Phase 1, first-in-human trial of JTX-8064, an anti-LILRB2/ILT4 monoclonal antibody, as monotherapy and in combination with anti-PD-1 in adult patients with advanced solid tumors (INNATE).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2672-TPS2672
Author(s):  
Kyriakos P. Papadopoulos ◽  
Nehal J. Lakhani ◽  
Timothy A. Yap ◽  
Allison L Naumovski ◽  
Karen S Brown ◽  
...  
Keyword(s):  
Solid Tumors ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Phase 1 ◽  
Predictive Biomarkers ◽  
Published Data ◽  
Advanced Solid Tumors ◽  
Medical Needs ◽  
Specific Expansion

TPS2672 Background: Leukocyte Immunoglobulin-like receptor B2 [LILRB2; immunoglobulin-like transcript 4 (ILT4)] is an immunoinhibitory protein expressed on the surface of myeloid cells and is a therapeutic target of interest in immuno-oncology. Published data showed that antagonism of LILRB2 resulted in the repolarization of human macrophages from an M2 (suppressive) to M1 (pro-inflammatory) phenotype, and enhancement of anti-tumor immunity in a mouse model (Chen 2018). JTX-8064 is a novel humanized IgG4 monoclonal antagonist antibody that selectively binds LILRB2 and prevents it from binding its ligands, classical and non-classical MHC I molecules. By blocking the ability of LILRB2 to bind HLA-A/B and/or HLA-G, a marker of immunotolerance on cancer cells, JTX-8064 has been shown to enhance pro-inflammatory cytokine production in macrophages (Cohen 2019). Additionally, blocking HLA-A/B-LILRB2 binding with JTX-8064 may augment antigen presentation and has been shown to lead to enhanced T cell activation and IFNg production (McGrath 2021). Using an ex vivo tumor explant model, we observed an IFNg-associated pharmacodynamic response in tumor tissue treated with JTX-8064 and a PD-1 inhibitor (PD-1i) that was not observed with PD-1i alone. Biomarkers were identified that predicted this JTX-8064 driven response (Hashambhoy-Ramsay 2020). It is hypothesized that JTX-8064 is a novel macrophage immune checkpoint inhibitor that may overcome mechanisms of resistance to PD-1i in tumors not responsive to JTX-8064 or PD-1i alone. Methods: The primary objectives of this open-label, phase 1, first-in-human, multicenter trial are to determine the safety and tolerability, and the recommended phase 2 dose (RP2D) of JTX-8064 as a monotherapy and in combination with a PD-1i, JTX-4014 (a Jounce investigational agent) or pembrolizumab, in patients with advanced solid tumors (NCT04669899). The INNATE study will consist of 4 stages: 1) JTX-8064 monotherapy dose escalation, 2) JTX-8064 dose escalation in combination with a PD-1i, 3) JTX-8064 monotherapy in indication-specific expansion cohorts and 4) JTX-8064 in combination with a PD-1i in indication-specific expansion cohorts. Stages 1 and 2 will employ an innovative interval i3 + 3 design with Bayesian decision framework to guide dose escalation. Safety, pharmacokinetic and receptor occupancy data will be considered during dose escalation. INNATE will assess pharmacodynamic and potential predictive biomarkers of response, and the expansion cohorts will explore multiple patient populations, including PD-(L)1i sensitive and PD-(L)1i-resistant (primary or acquired) patients to address current unmet medical needs. Enrolment in INNATE began in January 2021. Clinical trial information: NCT04669899.

A phase 1, multicenter, open-label, dose-escalation, safety, pharmacodynamic, pharmacokinetic study of Q702 with a cohort expansion at the RP2D in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2673-TPS2673
Author(s):  
Angela Tatiana Alistar ◽  
Anthony B. El-Khoueiry ◽  
Devalingam Mahalingam ◽  
Monica M. Mita ◽  
Hwankyu Kang ◽  
...  
Keyword(s):  
Solid Tumors ◽  
T Cell Activation ◽  
Pharmacokinetic Study ◽  
Dose Escalation ◽  
Cell Activation ◽  
Phase 1 ◽  
Innate Immune ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Label Dose

TPS2673 Background: Immune checkpoint inhibitors directly targeting T cell activation have been successfully used in the treatment of various malignancies, nevertheless, the durable ORRs are low for certain indications. The low ORRs have been attributed to the immune suppressive tumor microenvironment (TME), composed of innate immune suppressive components such as tumor associated macrophages (TAM) and myeloid-derived suppression cells (MDSC). The potential contributions of innate immune modulation to anti-tumor immunity, suggest the need for the novel strategies to elicit a more efficient/robust immune response against the targeted malignant cells. Axl, Mer and CSF1R receptor tyrosine kinases play vital roles in promoting an immune suppressive TME by affecting TAM and MDSC populations and by decreasing antigen presentation on tumor cells. Q702 is a novel Axl/Mer/CSF1R inhibitor, able to modulate the TAM and MDSC population leading to CD8+ T cell activation and to increase antigen presentation of the tumor cells in syngeneic animal models. Q702, as a monotherapy, shows significant tumor growth inhibition in multiple syngeneic tumor models, and demonstrates synergistic effects with anti-PD-1 treatment particularly in high myeloid containing tumor models. Interestingly, intermittent administration of Q702 monotherapy demonstrates a more favorable immune cell population changes, possibly through preventing immune exhaustion secondary to negative feedback with continuous activation. These results suggest that Q702 monotherapy or in combination with existing therapies have a good potential to become a novel treatment strategy for patients with advanced solid tumors. Methods: “A Phase 1, Multicenter, Open-label, Dose-Escalation, Safety, Pharmacodynamic, Pharmacokinetic Study of Q702 with a Cohort Expansion at the RP2D in Patients with Advanced Solid Tumors. (NCT04648254)” is open and recruiting patients at 4 US investigative sites. Patients with histologically or cytologically confirmed advanced or metastatic solid tumors, that have progressed following SOC or for which there is no SOC which confers clinical benefit are being enrolled in this study. The study follows a standard dose escalation. The study will enroll up to 78 patients. The primary endpoint is to establish safety, PK profile and define the recommended phase 2 dose. The secondary and exploratory endpoints include establishing pharmacokinetic/pharmacodynamic relationship, potential biomarkers and preliminary anti-tumor activity. Clinical trial information: NCT04648254.

Phase Ib study to test the safety and activity of pembrolizumab (anti-PD-1) and trebananib (angiopoietin-2 inhibitor [Ang-2]) in patients with advanced solid tumors: Updated analysis of the colorectal cancer (CRC) cohort.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 155-155
Author(s):  
Osama E. Rahma ◽  
James M. Cleary ◽  
Kimmie Ng ◽  
Benjamin L. Schlechter ◽  
Jessica Eno ◽  
...  
Keyword(s):  
Overall Survival ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Abdominal Distension ◽  
Induction Phase ◽  
Advanced Solid Tumors ◽  
Pre Treatment ◽  
Angiopoietin 2

155 Background: Ang-2 is produced by endothelial cells, predominantly in tissues undergoing vascular remodeling. Current studies suggest that Ang-2 partially suppresses T cell activation by increasing PD-L1 expression and decreasing activation of monocytes. We demonstrated that high pre-treatment serum Ang-2 is associated with reduced overall survival in patients treated with PD-1 blockade. We therefore hypothesized that the combination of Ang-2 and PD-1 blockade may be effective for treatment of patients with advanced cancer. Methods: We initiated a phase 1b trial of the combination of pembrolizumab and trebananib, an Ang-1/2 neutralizing peptibody in advanced solid tumors. Treatment consisted of an induction phase of pembrolizumab 200 mg every 3 weeks and trebananib weekly (with an initial run-in dose escalation of 15-30 mg/kg) for 12 weeks followed by pembrolizumab alone for 2 years. Here we present the updated data in the fully enrolled CRC expansion cohort. Results: The study enrolled 18 microsatellite stable (MSS) CRC patients. There were no DLTs in the dose escalation phase, and 30mg/kg was deemed to be the MTD. This summary is based on 15 CRC patients treated with 30 mg/kg trebananib plus pembrolizumab. The most common treatment-related adverse events (AEs) were abdominal distension, diarrhea, limb edema, transaminitis, and proteinuria, each reported in 40% of the patients. As of September 2019 (median follow up of 10 months), 13 patients were off treatment and two were continuing. Eleven patients were off treatment due to disease progression and 2 due to unacceptable toxicities (grade 4 pneumonitis and grade 3 transaminitis). The response rate was 7% (1 partial response for 23.8+ months) and the disease control rate was 27%, with 4 stable disease for a median of 10 months (4-18 months). Median time to progression and overall survival were 2.8 months (90% CI: 1.5 to 8.1 months) and 9.0 months (90% CI: 2.6 months to ∞), respectively. Conclusions: The combination of pembrolizumab and trebananib is well tolerated and demonstrated promising activity in patients with heavily treated MSS CRC. Clinical trial information: NCT03239145.

Phase I dose escalation of KD033, a PDL1-IL15 bispecific molecule, in advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2568-2568
Author(s):  
Jason J. Luke ◽  
Anthony J. Olszanski ◽  
Igor Puzanov ◽  
Dan Lu ◽  
Adrian Hackett ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Cell Activation ◽  
Nk Cell ◽  
Phase 1 ◽  
Locally Advanced ◽  
Advanced Solid Tumors ◽  
Efficacy Evaluation ◽  
Open Label

2568 Background: IL-2 and IL-15 signal through the shared IL-2/15 βγ receptor, but unlike IL-2, IL-15 does not expand regulatory T cells (Tregs), does not mediate activation-induced cell death and may have an improved therapeutic index. KD033 is a fusion antibody combining a fully human, high affinity anti-human Programmed Death Ligand 1 (PD-L1) IgG1 antibody with the human IL-15 receptor alpha (IL15Rα) sushi domain and human IL-15 (IL-15). KD033 (or its mouse cross reactive surrogate molecule, srKD033) has been extensively characterized in multiple in vitro and in vivo nonclinical studies. The fusion of anti-PD-L1 antibody to IL-15 significantly increases the maximal-tolerated dose (MTD) of srKD033 in mice compared to free IL-15. In addition, srKD033 has exhibited increased efficacy in rejecting tumors in mice as compared to the combination of its individual components, anti-PD-L1 antibody and IL-15. Methods: This is a phase 1, open-label, multiple ascending dose, multi-center clinical trial being conducted in patients with metastatic or locally advanced solid tumors (NCT04242147). The primary objective is to determine the safety and tolerability and the MTD of KD033. Secondary objectives include characterization of PK and immunogenicity, evaluation of CD8 T and NK cell activation and assessment of best overall response and duration of response. KD033 is administered by IV infusion over 30 minutes every 14 days. Accelerated intra-patient dose escalation across the initial three dose levels, followed by 3+3 escalation thereafter, is investigating dose ranges from 3 µg/kg to 600 µg/kg. Efficacy evaluation is planned in an expansion cohort of patients with PD-1/L1 refractory tumors. Results: A total of 7 patients have received treatment. Three patients were dosed in Cohort 1 and four patients were dosed in Cohort 2. Through two dose escalation cohorts (3 µg/kg – 25 µg/kg), no dose-limiting toxicities have been reported. Grade 1-2 treatment-related toxicities, when observed, resolved within 24 hours with supportive management. 6 patients are evaluable for treatment response with one patient (adenoid cystic carcinoma) in the first cohort having stable disease for more than 6 months. Conclusions: KD033 has been well tolerated early in dose escalation with on-mechanism pharmacodynamics consistent with IL-15 agonism. Clinical trial information: NCT04242147.

A phase I dose expansion cohort study of dasatinib in combination with bevacizumab in advanced solid tumors (NCT01445509).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2585-2585
Author(s):  
Akosua Osei-Tutu ◽  
Ana Tablante Nunes ◽  
Jung-min Lee ◽  
Minshu Yu ◽  
Lidia Hernandez ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Cell Activation ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Vegf Receptor ◽  
Advanced Solid Tumors ◽  
Expansion Cohort

2585 Background: Dasatinib is a known inhibitor of the SRC family kinases and is approved for use in chronic myelogenous leukemia. Bevacizumab inhibits angiogenesis, binding to human vascular endothelial growth factor (VEGF, or VEGF-A) with high affinity. VEGF receptor signals intracellularly via a cascade regulated by SRC. Given the presence of this signaling pathway in both tumor cells and endothelial cells, we hypothesized that attenuation of both SRC and VEGF simultaneously would have synergistic antitumor activity. We previously reported the maximum tolerated dose (MTD) of dasatinib 100mg daily with bevacizumab 10mg/kg q2wk in patients with advanced solid tumors. We now report clinical activity of the combination, and translational endpoints of an expansion cohort. Methods: This is a phase 1 dose escalation with non-randomized expansion cohort. We monitored safety, and response was assessed every 8 weeks using RECIST criteria. Correlative endpoints include blood flow by dynamic MR imaging, endothelial cell density by CD31 immunohistochemistry, functional angiogenic potential by plasma cytokines and rat aortic ring assay, and tumor cell activation state by phosphoprotein analysis. Results: We enrolled 39 patients at the MTD for a total of 50 patients on study, including both the dose escalation and dose expansion phases. No patient experienced dose limiting toxicities during dose escalation. The most common adverse events were grade 2 hypertension and proteinuria. By RECIST, 5 (10%) patients had a partial response, and stable disease was seen in 29 (58%) of patients with a range from 12-145+ weeks on study. We had two exceptional responders with endometrial carcinoma who continue on study to date (112 weeks and 145 weeks). Translational endpoints were correlated with clinical outcome. Conclusions: Bevacizumab and dasatinib are safe in combination, with potential clinical activity. This combination warrants further investigation in solid tumors. Ongoing translational research using specimens from exceptional responders will suggest potential biomarkers of clinical benefit, to be tested in future prospective clinical trials. Clinical trial information: NCT01445509.

FPT155-001: A phase Ia/Ib study of FPT155 (CD80-FC) in patients with advanced solid tumors.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. TPS42-TPS42
Author(s):  
Michael Millward ◽  
Hui Kong Gan ◽  
Anthony M. Joshua ◽  
James Chun-Yen Kuo ◽  
Amy Prawira ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Objective Response ◽  
Advanced Solid Tumors ◽  
Multiple Tumor ◽  
Secondary Endpoints ◽  
Phase 1B

TPS42 Background: Despite recent advances in immunotherapy, many patients with advanced solid tumors are refractory to available therapies or eventually relapse. Novel immune therapies are needed with differentiated mechanisms of action that result in improved response rates and durability across a broad range of tumors. FPT155 is a first-in-class therapeutic being developed to meet this need. FPT155 is a recombinant fusion protein composed of the extracellular domain of human CD80 fused with the Fc domain of human immunoglobulin G1. It is designed to act as a potent stimulator of anti-tumor immunity through CD28 and thereby co-stimulate T cell responses only in the presence of antigenic T cell receptor (TCR) signaling. FPT155 alone does not induce spontaneous cytokine release by primary human immune cells, in contrast to a CD28 superagonist antibody that exerts TCR stimulus-independent activity. FPT155 also blocks CTLA-4 from competing for endogenous CD80, allowing CD28 signaling to prevail in T cell activation. A murine surrogate of FPT155 is a potent inhibitor of tumor growth that induces complete tumor regression in multiple tumor models, including models that are insensitive to anti-PD1 or anti-CTLA4. Methods: The FPT155-001 study is a Phase 1a/1b open-label, multicenter, dose escalation and expansion study to evaluate the safety and tolerability of FPT155 monotherapy. Phase 1a dose escalation includes an accelerated titration design followed by a standard 3+3 design until the recommended dose for Phase 1b is determined by evaluation of all available safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. Eligible patients with advanced solid tumors who are refractory to all standard therapy for their malignancy will be enrolled in Phase 1a. Phase 1b dose expansion will enroll patients with select tumor types. The primary endpoint is safety in both phases. Key secondary endpoints in Phase 1a include characterization of the FPT155 PK profile and immunogenicity. Key secondary endpoints in Phase 1b include objective response rate, duration of response, progression free survival, and disease control rate. The FPT155-001 trial opened for enrollment in October 2018 and is in progress. Clinical trial information: Submitted - awaiting registration number.

AGEN1181, a clinical stage Fc-engineered anti-CTLA-4 antibody with improved therapeutic potential for the treatment of patients with advanced malignancies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3157-TPS3157
Author(s):  
Steven O'Day ◽  
Chethan Ramamurthy ◽  
Andrea J. Bullock ◽  
Anthony B. El-Khoueiry ◽  
Lernik Ohanjanian ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Dose Escalation ◽  
First Generation ◽  
Therapeutic Potential ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1 Study

TPS3157 Background: AGEN1181 is a novel Fc-optimized anti-CTLA4 antibody, currently being evaluated in an ongoing multi-center, open-label, phase 1 study in all advanced solid tumors as mono-therapy and combination with anti-PD-1 antibody, AGEN2034 (NCT03860272). AGEN1181 is Fc-engineered to harness a novel mechanism for enhanced FcγR-dependent functionality relative to first-generation CTLA-4 antibodies. In pre-clinical models, AGEN1181 enhances T cell priming, depletion of intratumoral regulatory T cells (Treg) and improved memory formation compared to first-generation anti-CTLA-4 antibodies. Most notably, AGEN1181 demonstrates improved binding to FcyRIIIA and superior T cell responsiveness in populations that only express the low affinity FcγRIIIA receptor relative to first-generation IgG1 CTLA-4 antibodies. The combination of AGEN1181 and AGEN2034 further enhances T cell activation and effector function. Methods: This phase 1 study is an open-label, multi-center dose-escalation designed to evaluate the safety, tolerability, dose limiting toxicity (DLT) PK, and pharmacodynamic profiles of patients with refractory advanced solid tumors who did not receive an anti-CTLA4 previously. The study is being conducted in 3 arms; with patients assigned using a standard 3+3 dose escalation design in the mono-therapy arms with AGEN1181 and an accelerated design in the combination with AGEN2034 arm. AGEN1181 is administered as IV infusion as mono-therapy on Day 1 of every 3 weeks (0.1,0.3,1,2,4 mg/kg), every 6-weeks (1,2,4 mg/kg) in parallel cohorts and every 6-weeks (0.1,0.3,1,2,4 mg/kg) in combination with AGEN2034 (3mg/kg Q2Weeks) until disease progression or unacceptable toxicity (maximum 2 years). All 3 Arms are open and enrolling patients. The study is expected to enroll approximately 80 evaluable patients with solid tumors. Dose reductions are not allowed in the event of AGEN1181-related toxicities. Currently 3 cohorts have been completed, first cohort in the combination arm and the fourth cohort in the monotherapy arm are enrolling. Preclinical and clinical assessment of AGEN1181 supports continued development as a potential therapy for refractory or relapsed advanced solid tumors. Clinical trial information: NCT03860272 .

406 CDX527–01, a phase 1 dose-escalation and expansion study of the PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A431-A431
Author(s):  
Michael Yellin ◽  
Tracey Rawls ◽  
Diane Young ◽  
Philip Golden ◽  
Laura Vitale ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Clinical Activity ◽  
Tumor Types ◽  
Anti Tumor Activity

BackgroundCD27 ligation and PD-1 blockade elicit complementary signals mediating T cell activation and effector function. CD27 is constitutively expressed on most mature T cells and the interaction with its ligand, CD70, plays key roles in T cell costimulation leading to activation, proliferation, enhanced survival, maturation of effector capacity, and memory. The PD-1/PD-L1 pathway plays key roles in inhibiting T cell responses. Pre-clinical studies demonstrate synergy in T cell activation and anti-tumor activity when combining a CD27 agonist antibody with PD-(L)1 blockade, and clinical studies have confirmed the feasibility of this combination by demonstrating safety and biological and clinical activity. CDX-527 is a novel human bispecific antibody containing a neutralizing, high affinity IgG1k PD-L1 mAb (9H9) and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb (2B3) genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies have demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations, and together with the IND-enabling studies support the advancement of CDX-527 into the clinic.MethodsA Phase 1 first-in-human, open-label, non-randomized, multi-center, dose-escalation and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 is ongoing. Eligible patients have advanced solid tumor malignancies and have progressed on standard-of-care therapy. Patients must have no more than one prior anti-PD-1/L1 for tumor types which have anti-PD-1/L1 approved for that indication and no prior anti-PD-1/L1 for tumor types that do not have anti-PD-1/L1 approved for that indication. CDX-527 is administered intravenously once every two weeks with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The dose-escalation phase initiates with a single patient enrolled in cohort 1. In the absence of a dose limiting toxicity or any ≥ grade 2 treatment related AE, cohort 2 will enroll in a similar manner as cohort 1. Subsequent dose-escalation cohorts will be conducted in 3+3 manner. In the tumor-specific expansion phase, up to 4 individual expansion cohort(s) of patients with specific solid tumors of interest may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX 527. Tumor assessments will be performed every 8-weeks by the investigator in accordance with iRECIST. Biomarker assessments will include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment.ResultsN/AConclusionsN/ATrial RegistrationNCT04440943Ethics ApprovalThe study was approved by WIRB for Northside Hospital, approval number 20201542

scholarly journals Safety and tolerability of quizartinib, a FLT3 inhibitor, in advanced solid tumors: a phase 1 dose-escalation trial

BMC Cancer ◽  
2018 ◽  
Vol 18 (1) ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
Eytan Ben-Ami ◽  
Amita Patnaik ◽  
Denise Trone ◽  
Jianke Li ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Flt3 Inhibitor
Sign in / Sign up

Export Citation Format

Share Document