scholarly journals 489 TWT-101: a phase 1 study of the novel HPK1 inhibitor CFI-402411 in patients with advanced cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A519-A519
Author(s):  
Omid Hamid ◽  
Johanna Bendell ◽  
Siqing Fu ◽  
Kyriakos Papadopoulos ◽  
Judy Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Ethics ◽  
Potent Inhibitor ◽  
Phase 1 ◽  
Institutional Review Board ◽  
Institutional Review ◽  
Research Ethics Board ◽  
Grade 3 ◽  
Advanced Tumors

BackgroundCFI-402411 is an orally available small molecule potent inhibitor of HPK1 (Hematopoietic progenitor kinase 1). T-cells are negatively-regulated at different junctures of cancer-immunity cycle by this regulatory kinase. HPK1, (also mitogen activated protein kinase kinase kinase kinase 1 (MAP4K1)) is a protein serine/threonine kinase predominantly expressed in hematopoietic cells. In T-cells, following T-cell receptor activation, HPK1 is recruited to the plasma membrane where it phosphorylates the adapter protein SH2 domain-containing leukocyte protein of 76 kDa (SLP-76), down-regulating signaling events required for T cell activation and proliferation. Selected for development based on its pharmacologic properties and preclinical activity in a variety of syngeneic cancer models and assays, with an IC50 = 4.0±1.3 nM, CFI-402411 is expected to relieve HPK1-mediated inhibition of T and B cells, facilitating an anti-tumor immune response.MethodsPhase 1, 3 + 3 design in patients. Patients have acceptable laboratory, other parameters for study entry. Single agent dose daily oral escalation cohort (A1) in advanced tumors, then dose expansion (A3) with biomarker backfill (A2) in select advanced tumors; combination with PD-1 Inhibitor (pembrolizumab) (B1, pembrolizumab eligible tumors with no prior grade >=3 related to CPI)) and expansion (B2, PD-1/PD-L1 naïve pembrolizumab eligible tumors). DLT defined as any grade >=3 toxicity in first cycle of therapy (21d cycles). Standard assessments for response per RECIST v1.1 or iRECIST. The starting dose level was 80mg.ResultsAt 10 June 2021 data is available for 12 patients from A1. Median age 61.5 years (range 33–73), 8 patients female, and 10 white. Diagnoses were pancreatic cancer, colorectal (3 pts), ovarian, basal cell, cholangiocarcinoma, sigmoid, salivary and breast cancer (1 pt). Six patients (50%) had 4 prior therapies, 1 patient (basal cell) had prior treatment with immune checkpoint inhibitor, pembrolizumab. Four doses studied: 80, 120, 180 and 270mg. TEAEs across all CTCAE grades, (in >2 patients) were diarrhea (6 patients), nausea (4 patients), dyspepsia (3 patients), fatigue (3 patients). No related grade 3–5 events, one immune related event (grade 1, weight loss). 3 grade 3 events all unrelated to study drug - pleural effusion, rash, thromboembolic event. Discontinuation due to disease progression was main reason (7 patients). PK and PD assessments will be updated at time of presentation.ConclusionsCFI-402411 is a potent inhibitor of HPK1 that is well tolerated with a manageable adverse event profile and dose escalations continue. Further safety and efficacy results will be presented at the meeting including additional cohorts if available.AcknowledgementsTreadwell Therapeutics thanks all sites, importantly their patients and their families.Trial RegistrationClinicalTrials.gov Identifier: NCT04521413Ethics ApprovalThis study obtained has obtained ethics approvals at multiple institutions globally including;USAWCG IRB - Western Institutional Review Board - MOD00002618 (Submission ID)IntegReview Institutional Review Board - N/AAdvarra Central IRB - SSU00130103IntegReview Institutional Review Board N/AAdvarra Central IRB - SSU00137751Advarra Central IRB - SSU00143275The University of Texas MD Anderson Cancer Center Institutional Review Board - 2020–0678 (IRB ID Number)Hong KongJoint Chinese University of Hong Kong - New Territories East Cluster Clinical Research Ethics Committee - 2020.367 (Ref Number)CanadaOntario Cancer Research Ethics Board - 3320 (Project ID)Health Research Ethics Board of Alberta, HREBA Cancer Committee - HREBA.CC-20–0504 (Ethics ID Number)South KoreaimCORE - Seoul National University Hospital Institutional Review Board - H-2012-094-1182 (IRB Number)National Cancer Institute Review Board - 2020–0525–0001 (Receipt Number)All participants gave informed consent before taking part in this clinical trial.

scholarly journals 545 A phase 2 study of retifanlimab in patients with advanced or metastatic merkel cell carcinoma (MCC) (POD1UM-201)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A574-A575
Author(s):  
Giovanni Grignani ◽  
Piotr Rutkowski ◽  
Celeste Lebbe ◽  
Natalie Prinzi ◽  
Jean-jaques Grob ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Research Ethics ◽  
Health Research ◽  
Institutional Review Board ◽  
Phase 2 ◽  
Merkel Cell ◽  
Institutional Review ◽  
Phase 2 Study ◽  
Research Ethics Board ◽  
Grade 3

BackgroundRetifanlimab (INCMGA00012) is a humanized, hinge-stabilized immunoglobulin G4 kappa (IgG4κ), anti-programmed cell death protein (PD)-1 monoclonal antibody with safety and clinical pharmacology that are characteristic for the class. Evaluation of retifanlimab in solid tumors is under investigation in phase 2 and 3 studies. POD1UM-201 is an open-label, single-arm, multicenter, phase 2 study evaluating the efficacy and safety of retifanlimab in patients with chemotherapy-naïve or chemotherapy-refractory advanced/metastatic Merkel cell carcinoma (MCC). Updated results from the chemotherapy-naïve cohort are reported here.MethodsEligible patients were ≥18 years of age, had metastatic or recurrent unresectable loco-regional MCC, Eastern Cooperative Oncology Group performance status ≤1, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and had not received prior systemic treatment for MCC. Retifanlimab 500 mg IV every 4 weeks (Q4W) was administered for up to 2 years. The primary endpoint was overall response rate (ORR) assessed by independent central review per RECIST v1.1. Secondary endpoints included duration of response, disease control rate (DCR; defined as proportion of patients with either an objective response or stable disease lasting at least 6 months), progression-free survival, overall survival, safety, and pharmacokinetics.ResultsAs of April 16, 2021, 87 patients with chemotherapy-naïve advanced/metastatic MCC had received retifanlimab. Per protocol, the primary efficacy analyses are based on the first 65 patients assessed. At the data cutoff, 34 of these 65 patients (52.3%) were on treatment; 4 (6.2%) had completed treatment; and 27 (41.5%) had discontinued treatment for reasons including disease progression (18 [27.7%]), adverse event (AE; 7 [10.8%]), death (1 [1.5%]), and physician decision (1 [1.5%]). The ORR in these patients was 46.2% (n=30: complete response, 8 [12.3%]; partial response, 22 [33.8%]). The DCR was 53.8% (n=35). Other secondary efficacy results are not yet mature. Among all treated patients (n=87), 66 (75.9%) had a treatment-emergent AE (TEAE), 25 (28.7%) had a grade ≥3 TEAE, and 12 (13.8%) had a grade ≥3 treatment-related AE. Twenty-three patients (26.4%) had an immune-related AE (irAE), and 8 (9.2%) had a grade ≥3 irAE. Four patients (4.6%) discontinued treatment due to irAEs (peripheral sensorimotor neuropathy, pancreatitis, eosinophilic fasciitis, and polyarthritis [each n=1]). One patient (1.1%) had a grade 3 infusion reaction.ConclusionsThese data from the POD1UM-201 trial show that retifanlimab monotherapy at 500 mg Q4W continues to demonstrate promising clinical activity and safety in patients with advanced/metastatic chemotherapy-naïve MCC. Updated results will be presented at the meeting.AcknowledgementsThe study is sponsored by Incyte Corporation (Wilmington, DE). Statistical support was provided by Xiaohan Xu of Incyte Corporation. Editorial assistance was provided by Matthew Bidgood of Envision Pharma Group (Philadelphia, PA, USA).Trial RegistrationClinicaltrials.gov NCT03599713; EudraCT 2018-001627-39Ethics ApprovalThe study was approved by institutional review boards or independent ethics committees in Canada (McGill University Health Center-Research Ethics Board [MP-37-2019-5103, MEO-37-2019-1616]; Ontario Cancer Research Ethics Board [1728]; Health Research Ethics Board of Alberta – Cancer Committee [HREBA.CC-19-0004, HREBA.CC-19-0020]); Czech Republic (Eticka komise Fakultni nemocnice Kralovske Vinohrady, Eticka komise IKEM a FTNsP, Eticka komise Nemocnice Na Bulovce, Statni ustav pro kontrolu leciv, Eticka komise FN a LF UP Olomouc [169/18MEK24, LEK/04/07/2018, (L-18-85) 8522/23.3.2021, 22.3.2021/9965/EK-Z]); France (Comité de Protection des Personnes Ile de France X [CNRIPH : 18.11.19.49212/Id. 2043]; Agence Nationale de Sécurité du Médicament et des Produits de Santé); Germany (Ethik-Kommission der Medizinischen Fakultaet der Universitaet Duisburg-Essen [18-8371-AF]; Bundesamt fuer Strahlenschutz; Paul-Ehrlich Institute); Hungary (Egeszsegugyi Tudomanyos Tanacs Klinikai Farmakologiai Etikai Bizottsaga [IV/2407-0/2021-EKL, OGYÉI/11697-2/2021]; Orszagos Gyogyszereszeti es Elelmezes-egeszsegugyi Intezet); Italy (Comitato Etico IRCCS Pascale Napoli [116/21 E - 87/18]; Comitato Etico IRCCS di Candiolo [232/2021]; Istituto Tumori Giovanni Paolo II IRCCS Ospedale Oncologico Bari [736/CE]; Comitato Etico Locale per la Sperim. Clin. dei Medicinali dell’Az. Osp.ra Univ.ria Senese di Siena [14107]; Comitato Etico dell’IRCCS Istituto Nazionale per la Ricerca sul Cancro di Genova [389/2018 - 24/05/2021]; Comitato etico degli IRCCS Istituto Europeo di Oncologia e Centro Cardiologico Monzino [IEO 948 - RE3065/IB Edition 7 dated 10Nov2020 (SA7)]; Comitato Etico, Fondazione IRCCS Istituto Nazionale dei Tumori, .c. Medicina Oncologica 1 – Fondazio [INT 01/19]; Comitato Etico IRCCS Istituto Oncologico Veneto di Padova [EM 109/2021]; Comitato Etico dell’IRCCS Istituto Dermopatico dell’Immacolata Ospedale Generale S. Carlo di Roma [550/7]; AIFA – Agenzia Italiana del Farmaco [0040152-01/04/2021-AIFA-AIFA_USC-P]; Comitatao Etico Policlinico di Modena [1017/2018/FARM/AOUMO - EMENDAMENTO SOSTANZIALE IB EDIZIONE 7 DEL 10/11/20 (201800162739-010) (p. 9869/21)]); Poland (Komisja Bioetyczna przy Centrum Onkologii [no. 55/2019]; Office for Registration of Medicinal Products, Medical Devices and Biocidal Products [UR/DBL/D/328/2019]); Spain (CEIC Hospital General Universitario Gregorio Marañon [280/18]; Agencia Española del Medicamento y Productos Sanitarios); Switzerland (Kantonale Ethikkommission Zürich (KEK-Zürich) [2019-00200]; Swissmedic [2019DR2035]); United Kingdom (North East – York Research Ethics Committee [248465]; Medicines and Healthcare products Regulatory Agency; Health Research Authority); United States (Copernicus Group IRB; Western Institutional Review Board [20181738, Work order number -– IQV1-18-309]; Roswell Park Cancer Institute IRB [STUDY00000802/P 75918]; Inova Institutional Review Board, Human Research Protection Program; Stanford IRB Research Compliance Office [48198]; Rush University Medical Center [18072304-IRB01]; University of Miami IRB; Mayo Clinic IRB – Rochester).

scholarly journals Phase 1 First-in-Human Trial of AMV564, a Bivalent Bispecific (2x2) CD33/CD3 T-Cell Engager, in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1455-1455 ◽  
Author(s):  
Peter Westervelt ◽  
Gail J. Roboz ◽  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Sangmin Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dose Level ◽  
T Cell Activation ◽  
Research Funding ◽  
Cell Activation ◽  
Phase 1 ◽  
Disease Stage ◽  
Molecular Abnormalities ◽  
Grade 3

Abstract Background: AMV564 is a novel bivalent, bispecific (2x2) CD33/CD3 targeted immunotherapy that binds both CD33 and the invariant CD3ε on T-cell receptors with strong avidity, thus creating an immune synapse between CD33-expressing cells and T cells, initiating T-cell directed lysis of CD33 expressing cells, and inducing expansion, differentiation and proliferation of T cells. By design, AMV564 has reduced clearance and therefore has a longer half-life (t1/2) than monovalent, bispecific T-cell engagers. In preclinical investigations using both leukemic cell lines and primary cells from AML patients, AMV564 eliminated myeloid blasts with picomolar potency and broad activity independent of cytogenetic or molecular abnormalities, CD33 expression level, and disease stage, with no nonspecific activation of T cells (Reusch U et al. Clin Cancer Res 2016;22:5829-38). Methods: This is an ongoing Phase 1 study with a 3+3 dose-escalation design (NCT03144245). The primary objectives of this study are to characterize the safety, tolerability, and preliminary anti-leukemic activity of AMV564. Evaluation of pharmacokinetics (PK), cytokine changes, and immunophenotyping are secondary objectives. Key inclusion/exclusion criteria are: adults with relapsed and/or refractory AML after 1-2 prior induction regimens (with a standard anthracycline-based regimen or hypomethylating agent) and no more than 2 prior salvage regimens. AMV564 is administered by continuous intravenous infusion (CIV) for 14 consecutive days for up to 2 induction cycles. AMV564 and cytokine (IL2, IL4, IL6, IL8, IL10, TNF-α, and IFN-γ) concentrations were measured by validated immunoassays. T-cell activation was measured using flow cytometry to quantify T cells expressing CD25, CD38, CD69, or HLA-DR. Results: To date, 19 patients (10 male/9 female) with a median age of 72 years (range 24-84) have been enrolled in 6 dosing cohorts: 0.5, 1.5, 5.0, 15, 50, and 100 mcg/day. Thirteen patients (68%) had secondary AML and/or adverse cytogenetics, including 6 patients (32%) with a p53 mutation. Fifteen patients (79%) had received at least 1 prior salvage regimen and 11 (58%) had received prior intensive chemotherapy, including 6 patients (32%) who had received a high-dose (≥ 1 gm/m2) cytarabine-based regimen. Overall, 18 patients were evaluable for toxicity and response. No dose-limiting toxicity or treatment-related grade ≥ 3 adverse events (AE) were reported. Grade 2 CRS was observed in 1 patient (treated at 50 mcg/day) without a lead-in dose and was managed with drug interruption and 1 dose of tocilizumab. The patient was able to resume dosing and completed the full 14-day scheduled therapy without recurrence of CRS. Subsequent patients treated at 50 mcg/day and above were given a 15 mcg/day lead-in dose for 3 days followed by 11 days at the assigned dose level. The most common grade ≥ 3 treatment-emergent AE has been febrile neutropenia, reported in 39% (7/18) of patients and all considered unrelated to study drug. No patient has died within 30 days of treatment initiation. AMV564 PK was linear with a terminal t1/2 of 2-3 days. Plasma concentrations increased gradually, with times to steady-state concentration of 3-7 days. Marked increases in IL6 (peak concentration, 1.1 ng/mL), IL8 (1.5 ng/mL), and IL10 (0.3 ng/mL) cytokines were observed and increased numbers of activated T-cells were detected post-treatment. Reductions in bone marrow blasts, ranging from 13% to 91%, were observed in 12 of 18 evaluable patients including a partial response after cycle 1 in 1 patient at the 100 mcg/day dose level. Conclusions: AMV564 is well-tolerated and demonstrates anti-leukemic activity through T-cell engagement. AMV564 has a unique PK profile with a gradual increase in drug concentration and thus the potential for controlled T-cell activation. Disclosures Roboz: Daiichi Sankyo: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sandoz: Consultancy; Novartis: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Orsenix: Consultancy; Celltrion: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Rettig:Amphivena Therapeutics: Research Funding; Novimmune: Research Funding. Han:Amphivena Therapeutics, Inc: Employment. Guenot:Amphivena Therapeutics, Inc: Employment. Feldman:Amphivena Therapeutics, Inc: Employment.

scholarly journals Adult Patients with ALL Treated with CD62L+ T Naïve/Memory-Enriched T Cells Expressing a CD19-CAR Mediate Potent Antitumor Activity with a Low Toxicity Profile

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4016-4016 ◽  
Author(s):  
Samer K. Khaled ◽  
Suzette Blanchard ◽  
Xiuli Wang ◽  
Jamie Wagner ◽  
Araceli Naranjo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Disease Burden ◽  
Phase 1 ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T ◽  
Manufacturing Platform ◽  
Grade 3

Abstract Introduction: Treatment of adults with relapsed/refractory (R/R) B-ALL using CD19-targeted chimeric antigen receptor (CAR) T cells has achieved remarkable remission rates, both in pediatric and adult populations. There are multiple CAR constructs and T cell manufacturing platforms in use, and both aspects of the therapy may impact efficacy and toxicity. Park et al. report that 83% of adult patients (pts) achieve complete response (CR) to their CD19 CAR T cells with a CD28 costimulatory domain (NEJM; 3785: 449), using an unselected peripheral blood (PBMC) manufacturing platform. Unfortunately, therapy-associated toxicities in adult and pediatric ALL pts are problematic, with grade 3/4 cytokine release syndrome (CRS) ranging from 26-49 % and neurotoxicity 18-42%. Here we report preliminary data from one arm of a phase 1 clinical trial (NCT02146924) in adult pts with R/R B-ALL testing a memory-enriched T cell starting population engineered to express a CD19-specific, CD28-costimulatory CAR (CD19:28z-CAR). All pts achieved CR or CRi with a low incidence of severe cytokine release syndrome (CRS) and neurotoxicity. Unique to this study is our Tn/mem-enriched manufacturing platform, a naïve/memory T cell-enriched T cell product that is lentivirally transduced to express our CD19:28z-CAR. The manufacturing process starts with patient PBMC, depletes the CD14+ monocytes and CD25+ Tregs, and selects for CD62L+ T cells. The resultant T cell population for CAR transduction includes both the central memory and stem cell memory populations along with naïve T cells. Preclinical studies in mice had suggested that using a more uniform T cell product with a less-differentiated T cell phenotype improved antitumor activity. This Tn/mem manufacturing platform is the same as our Tcm-derived platform (Blood;127:2980) except that CD45RA depletion was omitted. Patients and Methods: This phase I study used the activity constrained for toxicity (ACT) design, an extension of the toxicity equivalence range (TEQR) design of Blanchard and Longmate (Contemp Clin Trials; 32:114), that dose escalates based on lack of activity, while constraining the dose for toxicity. The primary objectives of this study were to test the safety and activity of Tn/mem-enriched CD19:28z CAR T cells, and to determine the phase 2 recommended dose. The primary endpoints were toxicity and disease response. Sixteen pts were consented and received a lymphodepleting regimen (LDR) of 1.5-3 gm/m2 cyclophosphamide over 2-3 days and 25-30 mg/m2 fludarabine for 3 days. Three pts received LDR, but did not receive T cells due to infection or lack of CD19+ disease. Patients received a flat dose of 200 million (M) CD19:28z-CAR T cells: 11 autologous and 2 allogeneic donor products. Of the 13 that received 200 M CAR+ T cells, 2 pts were deemed ineligible for dose escalation / disease response evaluation, as 1 received <80% of the prescribed dose (100 M) and the other had CD19-negative extramedullary disease. The median age of the 13 CAR T cell treated pts was 33 years (24-72). All pts had active bone marrow (BM) disease at the time of LDR: 8 pts (62%) had high disease burden (15-91% BM blasts) and 5 had low disease burden (</= 5% BM blasts). Patients were heavily pretreated, with a median of 5 (2-6), prior regimens. Six pts received prior allogeneic transplant (HSCT), 9 had prior blinatumomab, and 1 had prior CD19 CAR T cells. Results: Toxicity: Table 1 describes the major toxicities of the 13 CAR-treated pts, stratified based on disease burden. There were no DLTs, and T-cell therapy attributed (>/=possibly) toxicities were typically mild and reversible. Eight pts had grade 2 CRS, and 2 had grade 3 CRS. Three pts had grade 2 neurotoxicity and 2 had grade 3. Response: Eleven pts were evaluable for response, with best response of 4 CRs (MRD- by flow) and 7 CRi (6 MRD-, 1 not tested). Median response duration at last contact or HSCT start was 81 days (39-286); 8 pts proceeded to HSCT (in CR or CRi) at a median of 69 days post-CAR infusion (39-103). Conclusions: Our ongoing phase 1 trial demonstrates a 100% response rate to Tn/mem-enriched CD19:28z-CAR T cell therapy in adults with relapsed/refractory (R/R) B-ALL. Although the numbers are small, the unanimous response, combined with a tolerable and reversible toxicity profile in pts with both low and high disease burden is remarkable and suggests promise for this Tn/mem manufacturing platform for CD19 and other CAR targets. Disclosures Khaled: Juno: Other: Travel Funding; Daiichi: Consultancy; Alexion: Consultancy, Speakers Bureau. Wang:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Brown:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

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.

Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update of the phase 1/2 EVOLVE study (NCT03430011).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8504-8504 ◽  
Author(s):  
Sham Mailankody ◽  
Andrzej J. Jakubowiak ◽  
Myo Htut ◽  
Luciano J. Costa ◽  
Kelvin Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Median Time ◽  
Phase 1 ◽  
Objective Response ◽  
Bridging Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

8504 Background: Orva-cel is an investigational, BCMA-directed CAR T cell product with a fully human binder. Over 100 pts have been treated in the EVOLVE phase 1 study. Pts treated at 50 and 150 × 106 CAR+ T cells were previously reported (Mailankody ASH 2018 #957). We now report results of the higher dose levels (DLs) in 51 pts who received orva-cel manufactured using the process intended to support commercial use. Methods: Pts with RRMM who had ≥3 prior regimens, a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody (mAb), received orva-cel at 300, 450, and 600 × 106 CAR+ T cells after lymphodepletion with fludarabine/cyclophosphamide. Results: Median pt age was 61 (range, 33–77) y; median time from diagnosis was 7.0 (range, 1.7–23.6) y, with a median of 6 (range, 3–18) prior regimens. Overall, 92% of pts were penta-exposed (2 IMiDs, 2 PIs, and an mAb); 61% of pts received bridging therapy (77% were refractory to bridging therapy). Two pts had dose-limiting toxicities: grade 3 neurological event (NE) for >7 d at 300 × 106 CAR+ T cells and grade 4 neutropenia for >28 d at 450 × 106 CAR+ T cells. Key efficacy and safety outcomes are shown in the Table. Cytokine release syndrome (CRS)/NEs were managed with tocilizumab and/or steroids (78%), anakinra (14%), and/or vasopressors (6%). Grade ≥3 anemia, neutropenia, and thrombocytopenia at 29 d occurred in 21%, 55%, and 44% of pts (median time to resolution to grade ≤2 of any cytopenia, ≤2.1 mo). Grade ≥3 infections occurred in 14%. After a median follow-up (F/U) of 5.9 mo, median progression-free survival was not reached. Conclusions: Orva-cel at 300, 450, and 600 × 106 CAR+ T cells demonstrated manageable safety (CRS grade ≥3: 2%; NE grade ≥3: 4%) and compelling efficacy in heavily pretreated pts with RRMM, with a 91% objective response rate (ORR) and 39% complete response (CR)/stringent CR (sCR) rate. Updated results will be presented, including minimal residual disease, durability of response, and recommended phase 2 dose. Clinical trial information: NCT03430011 . [Table: see text]

scholarly journals Phase 1 Study of Pomalidomide Given at the Time of Early Lymphocyte Recovery after Induction Timed Sequential Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HR-MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2820-2820
Author(s):  
Joshua F. Zeidner ◽  
Raul Montiel-Esparza ◽  
Hanna A. Knaus ◽  
Sofia Berglund ◽  
Amer M. Zeidan ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Research Funding ◽  
Phase 1 ◽  
Newly Diagnosed ◽  
Tnf Α ◽  
Grade 3

Abstract Introduction: AML pts have a poor prognosis with conventional chemotherapy regimens. Early lymphocyte recovery (ELR) following intensive timed sequential therapy (TST) induction is characterized by a dysfunctional immunosuppressive state. Pomalidomide (Pom), a small molecule immunomodulatory agent (IMiD), has direct effects on T cell co-stimulation by promoting the ubiquitination of Aiolos, an IL-2 transcriptional repressor. We hypothesized that the administration of Pom at the time of ELR after induction TST may influence T cell differentiation and enhance an anti-leukemia immune effect. Methods: A multicenter phase 1 dose escalation study was conducted to determine the safety and tolerability of Pom after intensive induction TST in newly diagnosed AML and HR-MDS pts 18-65 years. Core-binding factor AML was excluded. All pts received induction chemotherapy with AcDVP16: cytarabine 667 mg/m2/day IV continuous infusion days 1-3, daunorubicin 45 mg/m2/day IV days 1-3, etoposide 400 mg/m2/day IV days 8-10. Pom was administered at the assigned dose and schedule after day 14 and within 3 days of the total white blood cell count (WBC) reaching >0.2x109/L above nadir, defined as ELR. Three dose levels were planned (2 mg, 4 mg and 8 mg) within 2 cohorts: 10 days of Pom and 21 days of Pom, in a traditional 3+3 dose escalation design. Results: 25 pts were enrolled on this study January 2014-June 2016 across 3 institutions (Table 1). Pom administration occurred at a median of 21 days after AcDVP16 induction. There were no dose-limiting toxicities (DLTs) in the first cohort of Pom x 10 days within each dose level- 2 mg (n=3), 4 mg (n=3) and 8 mg (n=7). There were no DLTs seen at 4 mg x 21 days (n=7). Two DLTs were seen at Pom 8 mg x 21 days (Grade 3 ALT increase and Grade 3 hypoxia, respectively). Thus, Pom 4 mg x 21 days will be further expanded. Nine (36%) pts discontinued Pom early (median duration = 5 days) due to: grade 3 rash (n=3), physician discretion (decreased WBC: n=1, fever and increased creatinine: n=1), grade 3 ALT increase (n=1), grade 3 hypoxia (n=1), disease progression (n=1), and pt preference (n=1). Adverse events (AEs) possibly associated with Pom that were seen in >1 pt included fever (n=8), rash (n=7), AST/ALT increase (grade 1: n=4, grade 3: n=1), mucositis (n=2), and fatigue (n=2). All of these AEs were self-limiting with supportive care and/or discontinuation of Pom. 60-day mortality was 0%. A complete remission (CR) was achieved in 18 pts and 1 achieved CR with incomplete platelet recovery (CRp) with a combined CR + CRp = 19/25 (76%). Among pts with adverse-risk AML, 5/6 (83%) achieved CR. One pt achieved a partial remission and 5 pts were refractory to treatment. Of the 19 CRs, 15 had no evidence of minimal residual disease by cytogenetics, FISH, or flow cytometry. Among pts who completed a course of Pom (10 days or 21 days), 14/16 (88%) achieved CR. As previously reported, a dramatic decrease of Aiolos expression via flow cytometry in T cell subsets was observed in vivo for the duration of POM treatment with doses > 2 mg, but the effect was lost after Pom was stopped. Figure 1 displays the pattern of cytokine production of CD4+ T cells visualized with pie charts, and shows a significantly different subset composition at ELR in Pom-treated pts compared to the same pts at full recovery (p=0.02), and compared to control AML pts at the same time point (p=0.004). Furthermore, there was a significant increase in TNF-α production (p=0.009) and the combination of TNF-α and IL-2 production (p=0.03) in stimulated CD4+ T cells during Pom treatment, which was reduced to baseline values after Pom was discontinued at full recovery (Figure 1: data analysis performed with the SPICE software). Conclusions: Pom can be safely administered at the time of ELR after intensive induction TST. Fever and rash are the most common AEs seen after Pom administration. Inhibition of Aiolos and consequent increase in both IL-2 and TNF-α expression, as measured by flow cytometry, appear to be reliable markers of Pom-induced T cell modulation in vivo. Planned expansion of the cohort of 4 mgx 21 days will allow further evaluation of safety and activity of Pom in AML. Expression of Cytokines in CD4+ T Cells Expression of Cytokines in CD4+ T Cells Disclosures Zeidner: Takeda: Research Funding; Merck: Research Funding; Agios: Honoraria; Otsuka: Consultancy; Tolero: Research Funding. Zeidan:Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Smith:Celgene: Consultancy, Other: member of DSMB. Levis:Millennium: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Foster:Celgene: Research Funding.

scholarly journals Updated Analysis of a Phase 1, Open-Label Study of LCAR-B38M, a Chimeric Antigen Receptor T Cell Therapy Directed Against B-Cell Maturation Antigen, in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 955-955 ◽  
Author(s):  
Wan-Hong Zhao ◽  
Jie Liu ◽  
Bai-Yan Wang ◽  
Yin-Xia Chen ◽  
Xing-Mei Cao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Median Duration ◽  
Phase 1 ◽  
Open Label ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract LCAR-B38M is a bispecific chimeric antigen receptor T cell (CAR T) therapy directed against B-cell maturation antigen (BCMA). The bi-epitope BCMA binding moieties confer high avidity binding and distinguish LCAR-B38M from other BCMA CAR constructs. Preliminary results of LCAR-B38M in patients (pts) with relapsed/refractory (R/R) multiple myeloma (MM) showed encouraging efficacy and manageable safety (Fan et al.JCO 2017;35:18_suppl LBA3001). Here we present updated safety and efficacy results of the trial. LEGEND-2 (NCT03090659) is an ongoing phase 1, single-arm, open-label multicenter study evaluating LCAR-B38M in pts (18-80 years) with R/R MM. Lymphodepletion was performed using 3 doses of cyclophosphamide 300 mg/m2 on days -5, -4, and -3. Five days after lymphodepletion, LCAR-B38M CAR T cells (median CAR+ cell dose = 0.5x106 cells/kg, [range, 0.07-2x106]) were given in 3 infusions (20, 30, and 50% of total dose). The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the anti-myeloma response of the treatment. Adverse events (AEs) were graded using the Common Terminology Criteria for AE, v.4.03, and cytokine release syndrome (CRS) was assessed according to Lee et al. (Blood 2014;124:188-95). Response was evaluated using International Myeloma Working Group criteria. This analysis presents data from a single institution. As of June 25, 2018, 57 pts have been infused with LCAR-B38M CAR T cells. The median age was 54 years (range, 27-72), median number of prior therapies was 3 (range, 1-9), and 74% of pts had stage III disease by Durie-Salmon staging. The median duration of follow-up for all pts was 12 months (range, 0.7-25). AEs were reported by all pts; most common were pyrexia (91%), CRS (90%), thrombocytopenia (49%), and leukopenia (47%). Grade ≥3 AEs were reported by 65% of pts; most common were leukopenia (30%), thrombocytopenia (23%), and increased aspartate aminotransferase (21%). CRS was mostly grade 1 (47%) and 2 (35%); 4 pts (7%) had grade 3 cases. Liver function abnormalities were the most common signs of end organ injury among pts with CRS. The median time to onset of CRS was 9 days (range, 1-19). All but 1 CRS events resolved, with a median duration of 9 days (range, 3-57). No clear relationship was demonstrated between dose and CRS; there may be some effect at higher doses, but conclusions are limited by the small number of pts in the grade 3 CRS group (n=4; Figure 1A). Neurotoxicity was observed in 1 pt who had grade 1 aphasia, agitation, and seizure-like activity. The overall response rate (partial response [PR] or better) was 88% (95% confidence interval [CI], 76-95). Complete response (CR) was achieved by 42 pts (74%; 95% CI, 60-85), very good partial response was achieved by 2 pts (4%; 95% CI, 0.4-12), and PR was achieved by 6 pts (11%; 95% CI, 4-22; Figure 1B). Among pts with CR, 39/42 were minimal residual disease (MRD) negative by 8-color flow cytometry. The median time to initial response was 1 month (range, 0.4-4). No clear relationship between LCAR-B38M CAR T cell dose and response was observed (Figure 1C). BCMA expression did not correlate with clinical response. The median duration of response (DOR) was 16 months (95% CI, 12-not reached [NR]). The median DOR for pts who achieved a CR was 22 months (95% CI, 14-NR). At data cutoff, 18 pts (36%) who achieved PR or better progressed. The median progression-free survival (PFS) for all treated pts was 15 months (95% CI, 11-NR); median PFS for pts who achieved CR was 24 months (95% CI, 15-NR). The median overall survival was not reached. Overall, 17 pts died during the study and follow-up period; causes of death were progressive disease (PD; n=14), suicide after PD (n=1), esophagitis (n=1), and pulmonary embolism and acute coronary syndrome (n=1). Peak levels of LCAR-B38M (≥1x104 copies/µg genomic DNA) were observed in a majority of pts with blood samples for analysis (n=32). LCAR-B38M CAR T cells were not detectable in peripheral blood in 71% of pts at 4 months; 5 pts showed CAR T cell persistence up to 10 months. This ongoing first-in-human study has provided initial proof-of-concept that bispecific LCAR-B38M CAR T cells may be a highly effective therapy for R/R MM. LCAR-B38M CAR T cell therapy displayed a manageable safety profile consistent with its known mechanism of action and demonstrated deep and durable responses in pts with R/R MM. A phase 1/2 study of LCAR-B38M in R/R MM has been initiated in the US (NCT03548207). Disclosures Zhuang: Nanjing Legend Biotech: Employment. Fan:Nanjing Legend Biotech: Employment.

298 Final analysis of the phase 1 trial of NY-ESO-1–specific T-cell receptor (TCR) T-cell therapy (letetresgene autoleucel; GSK3377794) in patients with advanced synovial sarcoma (SS)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A325-A325
Author(s):  
Sandra D’Angelo ◽  
George Demetri ◽  
Brian Van Tine ◽  
Mihaela Druta ◽  
John Glod ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lentiviral Vector ◽  
Phase 1 ◽  
Institutional Review Boards ◽  
T Cell Therapy ◽  
Mitt Population ◽  
Link Type ◽  
Number Of Patients ◽  
Grade 3

BackgroundNY-ESO-1–specific T cells (letetresgene autoleucel [lete-cel]; GSK3377794) are autologous T cells transduced with a self-inactivating lentiviral vector to express an engineered NY-ESO-1–specific TCR that recognizes HLA-A*02–presented peptides derived from NY-ESO-1, a cancer/testis antigen expressed in 70%–80% of SS. NCT01343043 was a Phase I, open-label trial assessing safety, efficacy, and pharmacokinetics of lete-cel in patients with SS; activity was evaluated after different lymphodepletion conditioning regimens and in patients with differing levels of NY-ESO-1 expression.MethodsPatients with unresectable, metastatic, or recurrent SS who were intolerant/nonresponsive to standard first-line chemotherapy enrolled in 4 cohorts based on NY-ESO-1 tumor expression were lymphodepleted and received lete-cel infusion (table 1). Primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1; secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Transduced cell persistence was measured by qPCR of transgene vector copies in DNA extracted from PBMCs. Study was not designed/powered to compare cohorts.ResultsOverall, 50 patients enrolled; 45 received lete-cel infusion (modified intent-to-treat population). Demographics were similar between cohorts. Median time in study was 480/278/605/643 days in Cohorts 1/2/3/4, respectively. At study completion, ORR ranged from 20%–50% between cohorts, with 1 complete (lasting 34 weeks) and 14 partial responses (table 1). In Cohorts 1/2/3/4, respectively, median DoR was 31.0/8.6/32.1/16.4 weeks; median PFS was 15.4/13.1/8.6/22.4 weeks (table 1). As of 27Jan2020, median OS for Cohorts 1/2/3 was 24.3/9.9/19.9 months; Cohort 4 median OS was immature (table 1). Across cohorts, Grade ≥3 adverse events (AEs) in ≥40% of patients were mostly hematologic in nature; Grade ≥3 serious AEs (SAEs) were most frequently febrile neutropenia, dyspnea, and neutropenia (table 2). AEs of special interest included cytokine release syndrome in 44% of patients (n=20; maximum Grade 1/2/3/4 in 9/7/3/1 patients, respectively; 5 patients had SAEs [Grade ≥3 in 2 patients]; all AEs/SAEs resolved); Guillain-Barré syndrome in 2 patients (Grade 3 SAEs; resolved with sequalae); and multilineage cytopenias in 96% of patients (n=43; maximum Grade 5 in 1 patient, Grade 3/4 in others). Peak persistence of transduced cells was generally higher in responders vs non-responders (table 1); time to peak persistence was similar between these groups (median 8 days). No patients tested positive for replication-competent lentivirus.Abstract 298 Table 1NY-ESO-1 expression and lymphodepletion regimen in Cohorts 1–4, efficacy, and peak persistence in responders and nonresponders; mITT populationAbstract 298 Table 2Number of patients with Grade ≥3 AEs in the mITT population*ConclusionsIn patients with advanced SS who need effective treatment, lete-cel had a manageable safety profile; responses occurred in all cohorts, but patients with high NY-ESO-1 expression and more intensive lymphodepletion regimen received greatest benefit.AcknowledgementsThis study (208466) was funded by GlaxoSmithKline. Medical writing assistance was provided by Gemma Corr, DPhil, and Tiffany Brake, PhD, of Fishawack Indicia, UK, and funded by GlaxoSmithKline. We thank Ran Ji for contributions to statistical analysis.Trial RegistrationClinicaltrials. gov NCT01343043Ethics ApprovalThis study was approved by the appropriate institutional review boards and independent ethics committees.

scholarly journals The Worm-Specific Immune Response in Multiple Sclerosis Patients Receiving Controlled Trichuris suis Ova Immunotherapy

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 101
Author(s):  
Ivet A. Yordanova ◽  
Friederike Ebner ◽  
Axel Ronald Schulz ◽  
Svenja Steinfelder ◽  
Berit Rosche ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Clinical Efficacy ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Th2 Cells ◽  
Continuous Increase ◽  
Trichuris Suis ◽  
Multiple Sclerosis Patients

Considering their potent immunomodulatory properties, therapeutic applications of Trichuris suis ova (TSO) are studied as potential alternative treatment of autoimmune disorders like multiple sclerosis (MS), rheumatoid arthritis (RA), or inflammatory bowel disease (IBD). Clinical phase 1 and 2 studies have demonstrated TSO treatment to be safe and well tolerated in MS patients, however, they reported only modest clinical efficacy. We therefore addressed the cellular and humoral immune responses directed against parasite antigens in individual MS patients receiving controlled TSO treatment (2500 TSO p.o. every 2 weeks for 12 month). Peripheral blood mononuclear cells (PBMC) of MS patients treated with TSO (n = 5) or placebo (n = 6) were analyzed. A continuous increase of serum IgG and IgE antibodies specific for T. suis excretory/secretory antigens was observed up to 12 months post-treatment. This was consistent with mass cytometry analysis identifying an increase of activated HLA-DRhigh plasmablast frequencies in TSO-treated patients. While stable and comparable frequencies of total CD4+ and CD8+ T cells were detected in placebo and TSO-treated patients over time, we observed an increase of activated HLA-DR+CD4+ T cells in TSO-treated patients only. Frequencies of Gata3+ Th2 cells and Th1/Th2 ratios remained stable during TSO treatment, while Foxp3+ Treg frequencies varied greatly between individuals. Using a T. suis antigen-specific T cell expansion assay, we also detected patient-to-patient variation of antigen-specific T cell recall responses and cytokine production. In summary, MS patients receiving TSO treatment established a T. suis-specific T- and B-cell response, however, with varying degrees of T cell responses and cellular functionality across individuals, which might account for the overall miscellaneous clinical efficacy in the studied patients.

627 The DLL3-targeted half-life extended bispecific T cell engager (HLE BiTE®) immune-oncology therapy AMG 757 has potent antitumor activity in neuroendocrine cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A663-A663
Author(s):  
Keegan Cooke ◽  
Juan Estrada ◽  
Jinghui Zhan ◽  
Jonathan Werner ◽  
Fei Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Mouse Models ◽  
T Cell Activation ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Human T Cells

BackgroundNeuroendocrine tumors (NET), including small cell lung cancer (SCLC), have poor prognosis and limited therapeutic options. AMG 757 is an HLE BiTE® immune therapy designed to redirect T cell cytotoxicity to NET cells by binding to Delta-like ligand 3 (DLL3) expressed on the tumor cell surface and CD3 on T cells.MethodsWe evaluated activity of AMG 757 in NET cells in vitro and in mouse models of neuroendocrine cancer in vivo. In vitro, co-cultures of NET cells and human T cells were treated with AMG 757 in a concentration range and T cell activation, cytokine production, and tumor cell killing were assessed. In vivo, AMG 757 antitumor efficacy was evaluated in xenograft NET and in orthotopic models designed to mimic primary and metastatic SCLC lesions. NSG mice bearing established NET were administered human T cells and then treated once weekly with AMG 757 or control HLE BiTE molecule; tumor growth inhibition was assessed. Pharmacodynamic effects of AMG 757 in tumors were also evaluated in SCLC models following a single administration of human T cells and AMG 757 or control HLE BiTE molecule.ResultsAMG 757 induced T cell activation, cytokine production, and potent T cell redirected killing of DLL3-expressing SCLC, neuroendocrine prostate cancer, and other DLL3-expressing NET cell lines in vitro. AMG 757-mediated redirected lysis was specific for DLL3-expressing cells. In patient-derived xenograft and orthotopic models of SCLC, single-dose AMG 757 effectively engaged human T cells administered systemically, leading to a significant increase in the number of human CD4+ and CD8+ T cells in primary and metastatic tumor lesions. Weekly administration of AMG 757 induced significant tumor growth inhibition of SCLC (figure 1) and other NET, including complete regression of established tumors and clearance of metastatic lesions. These findings warranted evaluation of AMG 757 (NCT03319940); the phase 1 study includes dose exploration (monotherapy and in combination with pembrolizumab) and dose expansion (monotherapy) in patients with SCLC (figure 2). A study of AMG 757 in patients with neuroendocrine prostate cancer is under development based on emerging data from the ongoing phase 1 study.Abstract 627 Figure 1AMG 757 Significantly reduced tumor growth in orthotopic SCLC mouse modelsAbstract 627 Figure 2AMG 757 Phase 1 study designConclusionsAMG 757 engages and activates T cells to kill DLL3-expressing SCLC and other NET cells in vitro and induces significant antitumor activity against established xenograft tumors in mouse models. These preclinical data support evaluation of AMG 757 in clinical studies of patients with NET.Ethics ApprovalAll in vivo work was conducted under IACUC-approved protocol #2009-00046.

Sign in / Sign up

Export Citation Format

Share Document