tbuckley/cabot-search huggingface dataset:
YL202/BNT326, a HER3-targeted ADC, in patients with locally advanced or metastatic non-small cell lung cancer and breast cancer: Preliminary results from a first-in-human phase I trial.
Authors: Ying Cheng, Xiaochen Zhang, Jian Liu, Zhangzhou Huang, Dongqing Lv, Yiping Zhang, Xiaojia Wang, Arvind Chaudhry, Harshad Amin, Senthil Damodaran, Shiven B. Patel, Hadeel Assad, Arielle Shebay Lee, Hui Zhao, Jinyun Bai, Tongtong Xue, Steve Chin
Journal: Journal of Clinical Oncology (2024)

3034 Background: YL202/BNT326 is a novel ADC consisting of an anti-HER3 IgG1 monoclonal antibody linked to 8 molecules of YL0010014, a novel topoisomerase I inhibitor, via a tripeptide linker. We report preliminary safety and efficacy results from a phase I trial of YL202/BNT326. Methods: This multinational trial is recruiting patients (pts) with locally advanced/metastatic non-small cell lung cancer (NSCLC) with an EGFR-activating mutation who were previously treated with 3rd generation TKI and platinum-based chemotherapy, and pts with unresectable, locally advanced or metastatic, HR-positive and HER2-negative (IHC 0,1+,2+/ISH-) breast cancer (BC) who were previously treated with CDK4/6 inhibitor and at least one line of chemotherapy. YL202/BNT326 was given at 6 dose levels (DLs, Q3W, iv) in a BOIN dose escalation (D-ESC) scheme, followed by cohort backfill(BF) at selected doses. Primary endpoints are safety and tolerability (dose-limiting toxicities [DLTs] and adverse events [AEs]). Secondary endpoints include pharmacokinetics [PK] and efficacy per RECIST v1.1(ORR, DCR, BOR). Results: At data cutoff (4 Feb 2024), 52 pts were enrolled in D-ESC and BF (39 NSCLC, 13 BC). One DLT (grade 3 febrile neutropenia) occurred during D-ESC at the highest dose. Most common TRAEs (&gt;20%, all grade / ≥ G3) were anemia (71%/20%), white blood cell count decreased (67%/31%), neutrophil count decreased (63%/29%), nausea (52%/0%), decreased appetite (42%/4%), lymphocyte count decreased (37%/23%), platelet count decreased (37%/10%), vomiting (37%/0%), dry mouth (25%/0%), fatigue (25%/0%), stomatitis (23%/2%), alopecia (21%/0%). Interstitial pneumonia occurred in 1 (2%) pt after COVID-19 infection. PK exposure was increased through dose escalation, with low systemic exposure of payload and no accumulation of YL202/BTN326 upon repeated administration. In 46 pts with at least 1 tumor assessment were evaluable for efficacy. Of the non-evaluable pts, 5 are on treatment pending first tumor assessment and 1 discontinued treatment prior to first assessment. In DL3 to DL5 dose range, ORR was 41.0% (95%CI, 25.6, 57.9), DCR was 94.9% (95%CI, 82.7, 99.4) across all tumor types; and the ORR in BC pts was 54.5% (95%CI, 23.4, 83.3), DCR was 100% (95%CI, 71.5, 100.0). Conclusions: YL202/BNT326 demonstrated encouraging efficacy in heavily pretreated locally advanced/ metastatic NSCLC and BC. The safety profile showed adequate safety and tolerability. Clinical trial information: NCT05653752 . [Table: see text]
A first-in-human phase I study of ATG-031, anti-CD24 antibody, in patients with advanced solid tumors or B-cell non-Hodgkin lymphomas (PERFORM).
Authors: Siqing Fu, Sarina A. Piha-Paul, Shivani Singh, Jing Peng, Bridget P. Keenan, Jay M. Mei, Kevin Lynch, Ling Li, Ming Song, Xiaojing (Amily) Zhang
Journal: Journal of Clinical Oncology (2024)

TPS2691 Background: ATG-031 is a first-in-class humanized cluster of differentiation 24 (CD24) antibody. By disrupting the interaction between CD24, a ‘do not eat me’ signal on cancer cells, and the inhibitory receptor Siglec-10 on tumor-associated macrophages (TAMs), it enhances macrophage-mediated phagocytosis of cancer cells and promotes cytotoxic T cell function in the tumor microenvironment. ATG-031 also triggers antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) towards target tumor cells through its immunoglobulin gamma 1 (IgG1) Fc-dependent effects. Preclinical studies indicated that ATG-031-induced phagocytosis transforms macrophages from a tumor-tolerant M2 phenotype to an antitumor M1 phenotype, significantly inhibiting tumor growth both as monotherapy and synergistically with immune checkpoint inhibitors (ICI) and/or chemotherapies in mouse models. Methods: ATG-031 is undergoing evaluation for safety and preliminary antitumor efficacy in a Phase I, multi-center, open-label clinical study, PERFORM (NCT04986865), in patients with advanced solid tumors or B-cell non-Hodgkin’s lymphoma. The study includes a dose escalation phase and a dose expansion phase. The dose escalation phase enrolls patients with advanced solid tumors (preferred tumor types: lung cancer, breast cancer, ovarian cancer, urothelial cancer, and liver cancer) using a Bayesian Optimal Interval (BOIN) design with 3 to 9 patients at each dose level. A priming dose, defined as an initial lower dose followed by escalation to the full treatment dose, will be applied if Grade ≥2 cytokine release syndrome (CRS) is observed during the dose-limiting toxicity (DLT) period. The dose expansion phase will enroll patients with specific tumor types and will randomize patients into two or more dose levels to determine the recommended Phase II dose (RP2D). The PERFORM study explores an intravenous dose of ATG-031 once every 21 days (1 cycle) to assess DLT during the first two treatment cycles in dose escalation. Key inclusion criteria include histological or cytological confirmation of a solid tumor that has relapsed or has been refractory to standard therapy, at least one measurable lesion per RECIST, and an ECOG performance status of 0 to 1. The study excludes patients with CNS malignancies and those who have experienced Grade ≥3 immune-related adverse events (irAEs) or irAEs leading to prior immunotherapy discontinuation. As of January 2024, 2 sites in the United States have initiated the study, and 4 patients have received ATG-031 treatment at 0.03mg/kg (dose level 1). Clinical trial information: NCT04986865 .
Phase I/II trial of LAVA-1207, a novel bispecific gamma-delta T-cell engager alone, or with low dose IL-2 or pembrolizumab, in metastatic castration resistant prostate cancer (mCRPC).
Authors: Niven Mehra, Jens Voortman, David R Wise, Emiliano Calvo, Josep M. Piulats, Enrique Gonzalez-Billalabeitia, Ignacio Ortego, Umang Swami, Joel Picus, Meghan Karlik, Teeru Bihani, Jurjen Ruben, Sonia Macia, Hans J. van der Vliet, Marya F. Chaney, Debbie Robbrecht
Journal: Journal of Clinical Oncology (2024)

TPS2672 Background: LAVA-1207 is a humanized bispecific antibody that binds with high affinity to the Vδ2 chain of Vγ9Vδ2-T cells and to prostate-specific membrane antigen (PSMA). It comprises a heterodimer of two fusion proteins, each consisting of a VHH linked to a human IgG1 Fc domain. Preclinical evidence demonstrates that, upon binding both targets, LAVA-1207 leads to potent Vγ9Vδ2-T cell degranulation and cytolytic activity against PSMA-expressing prostate cancer cells. IL-2 is an immune modulator which has been shown to support expansion of activated Vγ9Vδ2-T cells. PD-1 is an inhibitory immune checkpoint receptor that can dampen (Vγ9Vδ2-) T cell reactivity, suggesting that pembrolizumab could potentiate the effect of LAVA-1207. Methods: This trial is a phase 1/2a open label study with a 3+3 design in patients with refractory mCRPC to assess the safety of LAVA-1207 alone or with low dose IL-2 or with pembrolizumab, and to determine the recommended Phase 2a dose (RP2D). Secondary objectives include evaluation of pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity. Exploratory endpoints include evaluation of the effect of study treatment on circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). LAVA-1207 is administered IV every two weeks. Two parallel cohorts assessing LAVA-1207 with low dose subcutaneous IL-2 have been implemented: (1) single IL-2 administration and (2) three IL-2 administrations on consecutive days per cycle for up to four cycles. An additional dose escalation arm evaluates LAVA-1207 in combination with pembrolizumab, 400mg Q6W, IV. Patients with mCRPC that have failed at least one prior AR therapy and taxane-based chemotherapy (unless deemed medically unsuitable to receive a taxane) will be enrolled on the study. Patients should have progressive disease either by PSA or by RECIST 1.1 or appearance of 2 or more bone metastases. Patients must have ECOG performance status of 0-1. PSMA-PET is performed at baseline. Paired biopsies are requested to further assess LAVA-1207 activity. Dose escalation is ongoing. Expansion arm(s) will be included based on available data from part 1 of the study and may include one or more of LAVA-1207, LAVA-1207 with low dose IL-2, or LAVA-1207 in combination with pembrolizumab. Clinical trial information: NCT05369000 .
A phase 1, open-label, dose escalation study on the safety and tolerability of ANK-101 in advanced solid tumors.
Authors: Jong Chul Park, Marcus O. Butler, Brendan D. Curti, Leisha A. Emens, Danielle M. Pastor, Joseph Elassal, Howard L. Kaufman, John M. Kirkwood
Journal: Journal of Clinical Oncology (2024)

TPS2689 Background: IL-12 is a cytokine that can stimulate both innate and adaptive tumor immunity. Clinical trials of intravenous IL-12 demonstrated anti-tumor activity limited by significant systemic toxicity, including patient deaths. ANK-101 is an anchored immunotherapy that links IL-12 to aluminum hydroxide through an alum-binding protein (ABP). The ANK-101 complex anchors IL-12 in the tumor microenvironment (TME), resulting in prolonged local retention and low levels of systemic absorption. Preclinical studies in murine tumor models showed that ANK-101 is retained at the injection site for up to 28 days, recruits and activates T and NK cells, promotes M1 myeloid cell differentiation, induces regression of both injected and un-injected tumors, and induces immunologic memory. Methods: This is a first-in-human, open-label dose escalation study of ANK-101 in advanced solid tumors with a planned sample size of 12-36 participants. The first three dose escalation cohorts include a single participant, and then study enrollment follows a standard 3+3 dose escalation design. If no dose limiting toxicity (DLT) is observed, the dose level will be escalated until ≥1/3 or ≥2/6 patients experience a DLT. An additional ten patients will be enrolled at the recommended dose for expansion (RDE). Participants will be treated with intratumoral ANK-101 every 3 weeks for 4 cycles. Imaging or clinical assessments will be performed at week 12. If there is no significant clinical deterioration or unacceptable toxicity at this visit, participants may receive four more cycles. Eligible patients must have an advanced solid malignancy refractory to standard treatment and be accessible for injection and biopsy, measurable disease by RECIST v1.1, and ECOG PS of 0-1. Key exclusion criteria include tumors close to vital structures, uncontrolled bleeding disorders, and active autoimmune disease. Primary objectives of the study are to determine the safety and tolerability of ANK-101 and identify the RDE. Secondary objectives include pharmacokinetics (PK) and immunogenicity (ADA) of ANK-101 and clinical activity as measured by ORR, DCR, DOR and PFS by RECIST v1.1. Exploratory objectives include assessment of QOL using FACT-G and profiling immune-based pharmacodynamic (PD) changes. PD assessments will include serum cytokines and circulating immune cells, and local levels of PD-L1, CD8+ T cells, and CD68+ macrophages, and changes in gene expression within the TME. This clinical trial is in progress. Clinical trial information: NCT06171750 .
Immune-phenotyping of peripheral blood mononuclear cells from patients with early triple-negative breast cancer: Identification of a systemic immunosuppressive CD3+ CD4+ CD39+ Treg subset.
Authors: Bernardo Leon Rapoport, Nicole Chicken, Pieter Meyer, Ronald Anderson, Liezl Heyman, Teresa Smit, Catherine Worsley
Journal: Journal of Clinical Oncology (2024)

3040 Background: Cells of the immune system and malignant cells interact in the tumor microenvironment, influencing response to treatment and survival. The current study was undertaken to assess the prevalence of these immune cells systemically in patients with early triple-negative breast cancer (TNBC). Methods: Multi-parameter flow cytometry was used to examine the percentages and phenotypes of cytotoxic T cells, natural killer (NK) cells, monocyte subsets, and regulatory T cell (Treg) subsets in the peripheral blood of 19 TNBC patients (pts) and 10 controls (cnt). Multicolor flow cytometry was carried out using DURAClone IM phenotyping (basic and Treg tubes) with a CytoFLEX Flow Cytometer (Beckman Coulter, California, USA), and data analyzed with FlowJo v 10.10.0 software (BD Life Sciences, USA). The Mann-Whitney U-test was used to compare non-parametric data where appropriate. Results: Significant increases in the percentages of immunosuppressive CD3+ CD4+ CD39+ Tregs cells in the setting of a significant decrease of CD19+ B cells were observed in pts with TNBC (Table).Tumour size, nodal status, age and ki-67 did not correlate with the percentages of any type of circulating immune cell. Conclusions: TNBC is associated with severe immunosuppression. In this context, percentages of circulating CD19+ B cells were significantly lower, while CD3+ CD4+ CD39+ Tregs were significantly higher in early TNBC pts. The peripheral blood immunome of TNBC pts identified a subset of immunosuppressive Tregs. A study is ongoing to identify the prognostic and predictive values of this systemic subset of Tregs for pCR in early TNBC pts undergoing neoadjuvant chemotherapy. [Table: see text]
First-in-human phase I clinical trial of RSO-021, a first-in class covalent inhibitor of mitochondrial peroxiredoxin 3 (PRX3), in patients with malignant pleural effusion due to mesothelioma and other advanced solid tumors (MITOPE).
Authors: Dean Anthony Fennell, Sean Dulloo, Simon Lord, Fiona Thistlethwaite, Kevin G Blyth, Peter Wojciech Szlosarek, Nick Maskell, Sanjay Popat, Avinash Aujayeb, Burak Y Aktas, Sohail Rooman Javed, Julio Herrero Colomina, Brian Cunniff, Jarrett Duncan, Philippa Graham, Alice Susannah Bexon, George N Naumov, James F. Spicer
Journal: Journal of Clinical Oncology (2024)

3019 Background: Malignant cells rely on buffering oxidative stress through mitochondrial PRX3. Oxidative stress is selectively lethal to cancer cells and may be leveraged therapeutically. RSO-021 is a naturally-occurring, sulfur-rich, cyclic oligopeptide of the thiopeptide class, which covalently inactivates PRX3, leading to catastrophic oxidative stress and cell death. We conducted a phase 1 study to explore safety and identify the maximum tolerated dose (MTD) of intra-pleural RSO-021 in patients with mesothelioma, or other predominantly pleural cancer, with pleural effusion. Methods: MITOPE was a multicenter trial of weekly intrapleural RSO-021 (90, 120, and 180 mg) with a 3 + 3 dose-escalation design. The primary objective was to assess RSO-021 safety/tolerability. Secondary objectives included establishing local and systemic pharmacokinetic profiles and early anti-tumor activity. We defined dose-limiting toxicity (DLT) as grade (G) ≥3 non-hematological AEs with exceptions for some manageable G3 AEs that resolved within 72 h and complicated G4 hematological AEs or those lasting &gt;7 days. We also studied inflammatory and pharmacodynamic markers in local/systemic samples. Efficacy was assessed using mRECIST 1.1 (mesothelioma) and RECIST 1.1 (other tumors). Results: Of 15 patients treated (90 mg/wk, n=7; 120 mg/wk, n=6; 180 mg/wk, n=2), 12 (80%) had ≥3 prior anti-cancer regimens; 12 (80%) had mesothelioma. See table for AE and efficacy data. The commonest all-grade treatment-related AEs (TRAE) were fatigue (33%), pyrexia (20%), and elevated creatinine (20%). Three patients (20%) had DLTs: G3 dyspnea and G3 acute inflammatory response at 120 mg/wk; G3 dyspnea at 180 mg/wk. MTD was 90 mg/wk. Pro-inflammatory cytokines in pleural fluid/serum correlated with AEs suggestive of local inflammation. Prophylaxis mitigated local inflammatory TRAEs. PRX3 target binding in cell pellets from pleural fluid confirmed on-target activity. Systemic exposure was minimal. Disease control was 70% in 10 evaluable patients. The partial response at 90 mg/wk was a 59% reduction in mesothelioma target lesions. Median PFS at MTD was 5.7 months (95% CI, 1.4-NR). Two patients had disease control (DC) &gt;30 wks. Conclusions: Weekly intrapleural RSO-021 was safe with signs of anti-tumor activity in patients with pleural mesothelioma. Phase 2 exploration of this novel agent is ongoing at 2 doses, as a single agent and in combination. Clinical trial information: NCT05278975 . [Table: see text]
Enrichment of somatic mosaic states involving DNA damage response and repair genes in patients treated with <sup>177</sup>Lutetium.
Authors: Yael Kusne, Osama M Mosalem, Terra L. Lasho, Stephanie L Pritzl, Christy Finke, Timothy J. Hobday, Jason S. Starr, Tanios S. Bekaii-Saab, Thorvardur Ragnar Halfdanarson, Mohamad B. Sonbol, Jacob Orme, Daniel S Childs, Oliver Sartor, Mrinal Patnaik
Journal: Journal of Clinical Oncology (2024)

3020 Background: Radioligand therapy (RLT) use has been increasing with the approval of 177 Lu-Dotatate for metastatic neuroendocrine tumors (NET) &amp; 177 Lu-PSMA-617 for metastatic castration resistant prostate cancer (mCRPC). Therapy-related myeloid neoplasms [tMN, including myelodysplastic syndrome (MDS) &amp; acute myeloid leukemia, (AML)] have been reported after 177 Lutetium ( 177 Lu) for NET with rates of 2-20% &amp; median time from first 177 Lu to tMN of 2.8yrs [4-12]. Clonal hematopoiesis (CH) is a risk factor for tMN, with the spectrum of CH depending on selection pressures. To describe the prevalence of therapy selected CH &amp; tMN, we performed a retrospective analysis of patients (pts) who had a bone marrow biopsy (BMB) post- 177 Lu. Methods: After IRB approval, we queried the electronic health record for pts with BMB post- 177 Lu. Pt demographics, treatment history, labs &amp; BMB results were collected. Results: Fifty-seven pts met criteria, 41 (72%) with NET &amp; 16 (28%) with mCRPC. . Median age at BMB was 68yrs (range, 28-85). Of the 57pts, prior treatments included: radiation (RT) in 21 (37%), temozolomide in 14 (25%), taxane in 15 (26%), &amp; platinum agents in 10 (18%). The median number of 177 Lu cycles was 4 (range, 1-11).Cytogenetics were available in 84% (n = 48) &amp; were normal in 60% (n = 29). Of those with abnormal cytogenetics (n = 18, 38%), the most common abnormalities involved chromosome (chr) 7 (n = 12, 26%), chr 5 (n = 7, 15%), chr 20 (n = 5, 11%) and complex karyotypes in 7 (15%), with 3 (17%) of these patients having no mutations. Diagnoses were assessable in 49 (86%) pts: 15 (31%) with undefined cytopeniasand 16 (33%) with tMDS. Metastatic carcinoma was identified in 17 Fifty-one percent (n = 29), at a median of 0.5yrs (range, 0.04-2.6) after hematologic diagnosis. Conclusions: The enrichment of CH involving the DDR pathway in recipients of 177 Lu underscores the impact of RLT on bone marrow progenitors.
Combination therapy with the oncolytic virus CF33-CD19 and blinatumomab for the treatment of advanced solid tumors.
Authors: Daneng Li, Amanda Seiz, Seymour H. Fein, John Chong Han Byon, Grey A Wilkinson, Paul Paul Woodard
Journal: Journal of Clinical Oncology (2024)

TPS2687 Background: CF33-CD19 is a novel chimeric vaccinia virus that selectively replicates in tumor cells and can provoke anti-tumor immunity. CF33-CD19 expresses a truncated and non-signaling CD19 protein on the surface of infected tumor cells before virus-mediated tumor lysis, labeling them for CD19-targeted therapies. Preclinical studies with CF33-CD19 have shown that combination therapy with CD19 targeting chimeric antigen receptor T cells is more effective than either monotherapy in murine xenograft and syngeneic models [1]. Likewise, combination therapy with bispecific T-cell engagers (BiTE)s that bind CD3-positive T cells and infected solid tumor cells that express de novo CD19, showed pronounced recruitment of T cells to the tumor microenvironment, resulting in tumor growth inhibition in mouse models. CD19xCD3 targeting BiTEs such as blinatumomab may offer an off-the-shelf alternative to adoptive cell therapies. This phase I study, called OASIS, dose escalates CF33-CD19 administered intravenously (IV) or intratumorally (IT) combined with blinatumomab in adults with advanced or metastatic solid tumors. Methods: The OASIS study (NCT06063317) is enrolling patients with advanced or metastatic solid tumors with ≥ 2 prior lines of therapy. Patients who have received prior treatment with a poxvirus based oncolytic virus or a bispecific CD19-directed CD3 T-cell engager are excluded. A safety run-in will evaluate the safety of CF33-CD19 monotherapy administered IT or IV before initiating the combination therapy regimen. Combination therapy will be administered in 28-day cycles with CF33-CD19 on days 1 and 15. Following viral transduction to promote de novo CD19 expression, blinatumomab is given on days 2-9 and 16-23 via a 7-day continuous infusion. Patients &gt; 45 kg will receive 9 mcg of blinatumomab during the first week of cycle 1, then 28 mcg during the third week of cycle 1 and subsequent cycles. The study consists of two parts. Part 1 follows a 3+3 dose escalation scheme independently of each route of CF33-CD19 administration (IT and IV) with dose levels of CF33-CD19 ranging from 1.0x10 7 to 3.0x10 9 PFU. Part 2 is a cohort expansion in select indications at the optimal dose. The co-primary endpoints are safety and identification of the recommended phase 2 dose. Secondary endpoints include objective response rate according to RECIST v1.1 and iRECIST. Enrollment began in October 2023. 1. Park et al. Sci Transl Med. 2020 Sep 2;12(559):eaaz1863. doi: 10.1126/scitranslmed.aaz1863. PMID: 32878978. Clinical trial information: NCT06063317 .