A phase I study of AK119, an anti-CD73 monoclonal antibody, in combination with AK104, an anti-PD-1/CTLA-4 bispecific antibody, in patients with advanced or metastatic solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2675-TPS2675
Author(s):  
Ben Markman ◽  
Amy Hsin-Chieh Hsieh ◽  
Jermaine Coward ◽  
Matteo S. Carlino ◽  
Sophia Frentzas ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Checkpoint Inhibitors ◽  
Primary Objective ◽  
Open Label ◽  
Tumor Types ◽  
Anti Tumor Activity

TPS2675 Background: AK119 is a humanized IgG1 monoclonal antibody (mAb) that selectively binds to and inhibits the ectonucleotidase activity of CD73, a cell surface enzyme that converts adenosine monophosphate (AMP) into adenosine. Adenosine has been shown to facilitate tumor-mediated evasion. CD73 inhibition may therefore reduce adenosine accumulation and promote anti-tumor immunity. AK104 is a recombinant humanized IgG1 bispecific antibody that simultaneously binds to programmed cell death protein 1 (PD-1) and cytotoxic T- lymphocyte-associated antigen protein 4 (CTLA-4). Preliminary data from phase I and II studies suggest that AK104 has encouraging anti-tumor activity in selected tumor types and an improved safety profile compared to the co-administration of anti-PD-1 plus anti-CTLA-4 mAbs. Preclinical studies show that CD73 inhibition synergistically increases the anti-tumor activity of PD-1 and CTLA-4 immune checkpoint inhibitors (ICIs). Published early clinical data suggests that anti-CD73 therapy in combination with ICIs produces improved clinical outcomes. Thus, AK119 plus AK104 is postulated to have synergistically enhanced anti-tumor activity compared to the administration of anti-CD73 monotherapy or ICIs alone. Methods: This is a phase 1a/1b, first-in-human, multicenter, open-label study in patients with advanced solid tumors that are refractory to standard therapies. The primary objective is to assess safety, tolerability and dose limiting toxicity; and to determine the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of AK119 in combination with AK104. Secondary objectives are to evaluate antitumor activity, PK and AK119 immunogenicity. The dose-escalation phase will evaluate 5 dose levels of AK119 (1mg/kg to 40 mg/kg Q2W IV) in combination with 6mg/kg AK104 Q2W IV using a 3+3+3 study design. Eligible pts will receive a single dose of AK119 on C0D1 of a 14-day “lead-in” period. Thereafter, from C1D1 pts will receive AK119 in combination with AK104 on a 28-day cycle, until unacceptable toxicity, confirmed progressive disease, subject withdrawal, or for a maximum of 24 months. The “lead-in” period is only applicable for dose-escalation cohorts. Any dose-escalation cohort not exceeding the MTD may be expanded to a maximum of 18 subjects with selected solid tumor types for further evaluation of safety, PK/ PD, immunogenicity, and preliminary anti-tumor activity. Cohort 1 is currently in progress with the first patient enrolled in January 2021. For the dose-expansion phase, cohorts of pts with advanced/metastatic pancreatic cancer or MSS/pMMR colorectal cancer will be enrolled. Cohorts of other tumor types may be added based on emerging pharmacodynamic and anti-tumor response data. Clinical trial information: NCT04572152.

A phase Ia/b study of TIM-3/PD-L1 bispecific antibody in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2654-TPS2654 ◽  
Author(s):  
Matthew David Hellmann ◽  
Toshio Shimizu ◽  
Toshihiko Doi ◽  
F. Stephen Hodi ◽  
Sylvie Rottey ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Checkpoint Inhibitors ◽  
Primary Objective ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Open Label Phase ◽  
Phase 1B

TPS2654 Background: Programmed cell death 1 immune checkpoint inhibitors (anti-PD-1, anti-PD-L1) have demonstrated clinical benefit in a subset of patients with manageable safety across a variety of tumor types. T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) can be co-expressed with PD-1 on exhausted T-cells and may be upregulated in tumors refractory to anti-PD-1 therapy (Koyama et al. 2016). Pre-clinical studies demonstrated that blockade of both PD-1 and TIM-3 improved survival of tumor-bearing mice compared to blocking anti-PD-1 only (Koyama et al. 2016). LY3415244 is a TIM-3/PD-L1 bispecific antibody that has the ability to target and inhibit both TIM-3 and PD-L1 and the potential to overcome primary and acquired anti-PD-(L)1 resistance by a novel mechanism to bridge TIM-3- and PD-L1-expressing cells. Methods: Study JZDA is a multicenter, nonrandomized, open-label, Phase 1a/1b study of LY3415244 in patients with advanced solid tumors. In Phase 1a, subjects with any tumor type who are either PD-(L)1 inhibitor-naïve or exposed are eligible. In Phase 1b, expansion cohorts are planned in subjects with PD-(L)1-experienced NSCLC, urothelial carcinoma, and melanoma. Patients with malignant mesothelioma are not required to have received prior anti-PD-(L)1 therapy. The primary objective is to assess safety and tolerability of LY3415244 and identify the recommended Phase 2 dose (RP2D) in Phase 1a (dose escalation). Safety and tolerability of the RP2D will be assessed in Phase 1b (dose expansion). The secondary objectives are to assess the pharmacokinetics of LY3415244 in Phase 1a/1b and assess early antitumor activity of LY3415244 in Phase 1b cohorts. Pre- and on-treatment biopsies will be obtained to explore potential biomarkers of response. During Phase 1a, dose escalation cohorts will proceed via a modified toxicity probability interval-2 (mTPI-2) design with a 1-cycle (28-day) dose-limiting toxicity (DLT) observation period. LY3415244 will be dosed intravenously every 2 weeks. Data from Phase 1a will determine the RP2D, which will be used for all cohorts in Phase 1b. The study is currently open to enrollment. Clinical trial information: NCT03752177.

Phase I, first-in-human, open-label, dose-escalation study of U3-1565, a fully human anti-HB-EGF monoclonal antibody, in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2519-2519 ◽  
Author(s):  
Kathleen N. Moore ◽  
Johanna C. Bendell ◽  
Anthony J. Olszanski ◽  
Madhuri Desai ◽  
Mendel Jansen ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factor ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Tumor Growth Inhibition ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Anti Tumor Activity

2519 Background: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an EGF family member and a ligand for EGFR and Her4. U3-1565 is a fully human anti-HB-EGF monoclonal antibody with preclinical anti-tumor and anti-angiogenesis activity. In this study, we evaluated safety, tolerability, immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of U3-1565 in patients with advanced solid tumors refractory to standard treatment. Methods: The 3+3 method of enrollment and dose-escalation was used to test U3-1565 at 2, 8, 16, and 24 mg/kg once every two weeks (with the second dose given three weeks after the first), and at 24 mg/kg weekly. Results: 15 patients (11 females, 4 males; median age 62 (range 47-77) years; 5 CRC, 5 NSCLC, 3 ovarian and 2 other cancer) were enrolled, 3 in each dose level cohort. No dose-limiting toxicity was observed and a maximum tolerated dose was not reached. The highest administered dose of 24 mg/kg weekly generated Cmin above the predetermined target concentration corresponding to Cave resulting in 90% preclinical tumor growth inhibition. U3-1565 was safe and well tolerated with related AE consisting of infrequent and non-dose-related G2 (fatigue, anemia, and appetite loss, seen in 20, 13, and 7% of cases, respectively) and G1 toxicities. No anti-U3-1565 antibody was detected. U3-1565 showed bi-exponential disposition with Cmax and AUC increasing proportional to the dose across all dosing regimens. 13 patients discontinued the study, 12 due to progressive disease and 1 due to non-drug-related AE. After 6 months on study, 2 patients entered study extension phase: A 77 year-old female with NSCLC given 24 mg/kg every two weeks, showed SD (best SLD change -3%) for 26 weeks before progression; and a 76 year-old female with CRC given 24 mg/kg weekly, showed PR (best SLD change -35%) and remains on treatment after 71 weeks. Conclusions: U3-1565 is safe and well tolerated up to 24 mg/kg weekly. Anti-tumor activity was observed and is being further explored in an open-label, dose-expansion study. Clinical trial information: NCT0129041.

Phase I safety and tolerability of once daily oral afatinib (A) in combination with gemcitabine (G) in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13009-e13009 ◽  
Author(s):  
Sylvie Zanetta ◽  
Jaafar Bennouna ◽  
Nicolas Isambert ◽  
Helene De-Montserrat ◽  
Patrick J. Squiban ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Primary Objective ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Once Daily ◽  
Initial Starting

e13009 Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability and pharmacokinetics of A in two parallel dose cohort expansion parts, in combination with either G (Part A) or docetaxel (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part A are presented here. Methods: Eligible patients (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once-daily, oral dosing of A in combination with G, given intravenously at Day 1 and at Day 8 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. The primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLTs) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 patients using a 3+3 design. Initial starting dose level was A 30 mg/day and G 1000mg /m², escalating up to A 50 mg/day and G 1250 mg/m², until the MTD was reached, and followed by a PK expansion cohort of 12 patients at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 19 patients have been treated on study with the following baseline characteristics: mean age (53.7 years), women (63.2%) and number of prior chemotherapies (≤2: 26%, >2: 74%). Twelve patients received 2–4 cycles of treatment and five patients received 4 or more cycles. AEs observed in most patients were diarrhea (89.5%) and rash (63.2%). In Cycle 1, DLTs were experienced by one patient out of six receiving A 30 mg and G 1250 mg/m². MTD was exceeded at a dose level of at least A 40 mg/day and G 1250 mg/m². An intermediate dose level of A 40 mg/day and G 1000 mg/m² is currently under evaluation. Conclusions: In patients with relapsed or refractory advanced solid tumors, the combination of A with G is well tolerated, with manageable AEs. Dose finding is ongoing and MTD, safety profile and preliminary evidence of activity are anticipated to be reported at time of presentation.

Safety and efficacy of AK112, an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors in a phase I dose escalation study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2515-2515
Author(s):  
Jermaine Coward ◽  
Anna Rachelle Austria Mislang ◽  
Sophia Frentzas ◽  
Charlotte Rose Lemech ◽  
Adnan Nagrial ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Advanced Solid Tumors ◽  
Antitumor Effects ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Anti Vegf ◽  
Anti Tumor Activity

2515 Background: AK112 is a tetrameric bispecific antibody targeting PD-1 and VEGF-A. Published data suggests that the combination of anti-VEGF-A with immune checkpoint inhibitor (ICI) therapy produces complementary and synergistic antitumor effects. Given the strong correlation between VEGF-A and PD-1 expression in the tumor microenvironment, it is postulated that the simultaneous blockade of these 2 targets by AK112 as a single agent might achieve higher target binding specificity and produce enhanced antitumor activity, with an improved safety profile, compared to the co-administration of anti-PD-(L)1 and anti-VEGF therapies. Here, we present preliminary safety and efficacy data from a dose escalation study of AK112. Methods: A multicenter, phase I, open-label dose escalation and expansion study in advanced solid tumors that are resistant/refractory to standard therapies, began in December 2019 to determine the safety and efficacy of AK112 (0.3 mg/kg to 30 mg/kg) administered IV every 2 weeks (Q2W) using an accelerated titration followed by 3+3+3 dose escalation design. Selected dose escalation cohorts were expanded to a maximum of 18 subjects with selected solid tumor types for further evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and anti-tumor activity. Pts with prior exposure to ICI were eligible. PD studies examined serum VEGF levels and PD-1 receptor occupancy (RO) on circulating T-cells as an indication of target engagement. Results: As of 13 Jan 2021, 29 pts, median age 60 years [30-76], have received AK112 at doses of 0.3 mg/kg (n = 1), 1.0 mg/kg (n = 3), 3.0 mg/kg (n = 3), 10.0 mg/kg (n = 13), 20.0 mg/kg (n = 8), and 30.0 mg/kg (n = 1) Q2W. Treatment-related adverse events (TRAEs) occurred in 55.2% of pts. G3 TRAEs occurred in 10.3% [3/29] and treatment-related SAEs occurred in 3.4% [1/29] of pts. There was no G4 TRAE. No DLT occurred. TRAEs leading to treatment discontinuation occurred in 6.9% of pts [2/29]. Most frequent TRAEs were arthralgia (17%), diarrhea (14%), rash (10%), and fatigue (10.3%). Of the 17 evaluable pts treated at doses ≥ 3 mg/kg Q2W, the ORR was 23.5% (4/17) and disease control rate (DCR) was 64.7% (11/17). Among the 4 responders, a responder (endometrial ca) had not received prior ICI or bevacizumab, 2 responders (ovarian ca, mesothelioma) had received prior ICI therapy; and a responder (microsatellite stable colorectal ca) was previously treated with bevacizumab. Conclusions: AK112, up to 20 mg/kg Q2W (inclusive), can be given safely to pts and demonstrated encouraging anti-tumor activity with an ORR of 23.5% when dosed ≥ 3 mg/kg Q2W in a pt population with various solid tumors resistant/relapsed to standard therapies. Enrolment is currently ongoing at 30.0 mg/kg Q2W and in dose escalation cohorts selected for expansion. Updated data, including PK, serum VEGF, and RO will be presented. Clinical trial information: NCT04047290.

386 Phase I/Ib first-in-human study of HEK-NIZ985, a recombinant IL-15/IL-15Rα heterodimer, alone and in combination with spartalizumab, in adults with advanced and metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A411-A411
Author(s):  
Rom Leidner ◽  
Andrea Wang-Gillam ◽  
Sumati Gupta ◽  
Robert Wesolowski ◽  
Douglas McNeel ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Single Agent ◽  
Human Study ◽  
Primary Objective ◽  
Time Dependent ◽  
Open Label ◽  
Dose Proportional

BackgroundHEK-NIZ985 (NIZ985) is a recombinant heterodimer of IL-15/IL-15Rα that expands effector lymphocytes and antitumor activity in animal models and a human clinical trial. We report interim data from the first-in-human study of NIZ985.MethodsCNIZ985X2102J is an open-label Phase I/Ib dose-escalation/expansion trial evaluating the safety of subcutaneous NIZ985 three-times-weekly (TIW; 2-weeks-on/2-weeks-off) or once-weekly (QW; 3-weeks-on/1-week-off) as a single agent (SA) or in combination (CM) dosing with 400 mg of the PD-1 inhibitor spartalizumab every 4 weeks, in adults with metastatic/unresectable solid tumors. SA dosing was 0.25–4 µg/kg TIW or 2–10 µg/kg QW; CM dosing was 1 µg/kg TIW or 2–4 µg/kg QW. The primary objective was to characterize the safety and tolerability of NIZ985 ± spartalizumab. Data are presented for dose escalation, and CM-TIW expansion.ResultsOverall, 83 patients entered dose escalation (n=47) or CM-TIW expansion (n=36), of whom 63.8% (30/47) and 69.4% (25/36), respectively, had received ≥3 prior lines of antineoplastic treatment. At data cut-off (March 2, 2020), 91.6% (76/83) had discontinued study treatment. Adverse events (AEs) are summarized below (table 1). There were no dose-limiting toxicities during the first 28-day cycle in any cohort. Systemic skin AEs (Cycle 2) occurred in three SA-TIW patients receiving 2 or 4 µg/kg (bullous pemphigoid, purpura, vasculitis), limiting TIW escalation and initiating QW dose exploration; these were not observed at 1 µg/kg TIW (± spartalizumab) or for QW doses up to 10 µg/kg. CM-TIW dose expansion was therefore at 1 µg/kg; the recommended QW expansion dose is currently undetermined. For SA NIZ985, best overall response (RECIST 1.1) was stable disease (SD; 8/27 patients [29.6%]). Objective responses for NIZ985 plus spartalizumab (3/56 partial response [PR; 5.3%], 15/56 SD [26.8%]) occurred in both immuno-oncology treatment (IO)-naïve and IO-experienced patients, including 5/8 IO-experienced melanomas (cutaneous: 3 SD, 1 PR; uveal: 1 SD). Systemic NIZ985 exposure was approximately dose-proportional after first dose for ≥1 µg/kg TIW and <10 µg/kg QW, with time-dependent clearance without accumulation. Proliferation of peripheral CD8+ and NK lymphocytes, and increased inflammatory cytokines, were observed for both dosing schedules.Abstract 386 Table 1Adverse event summaryConclusionsNIZ985 is safe and tolerable at both TIW and QW dosing ± spartalizumab. It displays approximately dose-proportional, time-dependent PK, and a biomarker and lymphocyte response profile consistent with target engagement. Limited antitumor activity was reported during dose escalation; however, preliminary responses in both IO-experienced and IO-naïve patients were seen in combination with spartalizumab that warrant further investigation.Ethics ApprovalThe study was approved by an independent ethics committee and/or institutional review board at each participating site.

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

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

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

scholarly journals 523 Preliminary clinical experience with XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A553-A553
Author(s):  
Elaine Shum ◽  
Matthew Reilley ◽  
Yana Najjar ◽  
Adil Daud ◽  
John Thompson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Objective Response ◽  
Checkpoint Blockade ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Tumor Types

BackgroundXmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report updated data on patients treated at the recommended expansion dose from an ongoing, multicenter, Phase 1, dose-escalation and -expansion study of intravenous XmAb20717 in patients with selected advanced solid tumors that progressed after treatment with all standard therapies or with no standard therapeutic options.MethodsA maximum tolerated dose was not reached in dose escalation. XmAb20717 10 mg/kg every 2 weeks (Q2W) was selected as the expansion dose, based on consistent T-cell proliferation in peripheral blood indicative of dual PD-1/CTLA-4 checkpoint blockade, and response to treatment (RECIST[1.1]).1 Parallel expansion cohorts included ~20 patients each with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI). Patients treated with 10 mg/kg in dose escalation were pooled with expansion cohorts for analysis of clinical activity and safety.ResultsAs of 9 June 2021, 110 patients, ranging in age from 39 to 89 years and 66.4% male, were treated, and 5 were continuing treatment. Patients had received a median of 4 prior systemic treatment regimens, including CI therapy for 64.5%. The objective response rate was 13.0% (10/77 patients evaluable for efficacy), including 1 complete response (melanoma [confirmed]) and 9 partial responses (confirmed: 1 melanoma, 2 RCC, 2 CRPC, 1 ovarian cancer; unconfirmed: 1 melanoma, 2 NSCLC). The CRPC responders (2/7 with RECIST-measurable disease) had confirmed PSA decreases ≥ 50% from baseline (to 0.02 and 0.3 ng/mL); neither had progression on bone scans. All responders had prior CI exposure, except those with CRPC. Robust CD4 and CD8 T-cell activation was seen. Low baseline tumoral expression of myeloid recruitment genes, including IL-8, was associated with clinical benefit. Grade ≥ 3 immunotherapy-related adverse events in ≥ 3 patients included rash (16.4%), transaminase elevations (9.1%), hyperglycemia (4.5%), acute kidney injury (3.6%), amylase and lipase increased (2.7%), and lipase increased (2.7%).ConclusionsPreliminary data indicate 10 mg/kg XmAb20717 Q2W was associated with complete and partial responses in multiple tumor types and was generally well-tolerated in these heavily pretreated patients with advanced cancer. Changes in T-cell populations in the periphery and tumor are consistent with robust dual checkpoint blockade. These findings support further development of XmAb20717 in advanced solid tumors, including metastatic prostate cancer.Trial RegistrationNCT03517488ReferencesShum E, Daud A, Reilley M, et al. Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors. JITC 2020;8(3):A247-8.Ethics ApprovalThe study was approved by each institution’s IRB.

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