scholarly journals 487 NC410, a fusion protein of LAIR-2 (Leukocyte Associated Immunoglobulin-like Receptor) with human IgG1 Fc, is safe & tolerable with evidence of immune modulation in subjects with advanced solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A516-A517
Author(s):  
Han Myint ◽  
Linjie Tian ◽  
Jahangheer Shaik ◽  
Emilia Barbu ◽  
Qinjie Zhou ◽  
...  
Keyword(s):  
T Cells ◽  
Informed Consent ◽  
Solid Tumors ◽  
Immune Modulation ◽  
Immune Cell ◽  
Phase 1 ◽  
Open Label ◽  
Dose Dependent Fashion ◽  
Pharmacodynamic Biomarkers ◽  
Dose Dependent

BackgroundCollagen and C1q in the extracellular matrix (ECM), are the predominant ligands for LAIR-1, an inhibitory receptor expressed on the cell surface of several immune cell subsets that inhibits immune activation and migration. LAIR-2, a soluble homolog of LAIR-1, competes for binding to collagen and C1q and serves as a natural decoy to promote immune function under normal conditions. Dysregulation of the ECM and increased expression of collagen and C1q within the tumor microenvironment (TME) plays a critical role in promoting tumor progression. NC410 was engineered to overcome this highly immunosuppressive environment by blocking LAIR-1 function, reversing immune suppression, and inducing ECM remodeling to promote immune cell infiltration within the TME.MethodsThis is a first in human, phase 1/2, open-label, single-armed dose-escalation study to determine the safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose, preliminary efficacy and to explore pharmacodynamic biomarkers of NC410 (figure 1). Key eligibility criteria include subjects with advanced or metastatic solid tumors with measurable disease based on RECIST v1.1.ResultsAs of 07/22/2021, a total of 16 patients have been enrolled, treated, and completed the DLT period. NC410 (up to 60 mg), was well tolerated, with no safety concerns, infusion-related toxicities, or DLT reported. No anti-drug antibody (ADA) was detected post-NC410 up to 60 mg treatment. As expected, the C1Q level decreased immediately after the NC410 infusion and was replenished after two hours. Evaluation from samples to date available up to cycle 5 suggests that there was no reduction in the baseline C1Q level with subsequent dosing (figure 2). LAIR-2 levels continued to increase in a dose-dependent fashion post-NC410 dosing and marginal increase pre-dose (figure 3). Interestingly, we observed an increase in soluble LAIR-1 over time in a similar pattern to LAIR-2 (figure 4). Furthermore, immunophenotyping of patient whole blood suggests a trend towards an increase in CD4+ and CD8+ T cells including LAIR-1+ T cells in cohort 4, although overall expression levels of LAIR-1 did not appear to increase (ongoing analysis). Cytokines, chemokines, and collagen degradation products (CDP) will be evaluated as potential pharmacodynamic biomarkers as we continue through higher dose cohorts.Abstract 487 Figure 1NC410: study schemaAbstract 487 Figure 2C1Q levels show immediate reduction after NC410 dosing with no accumulated depletionAbstract 487 Figure 3LAIR-2 levels show an increase in dose-dependent fashion after NC410 dosing with marginal increase pre-doseAbstract 487 Figure 4Soluble LAIR-1 levels show a similar pattern to LAIR-2 levelsConclusionsPreliminary evaluation of NC410 in subjects with advanced or metastatic solid tumors appears to be safe and well-tolerated with evidence of immune modulation consistent with predictive PK/PD modeling in a Phase 1/2 open-label study. Further evaluation will be done with increasing doses to confirm these initial findings.Trial RegistrationNCT04408599Ethics ApprovalThis study has been approved by the IRB of all the participating institutions, and all participants have given informed consent before taking part in the study.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

A phase I, first-in-human clinical trial of the GDF-15 neutralizing antibody CTL-002 in subjects with advanced-stage solid tumors (ACRONYM: GDFATHER).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2658-TPS2658
Author(s):  
Ignacio Melero ◽  
Emiliano Calvo ◽  
Reinhard Dummer ◽  
Elena Garralda ◽  
Martin H. Schuler ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Solid Tumors ◽  
Tumor Tissue ◽  
Immune Cell ◽  
Phase 1 ◽  
Neutralizing Antibody ◽  
Advanced Stage ◽  
Open Label ◽  
Effector T Cell

TPS2658 Background: Growth and differentiation factor 15 (GDF-15) is a TGF-β superfamily member physiologically expressed mainly in placenta and linked to feto-maternal tolerance. Under pathophysiologic conditions, prevention of excessive immune cell infiltration during tissue damage and cachexia induction have been ascribed to GDF-15. A recent study [Haake et al. AACR2020; Abstract #5597] elucidated a mechanism by which GDF-15 inhibits LFA-1 activation on CD8+ T cells, thus interfering with effector T cell recruitment to tissues. Importantly, several cancer entities secrete high levels of GDF-15, correlating with poor prognosis and reduced overall survival [reviewed in Front Immunol 2020 May 19;11:951]. To block this effect the GDF-15 neutralizing antibody CTL-002 was generated. In preclinical models CTL-002 demonstrated potent effector T cell shifting into tumor tissue by neutralizing GDF-15. Methods: This is a phase 1, first-in-human (FIH), two-part, open-label clinical trial of intravenous (IV) administration of CTL-002 given as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced-stage, relapsed/refractory solid tumors who relapsed post or were refractory to a prior anti-PD-1/PD-L1 therapy. Eligible subjects have exhausted all available approved standard treatments. Further key eligibility criteria include having received at least one prior anti-PD1/-PD-L1 treatment and having relapsed on or after it or having been refractory to it, and presenting with a biopsy-accessible tumor for serial biopsy taking. The trial is termed GDFATHER, for “GDF-15 Antibody-mediaTed Effector cell Relocation”. Main endpoints are safety of CTL-002 monotherapy and CTL-002 combination with an anti-PD-1 antibody, pharmacokinetics, pharmacodynamics (e.g. degree of GDF-15 neutralization achieved and change in immune-cell number and composition in the tumor tissue) as well as preliminary clinical efficacy (tumor mass reduction; anticachexia effect) In part A of the trial (dose escalation) up to 24 subjects will receive escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in a „mono-followed-by-combination“-design with CTL-002 given as monotherapy and followed by combination with an anti-PD-1 checkpoint inhibitor. In part B (expansion) up to 5 cohorts with up to 25 subjects per cohort with defined tumor entities expected to be GDF-15 dependent will be treated to determine the recommended phase 2 dose (RP2D) and further evaluate safety and preliminary efficacy of CTL-002 monotherapy and the combination. The study was initiated in December 2020 and enrolled the first patient on Dec 09, 2020. Cohort 1 has been completed without DLT and enrollment for cohort 2 began in February 2021. Clinical trial information: NCT04725474.

scholarly journals A phase 1, open-label, multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors and in combination with pembrolizumab in subjects with unresectable solid tumors (Keynote-603).

2019 ◽  
Vol 5 (suppl) ◽  
pp. 93-93
Author(s):  
Howard A. Burris III ◽  
Manish R. Patel ◽  
Daniel C. Cho ◽  
Jeffrey Melson Clarke ◽  
Martin Gutierrez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Phase 1 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Phase 2 Clinical Trial ◽  
Clinical Responses ◽  
Grade 3 ◽  
Personalized Approach

93 Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor (CPI) may elicit greater anti-tumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design. Methods: This is an interim report of a phase I dose escalation study of mRNA-4157 given as monotherapy in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. mRNA-4157 is a lipid encapsulated personalized vaccine encoding multiple neoantigens selected using a proprietary algorithm designed to induce neoantigen specific T cells and associated anti-tumor responses. Patients received up to 9 cycles (Q3W) of mRNA-4157 by IM injection (0.04 – 1 mg). In combination arm, pembrolizumab (200 mg) was administered for two cycles prior to combination with mRNA-4157 for up to 9 cycles and may continue on pembrolizumab monotherapy for up to 2 years. Results: As of 10-May-2019, 33 patients received mRNA-4157 alone or in combination. No DLTs or related SAEs or AEs ≥ grade 3 were reported. Of the 13 patients treated with monotherapy (3 melanoma, 8 NSCLC, 2 MSI-high CRC), 11 patients remain disease free on study, median follow-up of 10 months. Of the 20 patients treated in combination (1 TMB-high metastatic cutaneous squamous cell, 4 bladder, 2 HNSCC, 1 melanoma, 7 NSCLC, 2 SCLC, 3 MSI-high (CRC, prostate, endometrial), 13 had received prior CPI, 5 PRs (2 in patients previously treated with PD-1/L1 inhibitors), 6 SD, and 8 PD were reported. Neoantigen specific CD8+ T-cell responses have been detected. Conclusions: mRNA-4157 is safe and well tolerated at all dose levels tested. Clinical responses have been observed in combination with pembrolizumab and neoantigen-specific T cells have been induced, supporting the advancement of mRNA-4157 to phase 2. Clinical trial information: NCT 03739931.

Safety and tolerability of MEDI0562 in combination with durvalumab or tremelimumab in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3003-3003
Author(s):  
Jonathan Wade Goldman ◽  
Sarina Anne Piha-Paul ◽  
Brendan D. Curti ◽  
Katrina Pedersen ◽  
Todd Michael Bauer ◽  
...  
Keyword(s):  
T Cells ◽  
Solid Tumors ◽  
Memory T Cells ◽  
Phase 1 ◽  
Evaluation Criteria ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
The Impact

3003 Background: We report safety and tolerability of MEDI0562, a humanized IgG1κ OX40 monoclonal antibody (mAb), in combination with durvalumab (durva; anti-PD-L1 mAb) or tremelimumab (treme; anti-CTLA-4 mAb) in patients (pts) with previously treated advanced solid tumors. Methods: In this phase 1, open-label study (NCT02705482), adult pts received escalating doses of MEDI0562 (2.25, 7.5 or 22.5 mg/kg) every 2 wks (Q2W) in combination with durva (1500 mg/kg) or treme (75 or 225 mg/kg) Q4W, until confirmed disease progression or unacceptable toxicity. Tumor assessments were performed Q8W with immune-related Response Evaluation Criteria in Solid Tumors. Results: In total, 27 and 31 pts received MEDI0562 + durva or treme, across 5 dose combination cohorts (3 + 3 design), with a maximum tolerated dose of 7.5 mg MEDI0652 + 1500 mg durva and maximum administered dose of 10 mg MEDI0562 + 225 mg treme. Median duration of exposure was 12.0 (range 2.0–80.9) and 8.0 (range 2.0–42.0) wks, respectively. Two (22.5 mg MEDI10562 + durva) and 3 (2.25 mg MEDI0652 + 225 mg treme, 22.5 mg MEDI0562 + 75 and 225 mg treme) dose limiting toxicities were observed. For MEDI0562 + durva and MEDI0562 + treme groups respectively, treatment-emergent adverse events (TEAEs) were reported in 96.3% and 100% of pts; most common TEAEs were fatigue (55.6%) and pruritus (45.2%), Gr 3/4 TEAEs occurred in 74.1% and 67.7%; and MEDI0562-related AEs were reported in 20 (74.1%) and 24 (77.4%) pts. Six TEAEs in each group led to MEDI0562 discontinuation (22.2% and 19.4%, respectively), 2 led to death (renal failure [7.5 mg MEDI0562 + durva], multiple organ dysfunction syndrome [22.5 mg MEDI0562 + 225 mg treme]). Three response evaluable pts had PR (11.5% [7.5 and 22.5 mg MEDI0562 + durva, n = 26]). Median overall survival was 17.4 and 11.9 mos for MEDI0562 + durva and MEDI0562 + treme, with stable disease seen in 9 pts from each group, 34.6% vs 29.0%, respectively. Serum exposure of MEDI0562 increased dose proportionally. Post treatment serum antidrug antibody (ADA) was detected in 20 pts from MEDI0562 + durva and MEDI0562 + treme (74.1% and 71.4%, respectively). The impact of ADA on MEDI0562 pharmacokinetics was seen at all doses. Mean percentage of Ki67+CD4+ and Ki67+CD8+ memory T cells increased, while mean percentage of OX40+CD4+ memory T cells decreased following the first dose of MEDI0562 + durva or treme. Conclusions: The safety profile of MEDI0562 in combination with durva or treme was similar between groups. Clinical activity was observed with MEDI0562 + durva in pts with advanced solid tumors. Clinical trial information: NCT02705482 .

A phase 1/2, open-label, dose-escalation, safety and tolerability study of NC410 in subjects with advanced or metastatic solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2659-TPS2659
Author(s):  
Martin Gutierrez ◽  
Filip Janku ◽  
Linjie Tian ◽  
Jason J. Luke ◽  
Elaine Shum ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Solid Tumors ◽  
Tumor Immunity ◽  
Dose Escalation ◽  
Immune Cells ◽  
Phase 1 ◽  
Phase 2 ◽  
Open Label ◽  
Pharmacologically Active

TPS2659 Background: Leukocyte-Associated Immunoglobulin-like Receptor (LAIR)-1 and LAIR-2 are members of the Leukocyte Receptor Complex (LRC) (An & Brodsky, 2016). LAIR-1 is a co-inhibitory receptor expressed on several subsets of immune cells, and functions to delimit immune responses (Meyaard et al., 1997). LAIR-2 is a secreted protein with homology to the transmembrane protein LAIR-1 (Lebbink et al., 2008). In cancer, it is hypothesized that LAIR-1 expression on several subsets of leukocytes prevents optimal immune responses by limiting both innate and adaptive immune functionality. LAIR-1 serves to suppress anti-tumor immunity through the inhibition of stimulatory signaling pathways. Specifically, LAIR-1 is a checkpoint and adhesion receptor on T cells that limits T cell activation and increases adhesion to collagens (Meyaard, 2008). LAIR-2 is capable of blocking LAIR-1 functional interactions with ligands, resulting in improved immune function on multiple immune cell subsets. Dysregulation of LAIR-1 ligands in the tumor microenvironment results in excessive production of collagens and complement C1q as well as altered forms of collagens, that leads to immune inhibition through binding to LAIR-1+ immune cells. NC410 is a dimeric form of the LAIR-2 protein fused to a human Fc domain of the immunoglobulin (Ig) subtype IgG1. The rationale for developing NC410 as a cancer therapeutic is based on nonclinical data demonstrating LAIR-1 signaling blockade can improve the immune response. Because LAIR-2 binds to ligands shared with LAIR-1 with increased affinity, NC410 acts as a decoy receptor for LAIR-1 ligands releasing suppression from myeloid cells and T cells and promoting anti-tumor immunity. NC410 may also mediate remodeling of the tumor extracellular matrix, further contributing to anti-tumor activity. Methods: This is a multi-center, first in human, phase 1/2, open-label, single-armed study to determine the safety and tolerability, define maximum tolerated dose (MTD) and/or pharmacologically active dose, assess preliminary efficacy, and explore predictive and pharmacodynamic biomarkers of NC410 in subjects with advanced or metastatic solid tumors. Key eligibility criteria include measurable disease based on RECIST v1.1 and being able to consent for collection of biopsies at screening and on treatment. Phase 1 is a classic 3+3 dose escalation design to determine the safety, tolerability, DLT, MTD and recommended phase 2 dose (RP2D) (NCT04408599). Ongoing exploratory analyses include the assessment of predictive biomarkers associated with treatment benefit, and pharmacodynamic markers associated with study drug activity. Phase 2 is going to enroll ovarian, colorectal, NSCLC, H&N, and gastric carcinomas and other tumors depending on biomarker data available from the Phase 1 part of the study. Clinical trial information: 04408599.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

scholarly journals A phase 1, open-label, drug–drug interaction study of rucaparib with rosuvastatin and oral contraceptives in patients with advanced solid tumors

2021 ◽  
Author(s):  
Mingxiang Liao ◽  
Krzysztof G. Jeziorski ◽  
Monika Tomaszewska-Kiecana ◽  
István Láng ◽  
Marek Jasiówka ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Solid Tumors ◽  
Oral Contraceptives ◽  
Interaction Analysis ◽  
Phase 1 ◽  
Geometric Mean ◽  
Pharmacokinetic Analysis ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Drug Drug Interaction

Abstract Purpose This study aimed at evaluating the effect of rucaparib on the pharmacokinetics of rosuvastatin and oral contraceptives in patients with advanced solid tumors and the safety of rucaparib with and without coadministration of rosuvastatin or oral contraceptives. Methods Patients received single doses of oral rosuvastatin 20 mg (Arm A) or oral contraceptives ethinylestradiol 30 µg + levonorgestrel 150 µg (Arm B) on days 1 and 19 and continuous doses of rucaparib 600 mg BID from day 5 to 23. Serial blood samples were collected with and without rucaparib for pharmacokinetic analysis. Results Thirty-six patients (n = 18 each arm) were enrolled and received at least 1 dose of study drug. In the drug–drug interaction analysis (n = 15 each arm), the geometric mean ratio (GMR) of maximum concentration (Cmax) with and without rucaparib was 1.29 for rosuvastatin, 1.09 for ethinylestradiol, and 1.19 for levonorgestrel. GMR of area under the concentration–time curve from time zero to last quantifiable measurement (AUC0–last) was 1.34 for rosuvastatin, 1.43 for ethinylestradiol, and 1.56 for levonorgestrel. There was no increase in frequency of treatment-emergent adverse events (TEAEs) when rucaparib was given with either of the probe drugs. In both arms, most TEAEs were mild in severity and considered unrelated to study treatment. Conclusion Rucaparib 600 mg BID weakly increased the plasma exposure to rosuvastatin or oral contraceptives. Rucaparib safety profile when coadministered with rosuvastatin or oral contraceptives was consistent with that of rucaparib monotherapy. Dose adjustments of rosuvastatin and oral contraceptives are not necessary when coadministered with rucaparib. ClinicalTrials.gov NCT03954366; Date of registration May 17, 2019.

scholarly journals 412 First-in-human phase I/IIa trial to evaluate the safety and initial clinical activity of DuoBody®-PD-L1×4–1BB (GEN1046) in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A437-A437
Author(s):  
Elena Garralda ◽  
Ravit Geva ◽  
Eytan Ben-Ami ◽  
Corinne Maurice-Dror ◽  
Emiliano Calvo ◽  
...  
Keyword(s):  
T Cells ◽  
Informed Consent ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Therapeutic Window ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Link Type ◽  
Dose Levels

BackgroundAgonistic 4-1BB monoclonal antibodies were preclinically validated as promising cancer immunotherapies, both as monotherapy and as potentiators of the activity of PD-(L)1–blocking agents. However, toxicity and a narrow therapeutic window have hampered their clinical development. DuoBody-PD­-L1×4-1BB, a first-in-class, bispecific, next-generation checkpoint immunotherapy, was designed to overcome these limitations by activating T cells through conditional 4-1BB costimulation, while simultaneously blocking the PD-L1 axis. We present preliminary data from the ongoing, first-in-human, open-label, phase I/IIa trial of DuoBody-PD-L1×4-1BB in advanced solid tumors (NCT03917381).MethodsDuring dose escalation, patients with metastatic or unresectable solid tumors not eligible for standard therapy received flat-dose DuoBody-PD-L1×4-1BB (25–1200 mg) intravenously every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary endpoints included pharmacokinetic parameters and antitumor activity (RECIST 1.1). Pharmacodynamic biomarkers and antitumor activity (iRECIST) were assessed as exploratory endpoints.ResultsAs of June 22, 2020, 61 patients were enrolled (median age: 59 years). The most common cancer types were colorectal (19.7%), ovarian (14.8%), pancreatic (9.8%), and NSCLC (9.8%). Patients had previously received a median (range) of 3 (1–11) treatments; 44.2% had prior anti-PD-(L)1 immunotherapy. Patients received a median (range) of 4 (1–15) treatment cycles; Cmax was observed shortly after the end of infusion (mean T½: 2.3–10.3 days). Maximum tolerated dose was not reached; 6 patients experienced DLTs. The most common (=10%) treatment-related AEs (all grades; grades 3–4) were transaminase elevation (24.6%; 9.8%), hypothyroidism (16.4%; 1.6%), and fatigue (13.1%; 1.6%). Treatment-related grade-3 transaminase elevations decreased upon corticosteroid administration; no treatment-related bilirubin increases or grade-4 transaminase elevations occurred. Disease control, including stable disease at first assessment and partial responses in triple-negative breast cancer, ovarian cancer, and immune checkpoint inhibitor (ICI)–pretreated NSCLC, occurred in 40/61 patients (65.6%). Pharmacologic activity, as measured by modulation of adaptive immunity mediators, was observed across a broad range of dose levels. Peripheral proliferating (Ki67+) CD8+ effector memory T cells and serum interferon-gamma levels showed maximum induction relative to baseline (p=0.01) 8 days following treatment.ConclusionsDuoBody-PD-L1×4-1BB demonstrated biologic activity and a manageable safety profile. Encouraging early clinical activity across different dose levels was observed in a heavily pretreated population with advanced solid tumors, including those resistant to prior immunotherapy or typically less sensitive to ICIs. Expansion cohorts of patients for whom DuoBody-PD-L1×4-1BB treatment could be relevant and biologically sound have started enrollment. Updated data will be presented.AcknowledgementsThe authors thank Manish Gupta, Lei Pang, and Thomas Breuer at Genmab A/S; Alice Bexon, Alexander Muik, and Friederike Gieseke at BioNTech SE; and Zuzana Jirakova (formerly at BioNTech SE) for their valuable contributions. This trial was funded by Genmab A/S and BioNTech SE.Trial RegistrationClinicalTrials. gov; trial number: NCT03917381Ethics ApprovalThis trial is undertaken following full approval of the final protocol, amendments, informed consent form, applicable recruiting materials, and subject compensation programs by the Independent Ethics Committee/Institutional Review Board.ConsentWritten informed consent, in accordance with principles that originated in the Declaration of Helsinki 2013, current ICH guidelines including ICH-GCP E6(R2), applicable regulatory requirements, and sponsor policy, was provided by the patients.

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