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 Ib study of pembrolizumab and trebananib (angiopoietin-2 inhibitor [Ang-2]): Preliminary analysis of the colorectal cancer (CRC) cohort.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14160-e14160
Author(s):  
Osama E. Rahma ◽  
James M. Cleary ◽  
Benjamin L. Schlechter ◽  
Kimmie Ng ◽  
Jessica Eno ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Abdominal Distension ◽  
Data Retrieval ◽  
Induction Phase ◽  
Heavily Pretreated ◽  
Pre Treatment ◽  
Expansion Cohort ◽  
Angiopoietin 2

e14160 Background: Ang-2 is produced by endothelial cells, predominantly in tissues undergoing vascular remodeling and in hypoxic microenvironments. Ang-2 partially suppresses T cell activation by increasing PD-L1 expression and decreasing monocyte activation. Our group demonstrated that high pre-treatment serum Ang-2 is associated with reduced overall survival (OS) in patients treated with PD-1 blockade. Methods: We initiated a phase 1b trial to evaluate the safety, efficacy, and immunological effect of the combination of pembrolizumab and trebananib, an Ang-1/2 neutralizing peptibody, in 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 preliminary data in the fully enrolled CRC expansion cohort. Results: The study enrolled a total of 18 microsatellite stable (MSS) heavily pretreated CRC patients. There were no DLTs and 30mg/kg was deemed to be the MTD. This summary is based on 15 CRC patients treated with 30 mg/kg trebananib (3 in dose escalation, 12 in dose expansion) plus pembrolizumab. Nine patients (60%) were female and the median age was 51 years (43-63). The most common treatment-related adverse events (AEs) were abdominal distension, diarrhea, limb edema, transaminitis, and proteinuria (each reported in 40% of the patients). One grade 3 transaminitis and one grade 4 pneumonitis related to pembrolizumab were reported. As of the date of data retrieval, 11 patients were off treatment and four were continuing with a median follow-up of 6.1 months. The response rate was 7% (1 partial response for 14 months) and the disease control rate was 33% (4 stable disease with CEA trending down). Median time to progression and OS were 2.8 (90% CI: 1.5 to 4.9 months) and 11.4 months (90% CI: 2.6 months to ∞), respectively. Conclusions: The combination of pembrolizumab and trebananib is well tolerated and demonstrated promising activity in heavily pretreated MSS CRC. Paired biopsies and blood were collected for planned correlative immune analyses which will be presented at the meeting. Clinical trial information: NCT03239145.

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 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.

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.

A phase I study to evaluate the T-cell engager AMV564 alone and in combination with pembrolizumab in subjects with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3101-3101
Author(s):  
Alexander Starodub ◽  
Sarina Anne Piha-Paul ◽  
Raghad Karim ◽  
Curtis Ruegg ◽  
Victoria Smith ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cell Activation ◽  
Gastroesophageal Junction ◽  
Effector Memory ◽  
Cytotoxic T Cell ◽  
Advanced Solid Tumors

3101 Background: Overcoming the immune-suppressive tumor environment induced by myeloid-derived suppressor cells (MDSC) is a major challenge in immune therapy. CD33 signaling in immature myeloid cells promotes expansion of MDSC and production of immune-suppressive factors. AMV564 is a bivalent, bispecific T-cell engager that binds CD3 and CD33. Preferential binding of AMV564 to areas of high CD33 density enables selective targeting of MDSC. Ex vivo data (Cheng 2017; Blood;130:51) and an ongoing clinical trial in acute myeloid leukemia (NCT03144245) demonstrate the ability of AMV564 to deplete MDSC while sparing monocytes and neutrophils. Methods: In this 3+3 dose escalation study, patients with advanced solid tumors receive AMV564 once daily via subcutaneous (SC) injection for 2 out of 3 wks per cycle, alone or in combination with pembrolizumab (200 mg every 3 wks). Key objectives are to evaluate AMV564 safety, identify a maximum tolerated or recommended phase 2 dose, and evaluate PK, immunophenotype of myeloid and T cell compartments, and preliminary efficacy. Results: Eleven patients have been enrolled: 8 monotherapy (3 at 15 mcg/d, 5 at 50 mcg/d) and 3 combination (5 mcg/d). Tumor types include ovarian (n = 2), small bowel, gastroesophageal junction, endometrial, rectal, penile, urothelial, squamous cell carcinoma (skin), appendiceal, and non-small cell lung. AMV564 was associated with grade (G) 1-2 injection site reactions and G1-2 fevers, which were manageable with acetaminophen and diphenhydramine, as well as G2 weight gain and G3 anemia. No dose-liming toxicity has been observed in any cohort. Three monotherapy patients (15 mcg/d) were evaluable for efficacy with ≥1 on-treatment scan; 2 had SD and 1 PD per RECIST 1.1 criteria. T cell activation, as shown by redistribution from the periphery (margination), was apparent in the first week of dosing for most patients. Compensatory myelopoiesis led to initial expansion of MDSC which were then depleted by AMV564. Increased cytotoxic T cell activation and T-helper (Th) 1 response was evidenced by increased T-bet positive CD4 and CD8 cells and controlled or decreased regulatory T cells. In some patients, effector memory CD8 cell populations (Tem and Temra) were expanded. Conclusions: AMV564 is safe and tolerable when administered SC at doses of 15 mcg/d alone and 5 mcg/d in combination with pembrolizumab. AMV564 depleted MDSC populations and altered T cell profiles consistent with activation of cytotoxic T cells and a Th1 response. Clinical trial information: NCT04128423 .

Safety and Activity of Varlilumab, a Novel and First-in-Class Agonist Anti-CD27 Antibody, in Patients With Advanced Solid Tumors

2017 ◽  
Vol 35 (18) ◽  
pp. 2028-2036 ◽  
Author(s):  
Howard A. Burris ◽  
Jeffrey R. Infante ◽  
Stephen M. Ansell ◽  
John J. Nemunaitis ◽  
Geoffrey R. Weiss ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Costimulatory Molecule ◽  
Progression Free Survival ◽  
Advanced Solid Tumors ◽  
Free Survival ◽  
Metastatic Rcc

Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design (n = 25), patients received a single dose of varlilumab (0.1, 0.3, 1.0, 3.0, or 10 mg/kg intravenously) with a 28-day observation, followed by up to five multidose cycles (one dose per week for 4 weeks), depending on tumor response. Expansion cohorts were initiated at 3.0 mg/kg in patients with melanoma (n = 16) and renal cell carcinoma (RCC; n = 15). Primary objectives were to assess the safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics, and clinical antitumor activity of varlilumab. Results Exposure to varlilumab was linear and dose proportional across dose groups. Only one patient experienced a dose-limiting toxicity—grade 3 transient asymptomatic hyponatremia at the 1.0-mg/kg dose level. Treatment-related adverse events were generally grade 1 or 2 in severity. Evidence of biologic activity consistent with CD27 stimulation—chemokine induction, T-cell stimulation, regulatory T cell depletion—was observed at all dose levels. A patient with metastatic RCC experienced a partial response (78% shrinkage, progression-free survival > 2.3 years). Eight patients experienced stable disease > 3 months, including a patient with metastatic RCC with progression-free survival of > 3.9 years. Conclusion Dose escalation of varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.

A phase I study of CD40 agonist ABBV-927 plus OX40 agonist ABBV-368 with or without the PD-1 inhibitor budigalimab in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3147-TPS3147
Author(s):  
John D. Powderly ◽  
Anthony Tolcher ◽  
Patricia LoRusso ◽  
Martha Elizabeth Blaney ◽  
Daniel Dacosta ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cell Activation ◽  
Group Performance ◽  
Costimulatory Molecule ◽  
Eastern Cooperative Oncology Group ◽  
Cell Activity ◽  
Advanced Solid Tumors ◽  
Disease Specific

TPS3147 Background: CD40 is a key costimulatory molecule for both the innate and adaptive immune systems that is essential for T-cell activation and proliferation. OX40 is a costimulatory molecule that is involved in enhancing nascent immune responses and concomitantly acts to suppress regulatory T-cell activity. ABBV-927 and ABBV-368 are potent agonistic antibodies against CD40 and OX40, respectively. This open-label, Phase 1 study will evaluate the doublet combination of ABBV-927 and ABBV-368 and the triplet combination of ABBV-927, ABBV-368, and the programmed cell death protein-1 (PD-1) inhibitor budigalimab in patients with advanced solid tumors. Methods: For this study (NCT03893955), patients must be ≥18 y with an Eastern Cooperative Oncology Group performance status of 0-1. Patients must have an advanced solid tumor that has progressed on standard therapies. Disease-specific cohorts will include patients with non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC). Patients with NSCLC must have previously received a PD-1/PD-ligand 1 inhibitor and a platinum-based therapy and no more than one prior immunotherapy. Patients with TNBC must not have received immunotherapy. Patients with uncontrolled central nervous system metastases will be excluded. The recommended Phase 2 dose (RP2D) will first be identified with ABBV-927 + ABBV-368 in patients with solid tumors (Arm A) and will be expanded in disease-specific cohorts including TNBC. The RP2D of ABBV-927 + ABBV-368 + budigalimab will be identified in patients with NSCLC (Arm B). The primary endpoints are determination of the RP2D of ABBV-927 + ABBV-368, the RP2D of ABBV-927 + ABBV-368 + budigalimab, and overall response rate; duration of response, progression-free survival, safety, and pharmacokinetics are secondary endpoints. Screening began on 21 May 2019, and enrollment is ongoing. Clinical trial information: NCT03893955 .

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 escalation (DE) and cohort expansion (CE) study of ERY974, an anti-glypican 3 (GPC3)/CD3 bispecific antibody, in patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3112-TPS3112
Author(s):  
Kenji Hashimoto ◽  
Ayesh Perera ◽  
Naofumi Sugaya ◽  
Yoshitaka Ogita ◽  
Mikiko Nakamura ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Gastroesophageal Junction ◽  
Occurrence Rate ◽  
Cytotoxic T Cell ◽  
Therapy Strategy

TPS3112 Background: Bispecific antibodies to facilitate T-cell directed cytotoxicity (TDCC) is a proven therapy strategy in cancer. ERY974 is a humanized IgG4 bispecific antibody designed to simultaneously bind to cytotoxic T-cell CD3 receptors and GPC3 (a glycoprotein expressed on cell surface of several tumors) to elicit T-cell activation and TDCC. The objectives of this multi-country, phase 1 study of ERY974 is to determine the maximum tolerated dose (MTD) and to perform a preliminary assessment of anti-tumor activity in patients with solid tumors expressing GPC3. Methods: ERY974 is dosed IV weekly. All patients receive premedication with dexamethasone (DEX) prior to 1st and 2nd ERY974 dose. DE uses an accelerated titration design (ATD), then a modified continual reassessment method (mCRM) described by one-parameter logistic model, to determine MTD, where DLT occurrence rate is 0.25. Combining ATD and mCRM is to permit rapid dose escalation whilst minimizing patient numbers exposed to sub-therapeutic doses, and to accurately determine MTD. Once grade 2 (G2) cytokine release syndrome (CRS) is observed, DEX is increased. If ≥G2 CRS is again observed, then at all subsequent doses the 1st dose of ERY974 is fixed at the last dose level when < G2 CRS was not seen, DE proceeds with the 2nd dose. ATD commences with n = 1, increasing to n = 3 once drug-related ≥G2 toxicity is seen. mCRM starts after 1st dose limiting toxicity (DLT), with the modifications of at least 3 patients required to dose escalate and up to 1.5x increment to minimize risk of toxicity. CE has 3 arms: GPC3+ gastric/gastroesophageal junction adenocarcinoma; GPC3+ squamous esophageal cancer; and other GPC3+ tumors. A 2-stage design is used to allow CE to stop early for futility. Subjects are adults with histologically confirmed, measurable malignant solid tumors and/or metastatic disease not amenable to standard therapy, and life expectancy ≥3 months. Patients with > 1cm or > 1 brain metastasis, current/previous interstitial lung disease, and acute/chronic infection are excluded. 3 cohorts have been completed without DLT. Cohort 4 began in January 2017. Clinical trial information: NCT02748837.

scholarly journals 502 Recommended phase 2 dose, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the IL-15 superagonist SO-C101 as monotherapy in patients with advanced/metastatic solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A534-A534
Author(s):  
Aurelien Marabelle ◽  
Stéphane Champiat ◽  
Vladimir Galvao ◽  
Aung Naing ◽  
Filip Janku ◽  
...  
Keyword(s):  
Partial Response ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Stable Disease ◽  
Cell Activation ◽  
Maximum Tolerated Dose ◽  
Phase 2 ◽  
Open Label ◽  
Dose Escalation Study

BackgroundSO-C101 is a superagonist fusion protein of IL-15 and the IL-15 receptor α sushi+ domain. SO-C101 was investigated in a multicenter, open-label, dose escalation study as monotherapy and in combination with pembrolizumab in patients with selected advanced/metastatic tumors (NCT04234113).MethodsThe SO-C101 monotherapy part of the study followed a classical 3+3 dose escalation design. Study objectives were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D).The evaluation period for dose-limiting toxicities in each dose step was 21 days. The RP2D was defined as MTD or below, also considering pharmacokinetic and pharmacodynamic parameters.The study is ongoing (data cut-off 21 June 2021).ResultsThirty patients with a median of 3 (range 1–9) lines of previous systemic therapies were treated at doses 0.25, 0.75, 1.5, 3.0, 6.0., 9.0, 12.0, and 15 µg/kg. At 15 µg/kg, 2 of 3 patients had a dose-limiting toxicity (hyperbilirubinaemia grade [G] 4 and transaminase increase G3). The MTD was reached at 12 µg/kg. This dose was determined as the RP2D, supported by a dose-dependent increase in NK- and CD8+ T cell activation, the latter reaching a plateau at 12 µg/kg. SO-C101 plasma concentration increased dose-proportionally (Tmax was 5.5 hours and T1/2 was 4 hours).The most common adverse events (AEs) were G1 or G2 lymphopenia, local injection site reactions, transaminase increase, flu-like syndrome, and CRS-related symptoms such as fever and chills. Study drug-related AEs >G2 that occurred more than once were lymphopenia and transaminase increase. No treatment-related death was reported.One patient with cutaneous squamous cell carcinoma, who had previously progressed on cemiplimab, showed a partial response at 6.0 µg/kg (duration >4 months, target lesion decrease of 58%). After progression, the patient was put on combination treatment (SO-C101 and pembrolizumab) and again achieved a significant partial response. Two other patients treated with doses below the RP2D had confirmed stable disease for 6 and 15 weeks.At the RP2D, one patient out of 6 discontinued due to progression, while 5 are stable and receiving treatment (range 4–11 weeks).ConclusionsThe RP2D was defined at 12 µg/kg. SO-C101 administration induced a strong activation of peripheral NK and CD8+ T cells reproducible after each dosing. Related AEs were manageable and resolved quickly. Preliminary clinical efficacy signals including stable disease and partial response were observed in this heavily pretreated patient population. SO-C101 monotherapy has the potential to provide additional clinical benefit to patients with solid tumors.Trial RegistrationNCT04234113Ethics ApprovalThis study was approved by the FDA (IND 140011) and by the Ethics Boards of participating institutions.

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