3 months, and adequate baseline organ function to enroll. PBP1510 is administered as a 90-minute intravenous infusion in 28-day cycles and tumor assessments are performed every 8 weeks from the first dose. Phase 1 uses a 3 + 3 dose-escalation design to assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity of ascending doses of PBP1510 as a single agent or in combination with gemcitabine (Table 1). The observation period for dose-limiting toxicities (DLT) is 28 days. ORR and pre- and post-treatment PAUF levels in tumor tissue will be explored in the analyses. A recommended phase 2 dose (RP2D) will be selected based on PK, safety, and efficacy data from Phase 1. Phase 2a is the dose expansion phase which aims to evaluate the safety, tolerability, PK, immunogenicity, and efficacy of PBP1510 administered at RP2D in combination with gemcitabine. As of January 2024, 6 patients have been enrolled. The 1M cohort (1 mg/kg) was completed without any report of DLT. Dose escalation is in progress and DLT evaluation is ongoing for the 2nd and 3rd patients in the 2M cohort. TABLE 1: NAND Dose escalation and cohorts (Phase 1) Monotherapy Combination Cohort PBP1510 Dose (mg/kg) Gemcitabine Dose (mg/m2) Cohort PBP1510 Dose (mg/kg) Gemcitabine Dose (mg/m2) 1M 1 - 1C 1 1000 2M 3 - 2C 3 1000 3M 6 - 3C 6 1000 4M 10 - 4C 10 1000 5M 15 - 5C 15 1000 Citation Format: Jaime Feliu Batlle, Daniel A. King, Jamie Kim, Sumita Pradhan, Yun-Yong Park, Kedar Diwakar Mandakhalikar, Wei Qi Loh. A first-in-human phase 1/2a study of a novel anti-PAUF monoclonal antibody PBP1510 in patients with advanced/metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT083.

Abstract CT099: NGM707 in combination with pembrolizumab in advanced or metastatic solid tumors: Preliminary results from dose escalation

Abstract BACKGROUND: NGM707-IO-101 (NCT04913337) is a Phase 1/2, dose escalation/expansion study evaluating NGM707, a humanized monoclonal antibody that blocks ILT2 and ILT4 receptors, as monotherapy or in combination with pembrolizumab. Here we report data from the combination part of the study. METHODS: Eligible patients (pts) with advanced/metastatic solid tumors were enrolled into escalating dose cohorts of 200-1800 mg NGM707 combined with 200 mg pembrolizumab, administered Q3W iv. Assessment of safety and tolerability and recommended expansion doses for NGM707 in combination with pembrolizumab were the primary objectives of the study. Secondary and exploratory objectives included assessment of pharmacokinetics/receptor occupancy (RO), immunogenicity, biomarkers, and preliminary antitumor activity per RECIST v1.1. RESULTS: As of 06 Nov 2023, 46 pts have been enrolled in the combination escalation at dose levels up to 1800 mg; 5 pts crossed over from monotherapy. Median age 58.5 yrs [28-81]; ECOG PS 0 (19.6%), 1 (80.4%). Pts had received a median of 3 prior therapies (range 1-6) and all pts had metastatic disease. Overall, 20/45 pts had prior exposure to anti-PD1/anti-PD-L1. Treatment-related adverse events (any grade/grade ≥3) occurred in 41.3%/4.4% of pts. The most common treatment-related adverse events were fatigue (17.4%), diarrhea (6.5%), myalgia (4.3%), arthralgia (4.3%), and nausea (4.3%). No dose-limiting toxicities were observed. A maximum tolerated dose was not reached, and the maximum administered dose was 1800 mg NGM707 in combination with 200 mg pembrolizumab. Peripheral immune cells showed dose-dependent RO, with doses ≥ 200 mg maintaining ILT2 and ILT4 RO for the entire dosing interval. PK of NGM707 was typical for monoclonal antibodies, with a half-life of 12.8 days. Gene expression changes associated with myeloid cell and T cell activation were observed in tumor biopsies post-treatment. Of 37 response-evaluable pts, best overall responses to date are PR (confirmed) in 4 pts, SD in 12 pts, representing a DCR of ~43%. Nine pts had reduced target lesion (TL) size with a maximum reduction of 100%. Out of the 4 patients who had PR, 3 patients were pre-treated with anti-PD1/anti-PD-L1. Two subjects with MSS CRC achieved confirmed PR, one of them with TL reduction that allowed subsequent surgical resection of all gross residual disease and confirmed pathological CR with no active tumor cells and ctDNA below detection. CONCLUSIONS: NGM707 in combination with pembrolizumab appears to be safe and well tolerated at all dose levels. In this advanced and metastatic solid tumor cohort, early efficacy signals have been observed. Preliminary evidence of myeloid cell reprogramming was observed in paired tumor biopsies. Trial enrollment for the expansion part of the study is ongoing and updated data will be presented in the future. Citation Format: Judy S. Wang, Manish R. Sharma, William J. Edenfield, Kartik Sehgal, Do-Youn Oh, Yixing Jiang, Joel Michalski, Jeeyun Lee, Hans Hammers, Li-Yuan Bai, Chih-Hung Hsu, Brenda Dampier, Kefei Zhou, Li Yan, Lisa K. Blum, Joanne Sloan-Lancaster, Daniel D. Kaplan, Dhiraj Abhyankar, Hsiao D. Lieu, Vladimir Hanes, Aung Naing. NGM707 in combination with pembrolizumab in advanced or metastatic solid tumors: Preliminary results from dose escalation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT099.

Abstract CT194: N-myristoylation inhibitor zelenirstat: New mechanistic insights and efficacy signals from a first in human phase I study

Abstract Introduction. Zelenirstat (PCLX-001) is a small molecule inhibitor of N-myristoylation, a process that involves addition of the fatty acid myristate to over 200 proteins by two N-myristoyltransferases (NMT1 and 2). These include Src family kinases and c-Abl. Inhibition of N-myristoylation by zelenirstat leads to the degradation of non-myristoylated proteins and cancer cell death. We conducted a phase I trial to evaluate the safety, tolerability, and maximally tolerated dose (MTD) of zelenirstat in patients with refractory cancer. Methods. Differential mass spectrometry was performed in NMT1 and NMT2 CRISPR/Cas9 KOs or zelenirstat-treated HAP1 cells to identify N-myristoylation-regulated proteins. Fully consented patients with advanced solid malignancies or refractory B-cell lymphomas were administered escalating doses of zelenirstat in 28-day cycles until progression or dose-limiting toxicity (DLT). Results. Proteomic analysis of cells with genetic or pharmacological NMT inhibition was performed to gain insights into NMT substrates and function. In addition to the rapid degradation of SFKs, which disrupts the pro-survival signaling of RTKs, we identified multiple respiratory complex I proteins as the most degraded, including NDUFAF4. NMT1 KO and zelenirstat treatment disrupted complex I leading to oxidative phosphorylation (OXPHOS) inhibition, which is essential for both cancer stem cell survival and metastasis. Continuous once-daily zelenirstat at 20 mg to 210 mg was well tolerated, with no dose-limiting toxicities in 24 patients up to and including 210 mg. Gastrointestinal DLTs were observed in the 280 mg cohort, establishing 210 mg as the MTD. Oral absorption was rapid, and pharmacokinetics were suitable for once daily dosing. Seven patients had stable disease as best response, including pancreatic, ovarian and colon cancer patients; one colon cancer patient with 5 prior lines of therapy continues 210 mg beyond 11 cycles with reduction in carcinoembryonic antigen (CEA) and tumor dimensions. Kaplan-Meier analysis revealed longer progression-free survival (log-rank p=0.033) and overall survival (p=0.026) in the patients treated at 210 mg (n=7) when compared with patients treated in lower dose cohorts (n=17). Conclusion. Zelenirstat has a unique dual impact on growth signaling and OXPHOS. Having previously demonstrated pre-clinical efficacy in hematologic cancers in vitro and in vivo, we now demonstrate the therapeutic potential of zelenirstat in patients with refractory advanced solid malignancies, warranting further clinical evaluation in these indications. Citation Format: Luc Gerard Berthiaume, Erwan Beauchamp, Jay Gamma, Rony Pain, Morris A. Kostiuk, Christopher R. Cromwell, Eman W. Moussa, Olivier Julien, Basil P. Hubbard, John Kuruvilla, Laurie H. Sehn, Jennifer Spratlin, Rahima Jamal, Randeep Sangha, John R. Mackey. N-myristoylation inhibitor zelenirstat: New mechanistic insights and efficacy signals from a first in human phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT194.

Abstract CT173: Preliminary results from a phase I study of IMM0306 in patients with relapsed or refractory CD20-positive B-cell non-Hodgkin's lymphoma

Abstract Background: IMM0306 is a fusion protein of CD20 monoclonal antibody with the CD47 binding domain of SIRPα on both heavy chains. It exerts excellent cancer killing efficacy by activating both macrophages and NK cells via blockade of CD47-SIRPα interaction and FcɣR engagement. Here, we report the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy results of phase I in patients (pts) with relapsed or refractory (R/R) CD20-positive B-cell non-Hodgkin's lymphoma (B-NHL). Methods: Eligible pts with R/R CD20-positive B-NHL were enrolled in this open-label, multicenter phase I/II study (NCT05805943). IMM0306 was administered as monotherapy at escalating doses of 0.04, 0.1, 0.25, 0.5, 0.8, 1.2, 1.6, 2.0 mg/kg intravenously once a week after a 2-week single-dose observation period, until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated in the first 28 days. Safety was evaluated per CTCAE 5.0, PK and PD analysis were also assessed, tumor assessments performed once every 8 weeks by Lugano 2014. Results: As of Nov 21, 2023, 48 pts were enrolled. The median age was 56 years with 30 (62.5%) males. The median prior lines of therapy was 2. All pts received previous anti-CD20 therapy. No DLTs were observed. Recommended phase II dose (RP2D) was determined as 2.0 mg/kg. The most frequent treatment related adverse events (TRAEs) were WBC decreased (66.7%), anemia (64.6%), lymphocyte decreased (58.3%), ANC decreased (47.9%), PLT decreased (45.8%), infusion-related reactions (35.4%). Grade ≥3 TRAEs occurred in 33 (68.8%) pts, the most frequent grade ≥ 3 TRAEs were lymphocyte decreased (56.3%), WBC decreased (18.8%), ANC decreased (18.8%). Eight (16.7%) pts experienced treatment related serious adverse event, including PLT decreased, chest pain and pneumonia. Drug discontinuation due to AEs occurred in 1 pt (G4 PLT decreased occurred at 1.6mg/kg without any bleeding). No AE led to death. IMM0306 exhibited approximate dose-proportional increase in PK exposure from 0.5 to 2.0 mg/kg and no obvious accumulation was observed after repeated dosing. At 1.2 mg/kg, CD47 receptor occupancy on peripheral lymphocytes was saturated, suggesting IMM0306 is well tolerated from perspective of CD47 engagement in high dose cohorts. B-cell counts depleted rapidly at doses ≥ 0.8 mg/kg. Elevated cytokines levels were observed after first dosing of IMM0306, but multiple dosing did not stimulate further cytokine activation. Among 33 pts who received active doses ≥ 0.8 mg/kg, 5 CR (4 follicular lymphoma [FL], 1 marginal zone lymphoma [MZL]), 5 PR (3 FL, 1 MZL, 1 diffuse large B cell lymphoma) and 11 SD were seen. Among 17 FL pts, 7 (41%) responded including 4 CR and 3 PR; among 6 MZL pts, 2 (33.3%) responded including 1 CR and 1 PR. Conclusions: IMM0306 was well-tolerated and with a robust preliminary anti-tumor activity especially in pts with R/R FL and MZL. The phase II study is ongoing. Citation Format: Yuankai Shi, Jianliang Yang, Yongping Song, Keshu Zhou, Zhiming Li, Mingzhi Zhang, Hongmei Jing, Zhen Wang, Li Yu, Qiying Lu, Frank Gan, Wenzhi Tian. Preliminary results from a phase I study of IMM0306 in patients with relapsed or refractory CD20-positive B-cell non-Hodgkin's lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT173.

Abstract CT067: The anti-BCMA antibody-drug conjugate HDP-101 with a novel amanitin payload shows promising initial first in human results in relapsed multiple myeloma

Abstract Background: HDP-101 is a new antibody drug conjugatetargeting B-cell maturation antigen (BCMA) that carries a synthetic amanitin payload with a new mode of action. Amanitin inhibits RNA polymerase II, effectively stopping transcription and inducing apoptosis in tumor cells, regardless of their proliferation status. It's shown cytotoxicity in vitro against BCMA-positive myeloma cell lines and non-proliferating primary CD138+ cells from refractory myeloma patients withefficacy even in cells with low BCMA density. Clinical Study: HDP-101-01 is a first-in-human, open label, non-randomized, multicenter, phase 1/2a trial in patients with multiple myeloma whose disease has progressed or is refractory, aiming to determine the Maximum Tolerated Dose and/or the Recommended phase 2 Dose in Phase 1. Dose escalation is guided by an adaptive Bayesian logistic regression model with overdose control. The primary objective in phase 2 is to assess anti-tumor activity. Study Progress: As of November 2023, 18 patients (7 females, 11 males) were enrolled in 5 consecutive dose cohorts of 20, 30, 60, 80, and 100µg/kg. Patients had a median age of 70 years (48-82), were heavily pre-treated and multidrug-resistant, and had a median of 6,5 prior treatments (2-15). Study Results: Preliminary data shows that pharmacokinetics of HDP-101 aligns with expectations, and exposure to HDP-101 is dose proportional. Free payload was not detected in serum at a limit of detection of 30 ng/mL, and no anti-drug antibodiesor immunogenic reactions were noted. 17 of 18 patients were evaluable for dose limiting toxicities (DLT) in the 5 treatment cohorts. Initial cohorts were well tolerated, without any DLTs, including no signs of hepatic and renal toxicities, infusions reactions, or ocular disorders. All patients in Cohort 5 had Grade 1-4 transient thrombocytopeniawith platelet reductions starting on Cycle 1/Day 2 (C1/D2), a nadir on C1D5, and full recovery by C1D15 at the latest without any clinical sequelae or interventions. Notably, subsequent dosing with HDP-101 did not produce similarly deep episodes of thrombocytopenia, supporting the possibility that this event is not due to a direct cytotoxic effect against megakaryocytes. After Cohort 5, mitigation strategies are being considered and further dose and schedule optimization is planned with fractionated dosing and/or with premedication. Efficacy: Cohort3 has a patient with stable disease (SD) after 15 cycles. Cohort 5 has 4 ongoing patients with promising results after 3-4 cycles: 2 patients achieved PR, and 2 have SD. Updated data will be presented at the AACR2024 meeting. Citation Format: Jonathan Kaufman, Marc Raab, Shambavi Richard, Sebastian Grosicki, István Takács, András Strassz, Andreas Pahl, Michael Kulke, Thorsten Michael, Anette Last, Hajnalka Szabóki, Garrit Jentsch, Oliver Schönborn-Kellenberger, Robert Orlowski. The anti-BCMA antibody-drug conjugate HDP-101 with a novel amanitin payload shows promising initial first in human results in relapsed multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT067.

Abstract CT113: A dose-exploring, randomized, open-label, Phase I study for toripalimab subcutaneous injection in patients with advanced nasopharyngeal carcinoma

Abstract Background Toripalimab, a humanized IgG4K monoclonal antibody specific for PD-1, in combination with gemcitabine and cisplatin (GP) has been approved as a first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) by the US FDA in October 2023. This is the first-in-human clinical trial (NCT05751486) to investigate the pharmacokinetics of toripalimab subcutaneous (SC) formulation in RM-NPC and determine the appropriate subcutaneous administration regimen for subsequent clinical trials. Methods Patients with histologically confirmed RM-NPC and without previously systemic therapy for RM disease were enrolled. Eligible patients were assigned to receive toripalimab SC 240 mg every 3 weeks (Q3W), 360 mg Q3W or 480 mg Q6W, in combination with GP for up to 6 cycles, followed by toripalimab SC monotherapy until disease progression, intolerable toxicity, or completion of 2 years of treatment. Tumor response was assessed per RECIST v1.1. The primary endpoint was pharmacokinetic (PK) profile. Secondary endpoints included safety, efficacy, and immunogenicity. Results From November 24, 2022 to November 20, 2023, a total of 38 patients (240 mg cohort, n=12; 360 mg cohort, n=13; 480 mg cohort, n=13) were enrolled, the median follow-up time was 6.8 months. The median age was 49 years, and 28 (73.7%) patients were males. PK analysis showed that in the first cycle, the exposure (AUC0-21days and Ctrough) of toripalimab 360 mg Q3W SC regimen was comparable to that of 240 mg Q3W intravenous (IV) regimen (table 1). Objective Response Rates (ORR) in 240 mg, 360 mg and 480 mg cohorts were 100%, 92.3% and 92.3%, respectively. By November 20, 2023, 71.1% (27/38) patients have ongoing responses. No new safety signal was identified. The incidence of Grade ≥3 adverse events (AEs) was 76.3% with no fatal AEs. The incidence of investigator-determined immune-related AEs was 36.8% with 1 (2.6%) Grade ≥3. Conclusions Toripalimab SC formulation showed similar safety and clinical efficacy with toripalimab IV formulation when combined with GP in patients with RM-NPC. The exposure of toripalimab 360 mg Q3W SC was comparable to that of 240 mg Q3W IV. Toripalimab SC formulation is planned for phase III clinical development. Table 1. PK parameters of each dose cohort. Parameters JS001sc Cohorts (N = 36) IV ref-model based 240 mg SC Q3W, n=12 480 mg SC Q6W, n=12 360 mg SC Q3W, n=12 240 mg IV Q3W, n=1014 Cycle 1 Ctrough, μg/mL GM (% CV) 10.2 (57.1) 8.4 (43.5) 18.6 (50.1) 10.2 (61.8) Cycle 1 AUC (0-Xd), μg•d/mL GM (% CV) 8376 (0-21 d) (39.3) 25316 (0-42 d) (35.4) 14229 (0-21 d) (58.2) 13386 (27.0) Bioavailability 62.6% (25.3%-100.0%) Citation Format: Hai-Qiang Mai, Ya-Qian Han, Guo-Wu Wu, Kun-Yu Yang, Chuan-Ben Chen, Mo Wang, Xian-Ming Luo, Shuang-Hui Wei, Xi Tan, Peng Xue, Rui-Hua Xu. A dose-exploring, randomized, open-label, Phase I study for toripalimab subcutaneous injection in patients with advanced nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT113.

Abstract CT060: Phase 1 study of azacitidine in combination with evorpacept for higher-risk myelodysplastic syndrome (MDS)

Abstract Background:Evorpacept (EVO) is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to enhance the activity of other anti-neoplastic therapies with minimal additional toxicity. Here, we present final phase 1 results from the ASPEN-02 study. Methods:ASPEN-02 is an open-label, multicenter phase 1/2 study designed to evaluate the safety and activity of EVO in combination with azacitidine (AZA) in subjects with newly diagnosed (ND) higher-risk (HR) or relapsed/refractory (R/R) MDS. Adult subjects with ND HR (IPSS-R > 3.5) or R/R MDS were enrolled into phase 1 cohorts receiving escalating doses of EVO (20 mg/kg Q2W, 30 mg/kg Q2W, and 60 mg/kg Q4W) combined with AZA (75 mg/m2 IV/SC x 7d) in a 28-day treatment cycle. A phase 1 dose expansion portion enrolled adults with ND HR MDS into two dosing cohorts determined to be safe at EVO 40 mg/kg Q4W and 60 mg/kg Q4W. This clinical trial is registered at clinicaltrials.gov: NCT04417517. Results: As of June 2, 2023, 65 subjects were treated in the phase 1 portion, including 13 subjects with R/R MDS [EVO doses of 20 mg/kg Q2W (n=1) or 60 mg/kg Q4W (n=12)], and 52 subjects with ND HR MDS [EVO doses of 40 mg/kg Q4W (n=23) and 60 mg/kg Q4W (n=29)]. Of 52 ND HRMDS subjects, 9 (17.3%) had therapy-related MDS. Multi-hit TP53 mutations were present at baseline in 2/13 (15.4%) R/R MDS and 3/52 (5.8%) ND HR MDS patients. 13/13 (100%) R/R MDS patients had received prior hypomethylating agents or cytotoxic chemotherapy. Median age was 70 (range 24 - 88) years, and baseline ECOG scores were 0 (n=27, 41.5%), 1 (n=31, 47.7%), or 2 (n=7, 10.8%). No dose-limiting toxicity was observed, and a maximum tolerated dose (MTD) was not reached. Treatment-emergent AEs and treatment-related AEs for EVO were reported in 65/65 (100%) and 35/65 (53.8%) subjects respectively; discontinuation, however, was infrequent. Seven (10.8%) subjects experienced a serious adverse event related to EVO. There were no EVO-related deaths on study. Preliminary PK indicated dose-proportional pharmacokinetics consistent with prior studies. Objective response [complete remission (CR), partial remission (PR), marrow CR (mCR), hematologic improvement (HI)], per modified International Working Group 2006 criteria, was observed in 19/52 (36.5%) ND HR [CR=8, mCR=9, HI=2] and 2/13 (15.4%) R/R [mCR=2] MDS subjects. Conclusion:The myeloid checkpoint inhibitor EVO was well tolerated in combination with AZA with an initial safety and activity profile comparable to that of historical AZA monotherapy. Additional updated data will be provided at the time of presentation. Citation Format: Guillermo Garcia-Manero, Bart L. Scott, Ashwin Kishtagari, Srinivasa R. Sanikommu, Aref Al-Kali, Je-Hwan Lee, Juan M. Bergua Burgues, Maria Diez-Campelo, Harry P. Erba, Carmen Garcia-Hernandez, Guillermo Sanz Santillana, Casey O'Connell, Jun-Ho Jang, Dong-Yeop Shin, Hamid Sayar, Mayank Rao, Richard S. Schwartz, Grace An, Feng Jin, Alison J. Forgie, Athanasios C. Tsiatis, Jessica K. Altman. Phase 1 study of azacitidine in combination with evorpacept for higher-risk myelodysplastic syndrome (MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT060.

Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia

Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or β (PCCA or PCCB) subunits that leads to an accumulation of toxic metabolites and to recurrent, life-threatening metabolic decompensation events. Here we report interim analyses of a first-in-human, phase 1/2, open-label, dose-optimization study and an extension study evaluating the safety and efficacy of mRNA-3927, a dual mRNA therapy encoding PCCA and PCCB. As of 31 May 2023, 16 participants were enrolled across 5 dose cohorts. Twelve of the 16 participants completed the dose-optimization study and enrolled in the extension study. A total of 346 intravenous doses of mRNA-3927 were administered over a total of 15.69 person-years of treatment. No dose-limiting toxicities occurred. Treatment-emergent adverse events were reported in 15 out of the 16 (93.8%) participants. Preliminary analysis suggests an increase in the exposure to mRNA-3927 with dose escalation, and a 70% reduction in the risk of metabolic decompensation events among 8 participants who reported them in the 12-month pretreatment period.

A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas.

High-grade gliomas (HGG) carry a poor prognosis, with glioblastoma accounting for almost 50% of primary brain malignancies in the elderly. Unfortunately, despite the use of multiple treatment modalities, the prognosis remains poor in this population. Our preclinical studies suggest that the presence of aromatase expression, encoded by CYP19A1, is significantly upregulated in HGGs. Remarkably, we find that letrozole (LTZ), an FDA-approved aromatase inhibitor, has marked activity against HGGs. We conducted a phase 0/I single-center clinical trial (NCT03122197) to assess the tumoral availability, pharmacokinetics (PK), safety, and tolerability of LTZ in recurrent patients with HGG. Planned dose cohorts included 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and postsurgery or biopsy. Tumor samples were assayed for LTZ content and relevant biomarkers. The recommended phase 2 dose (R2PD) was determined as the dose that resulted in predicted steady-state tumoral extracellular fluid (ECF; Css,ecf) >2 μmol/L and did not result in ≥33% dose-limiting adverse events (AE) assessed using CTCAE v5.0. Twenty-one patients were enrolled. Common LTZ-related AEs included fatigue, nausea, musculoskeletal, anxiety, and dysphoric mood. No DLTs were observed. The 15 mg dose achieved a Css,ecf of 3.6 ± 0.59 μmol/L. LTZ caused dose-dependent inhibition of estradiol synthesis and modulated DNA damage pathways in tumor tissues as evident using RNA-sequencing analysis. On the basis of safety, brain tumoral PK, and mechanistic data, 15 mg daily is identified as the RP2D for future trials.

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)

Purpose5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU.Patients and methodsNUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity.ResultsFifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival.ConclusionNUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies.Trial registrationClinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240.

A Phase I Trial of Enzalutamide Plus Selective Glucocorticoid Receptor Modulator Relacorilant in Patients with Metastatic Castration-Resistant Prostate Cancer.

The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC). This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity. Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response. This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.

Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study

Frequent anti-vascular endothelial growth factor A (VEGF-A) injections reduce the risk of rapid and severe vision loss in patients with neovascular age-related macular degeneration (nAMD); however, due to undertreatment, many patients lose vision over time. New treatments that provide sustained suppression of VEGF-A are needed. RGX-314 (currently known as ABBV-RGX-314) is an adeno-associated virus serotype 8 vector that expresses an anti-VEGF-A antigen-binding fragment, which provides potential for continuous VEGF-A suppression after a single subretinal injection. We report results on the safety and efficacy of subretinal injection of RGX-314 in patients with nAMD. For this open-label, multiple-cohort, multicentre, phase 1/2a, dose-escalation study conducted at eight sites in the USA, we enrolled participants with nAMD aged 50-89 years who had previously been treated with anti-VEGF injections into five cohorts (with five different doses of RGX-314). To be eligible, participants had to have macular neovascularisation secondary to nAMD with subretinal or intraretinal fluid in the centre subfield, be pseudophakic (after cataract removal), and have a best-corrected visual acuity (BCVA) in the study eye between 20/63 and 20/400 for the first participant in each cohort and between 20/40 and 20/400 for others. Subretinal injection of RGX-314 was done without a pre-bleb by a wet-laboratory-trained vitreoretinal surgeon. Cohort 1 received 3 × 109 genome copies per eye, cohort 2 received 1 × 1010, and cohort 3 received 6 × 1010. Two additional dose cohorts (cohort 4: 1·6 × 1011; cohort 5: 2·5 × 1011) were added. Participants were seen 1 day and 1 week after administration of RGX-314, and then monthly for 2 years (up to week 106). The primary outcome was safety of RGX-314 delivered by subretinal injection up to week 26. This analysis includes all 42 patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT03066258. Between May 12, 2017, and May 21, 2019, we screened 110 patients for eligibility and enrolled 68. 42 participants demonstrated the required anatomic response to intravitreal ranibizumab and then received a single RGX-314 injection (dose range 3 × 109 to 2·5 × 1011 genome copies per eye) and were followed up for 2 years. There were 20 serious adverse events in 13 participants, of which one was possibly related to RGX-314: pigmentary changes in the macula with severe vision reduction 12 months after injection of RGX-314 at a dose of 2·5 × 1011 genome copies per eye. Asymptomatic pigmentary changes were seen in the inferior retinal periphery several months after subretinal injection of RGX-314 most commonly at doses of 6 × 1010 genome copies per eye or higher. There were no clinically determined immune responses or inflammation beyond that expected following routine vitrectomy. Doses of 6 × 1010 genome copies or higher resulted in sustained concentrations of RGX-314 protein in aqueous humour and stable or improved BCVA and central retinal thickness with few or no supplemental anti-VEGF-A injections in most participants. Subretinal delivery of RGX-314 was generally well tolerated with no clinically recognised immune responses. RGX-314 gene therapy provides a novel approach for sustained VEGF-A suppression in patients with nAMD that has potential to control exudation, maintain vision, and reduce treatment burden after a single administration. Results from this study informed the pivotal programme to evaluate RGX-314 in patients with nAMD. RegenxBio.

A population pharmacokinetic model using allometric scaling for baricitinib in patients with juvenile idiopathic arthritis.

Baricitinib is approved for the treatment of rheumatoid arthritis (RA) in more than 70 countries, and juvenile idiopathic arthritis (JIA) in the European Union. Population pharmacokinetic (PK) models were developed in a phase 3 trial to characterize PK in pediatric patients with JIA and identify weight-based dosing regimens. The phase 3, randomized, double-blind, placebo-controlled withdrawal, efficacy and safety trial, JUVE-BASIS, enrolled patients (aged 2 to <18 years) with polyarticular course JIA. During a safety/PK period, baricitinib concentration data from age-based dose cohorts were compared to concentrations from adult patients receiving 4-mg QD. PK data were used to develop a population PK model with allometric scaling to determine a weight-based posology in pediatric patients with JIA that matched the adult 4-mg exposure. Baricitinib plasma concentrations from 217 pediatric patients were used to characterize PK. Based on the adult model, pediatric PK was best described using a 2-compartment model with allometric scaling on clearance and volume of distribution and renal function (estimated with glomerular filtration rate [GFR], a known covariate affecting PK of baricitinib) on clearance. The PK modeling suggested the optimal dosing regimen based on weight for pediatric patients as: 2-mg QD for patients 10 to <30 kg and 4-mg QD for patients ≥30 kg. The use of a population PK model of baricitinib treatment in adult patients with RA, with the addition of allometric scaling for weight on clearance and volume terms, was useful to predict exposures and identify weight-based dosing in pediatric patients with JIA.

Abstract 6503: D3S-001, a second-generation GDP-bound KRAS G12C inhibitor, overcomes nucleotide cycling and demonstrates robust preclinical and clinical activities

Abstract First-generation KRAS G12C inhibitors [G12Ci(s)], such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses. One potential explanation for their modest clinical activity is the dynamic “cycling” of KRAS between its GDP- and GTP-bound states, raising controversy whether targeting the GDP-bound form can fully block this oncogenic driver. We herein report D3S-001, a second-generation GDP-bound G12Ci with faster target engagement (TE) kinetics, depletes cellular active KRAS G12C at sub-nanomolar concentrations, overcomes nucleotide cycling, and demonstrates durable anti-tumor activities preclinically and in a phase 1 clinical trial (NCT05410145). Covalent efficiency and TE kinetics were measured by SPR, LC-MS and ELISA. Anti-tumor efficacy was assessed in cell line-derived xenograft (CDX) and patient-derived xenograft or organoid (PDX or PDO) models. Activity in brain metastatic tumors and tumors with acquired resistance to sotorasib was investigated. Preclinically, D3S-001 exhibited exceptionally high covalent efficiency with a kinact/KI of 1.43 × 106 M−1s−1, the highest among all reported G12Ci(s) to date and a 20- to 70-fold improvement over adagrasib and sotorasib, respectively. In whole cells, D3S-001 depleted GTP-bound active KRAS G12C with an inactivation t1/2 of 5.8 minutes, allowing &amp;gt;95% TE (5x t1/2) in 30 minutes which is within the time required for epithelial growth factor (EGF) to induce KRAS GDP to GTP transition. By contrast, sotorasib and adagrasib required 3.7 and 2.8 hours, respectively, to reach 95% TE. In the presence of EGF, the ability of sotorasib and adagrasib to block KRAS was compromised by over 55%, whereas TE kinetics of D3S-001 was nearly unaffected, a unique feature differentiating D3S-001 from earlier GDP-bound G12Ci(s). The covalent efficiency of D3S-001 correlated with robust anti-tumor activity at sub-nanomolar concentrations and durable tumor regressions in CDX and PDX/PDO models of different cancer types. In a sotorasib-resistant PDX model, D3S-001 exhibited robust efficacy of tumor regression, while sotorasib and adagrasib showed no effect. Treatment with D3S-001 also resulted in sustained intracranial tumor remission in brain metastasis models. In the first-in-human trial of D3S-001, durable RECIST responses in patients were observed across all dose cohorts from 50 mg to 900 mg QD. Durable intracranial activity was also observed. Response rate and duration are reported in a companion clinical trial abstract submitted to this AACR meeting. In conclusion, D3S-001 is a second-generation GDP-bound KRAS G12Ci that overcomes GDP-to-GTP cycling. Its high covalent efficiency and rapid TE kinetics correlated with robust anti-tumor activity preclinically and translated into promising clinical activity with a high response rate and durable responses in a phase 1 trial. Citation Format: Jing Zhang, Sun Min Lim, Mi Ra Yu, Cheng Chen, Jia Wang, Wenqian Wang, Haopeng Rui, Jingtao Lu, Shun Lu, Tony Mok, Zhi Jian Chen, Byoung Chul Cho. D3S-001, a second-generation GDP-bound KRAS G12C inhibitor, overcomes nucleotide cycling and demonstrates robust preclinical and clinical activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6503.

Abstract 3636: Myeloid cell rebound associated with GD2-CAR-T cell therapy in solid tumor patients

Abstract GD2 is a validated cancer immunotherapy target with highly restricted normal tissue expression. Promising activity of GD2-CAR-T cell therapy in diffuse midline glioma and neuroblastoma has promoted interest in this therapy. We initiated three phase 1 clinical trials of escalating doses of intravenously administered autologous GD2-CAR-T cells in patients with advanced GD2-positive solid tumors. Emerging evidence suggests that CAR-T cells may increase circulating myeloid derived suppressor cells (MDSCs) and that this event may be mediated and/or triggered by CAR-T cell-derived cytokines and chemokines. These findings may help to explain the limited persistence of CAR-T cell therapy in solid tumor patients. Hence, we sought evidence of MDSC generation and secretion of relevant cytokines and chemokines in our clinical trial patients. The CARPETS trial (www.anzctr.org.au: ACTRN12620000622909) recently closed to recruitment after enrolling 12 patients (7 melanoma, 4 colorectal cancer, and 1 sarcoma). No significant adverse events were attributable to CAR-T cell therapy. We opened two other GD2-CAR-T cell therapy trials in 2023: LEVI’S-CATCH (ACTRN12622000675729) in patients with diffuse midline glioma at Sydney Children’s Hospital and KARPOS (ACTRN12622001514796) in adult patients with recurrent glioblastoma at Royal Adelaide Hospital. To date, 3 patients have enrolled to LEVI’S-CATCH with the first patient clearing the dose limiting (DLT) evaluation period. Three patients completed enrolment to the first dose cohort of KARPOS without DLTs. In all CARPETS patients, CAR-T cell expansion, which was measured by by DNA quantitative PCR and flow cytometry, peaked during the 6-week post-CAR-T infusion DLT evaluation period. In 6 CARPETS patients for whom peripheral blood samples were available, we found by flow cytometry, newly formed or increased size of pre-existing subpopulations of non-classical monocytes and/or MDSCs of mononuclear and/or polymorphonuclear class, which peaked at or after the time of peak CAR-T cell expansion. Typically, serum levels of inflammatory cytokines and chemokines such as TNF, IL-6, IL-8, CCL2, GM-CSF, and CXCL10, were detected only after the CAR-T cell infusion with variable patterns of the timing and concentration of analyte observed among the 12 patients. At the time of writing, blood samples from the first KARPOS patient showed CAR-T cell expansion and the subsequent increases in circulating myeloid derived suppressor cells and inflammatory cytokines. We expect that full data sets for these parameters will be presented for current and future enrolled patients to both studies. To improve CAR-T cell persistence in solid tumor patients, these data indicate the need for new therapeutic strategies to mitigate effects of CAR-T cell induced myeloid cells with antitumor activity. Citation Format: Michael P. Brown, Tessa Gargett, Nga T. Truong, Orazio Vittorio, David S. Ziegler. Myeloid cell rebound associated with GD2-CAR-T cell therapy in solid tumor patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3636.

Abstract 7274: Optimization of intermittent dosing strategies of KRAS G12C inhibitors in preclinical lung cancer model

Abstract Cysteine-binding targeted drugs AMG-510 and MRTX-849 provide a new therapeutic approach for advanced KRASG12C mutant cancers. However, clinical response has been limited. Responders eventually develop adaptive resistance by gaining additional MAPK pathway mutations, resulting in limited therapeutic benefit. High-dose pulsatile treatment with MAPK pathway inhibitors has been proposed as an alternative strategy to alleviate adaptive resistance while maintaining tumor control. The sensitivity of tumor cells to pan-inhibitors of the MAPK pathway, crucial for proliferation, creates a therapeutic opportunity window for immune cells to restore their function during an intermittent regimen. Congruently, we have previously shown that intermittent pan-MAPK pathway inhibitor treatment delays drug resistance, supports T cell activation, and enhances tumor delay when combined with immunotherapy. In this study, we investigated the effects of continuous and pulsatile KRASG12C inhibition on tumor and immune cells in order to design combinatorial strategies with immune-modulating agents that overcome drug resistance. Our data suggest that a weekly single high-dose regimen of AMG-510 is less effective at achieving tumor control in preclinical mouse models of KRAS mutant lung cancer compared to daily treatments. However, supplementing this pulsatile regimen with lower maintenance doses markedly slows the growth of LLC KRASG12C lung cancer. Flow cytometry analysis revealed that high-dose pulse regimen enhances T cell activation, evidenced by increased expression of TCF-1, Ki67, PD-1, and GITR, along with lower expression of co-inhibitory molecules Lag-3 and Tim-3, 3 days after treatment. In vitro, AMG-510 also improves the antigen presentation of OVA-expressing LLC-KML lung cancer cells via MHC class I and, to a lesser extent, MHC class II. Furthermore, we found that while combinatorial therapy with PD-1 blockade alone does not significantly impact tumor control, the combination with CTLA-4 blockade shows efficacy across pulsatile and continuous AMG-510 dosing cohorts. Overall, our findings suggest that the utilization of intermittent dosing regimens for selective KRASG12C inhibitors is a promising approach for improving clinical responses in lung cancers with KRAS mutations. Future experiments will aim to delineate MAPK pathway behavior in vivo and in vitro under pulsatile and continuous treatment, assess immunogenicity, and further characterize immune changes in the different treatment regimens, with the goal of designing more efficient cancer therapies utilizing selective KRAS inhibitors. Citation Format: Valeria Estrada Navarro, Vincent Panneton, Lauren Dong, Hyejin Choi, Divya Venkatesh, Rachana Maniyar, Isabell Schulze, Jedd D. Wolchok, Taha Merghoub. Optimization of intermittent dosing strategies of KRAS G12C inhibitors in preclinical lung cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7274.