First-in-human phase 1 trial (DRAGON) of SRK-181, a potential first-in-class selective latent TGFβ1 inhibitor, alone or in combination with anti-PD-(L)1 treatment in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3146-TPS3146
Author(s):  
Timothy A. Yap ◽  
Minal A. Barve ◽  
Justin F. Gainor ◽  
Colin D. Weekes ◽  
Bruno Bockorny ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Combination Treatment ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Phase 1 ◽  
Locally Advanced ◽  
Mouse Tumor ◽  
Advanced Solid Tumors

TPS3146 Background: Transforming growth factor-beta 1 (TGFβ1) is a key mediator of primary resistance to programmed cell death protein 1 (PD-1) pathway blockade. SRK-181 is a fully human, highly potent and selective monoclonal antibody that inhibits latent TGFβ1 activation. SRK-181 has minimal or no binding to latent TGFβ2 and TGFβ3 isoforms or to active TGFβ growth factors. In mouse tumor models (bladder, melanoma, and breast cancer), SRK-181 in combination with anti-PD1 therapy overcame primary anti-PD-1 resistance and showed survival benefit. No cardiotoxicities (valvulopathy) were observed with SRK-181 in 4-week GLP nonclinical toxicology studies. Thus, the potency and selectivity of SRK-181 may overcome PD-1 inhibitor resistance and toxicity of non-selective TGFβ pathway approaches. Methods: The DRAGON trial NCT04291079 is an ongoing multicenter, open-label, phase 1 study of SRK-181 administered by IV infusion every 3 weeks (Q3W) alone or in combination with anti-PD-(L)1 in patients (pts) with locally advanced or metastatic solid tumors. The study comprises 3 parts: Part A of the study follows a standard 3+3 dose escalation trial design to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of SRK-181 alone (Part A1) or in combination with the anti-PD-(L)1 agent that is approved for the respective tumor indication (Part A2). Part A1 and Part A2 will determine maximum tolerated dose (MTD) or maximum administered dose and Recommended Phase 2 Dose (RP2D) for Part B. Part B (expansion phase) will evaluate combination treatment of SRK-181 with anti-PD-(L)1 in pts with non-small cell lung cancer, urothelial carcinoma (UC), melanoma or other advanced solid tumors, to confirm the tolerability of the RP2D and to evaluate the antitumor activity of combination treatment. Pts in Part A2 and Part B must have previously received an anti-PD-(L)1 therapy approved in their tumor indication and considered non-responders (best response of stable disease or disease progression) to anti-PD-(L)1 monotherapy. Pts in Part B must have received the most recent dose of the prior anti-PD-(L)1 within 6 months of study enrollment (9 months for UC cohort). Safety, PK, PD and efficacy data will be collected and monitored throughout the study. Detailed translational PD and predictive biomarker studies for SRK-181 will include a novel digital pathology analysis of CD8 to assess the alteration of immune profile in tumor microenvironment and TGFb pathway biomarkers, such as quantitative analysis of tumor phospho-Smad2 and circulating levels of TGFb1 ligand. As of Feb 01 2021, dose escalation has proceeded to the highest planned dose of 2400 mg Q3W in Part A1 (monotherapy) and to 800 mg Q3W in Part A2 (anti-PD-(L)1 combination). Additional planned doses in Part A2 are 1600 mg and 2400 mg Q3W. Clinical trial information: NCT04291079.

A phase I study evaluating COM701 in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2657-TPS2657
Author(s):  
Drew W. Rasco ◽  
Daniel A. Vaena ◽  
Ryan J. Sullivan ◽  
Jason J. Luke ◽  
Adam ElNaggar ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Locally Advanced ◽  
Maximum Tolerated Dose ◽  
Tumor Growth Inhibition ◽  
Mouse Tumor ◽  
Advanced Solid Tumors ◽  
Open Label

TPS2657 Background: There is a high unmet medical need for the treatment (tx) of patients (pt) who are refractory to or relapse following tx with checkpoint inhibitors. Newer checkpoint therapies with novel mechanisms of action that can activate T cells and demonstrate antitumor activity in this pre-tx pt population are urgently needed. COM701 is a novel first-in-class humanized IgG4 monoclonal antibody that binds with high affinity to PVRIG (poliovirus receptor related immunoglobulin domain containing) blocking its interaction with its ligand, PVRL2. Both PVRIG and PVRL2 are part of the DNAM axis as are TIGIT and PD1. Inhibition of PVRIG leads to enhanced activation of T and NK cells, and PVRIG results in tumor growth inhibition in mouse tumor models. We hypothesize that COM701 will demonstrate antitumor activity in pts who are checkpoint inhibitor pre-tx. Methods: NCT03667716 is an ongoing open-label first-in-human phase 1 study in pts with advanced solid tumors. The initial part of this study (Arm A) will evaluate escalating doses of COM701 monotherapy IV Q3 weekly with single pt cohorts for the initial 4 and then 3+3 design. Key Inclusion Criteria: Age ≥18 yrs, histologically confirmed locally advanced/ metastatic solid malignancy and has exhausted available standard therapy, ECOG 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137 permissible. Key Exclusion Criteria: Active autoimmune disease requiring systemic therapy in the last 2 years, symptomatic interstitial or inflammatory lung disease, untx or symptomatic central nervous system metastases. Primary objectives are safety and tolerability of COM701 as measured by the incidence of adverse events (AEs) and dose-limiting toxicities (21-day DLT window), pharmacokinetics of COM701, and to identify the maximum tolerated dose and/or the recommended dose for expansion. Secondary objectives are to characterize the immunogenicity and preliminary antitumor activity of COM701. Statistical Considerations: AEs graded as per CTCAE v4.03, responses as per RECIST v1.1. The analyses of all study objectives will be descriptive and hypothesis generating. No DLTs have been observed in the single pt cohorts. Assessment of pts enrolled into cohort 5 is ongoing at the time of this submission. Clinical trial information: NCT03667716.

scholarly journals Surufatinib Plus Toripalimab in Patients with Advanced Solid Tumors: A Single-Arm, Open-Label, Phase 1 Trial

2020 ◽  
Author(s):  
Yanshuo Cao ◽  
Ming Lu ◽  
Yu Sun ◽  
Jifang Gong ◽  
Jie Li ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1 Trial ◽  
Open Label Phase ◽  
Grade 3

Abstract BackgroundPreclinical studies have supported a potential synergistic antitumor activity between surufatinib and anti-programed death ligand-1 (PD-L1). We describe here the results of a single-arm, open-label phase 1 trial to evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) in patients with advanced solid tumors treated with surufatinib combined with toripalimab, an inhibitor of PD-L1.MethodsThis is an open-label, dose escalation and expansion study in patients with solid tumors who had failed standard therapies or had no effective treatment. In the dose escalation stage, 3 cohorts of patients were treated with surufatinib, at dose levels of 200, 250, or 300 mg once daily (QD) in combination with a fixed dose of toripalimab 240 mg, every 3 weeks (Q3W), to evaluate maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Additional patients were enrolled in the dose expansion phase to further assess the efficacy, safety, and PK profile.ResultsFrom April 1, 2019 to July 10, 2020, 31 patients were screened, of which 28 patients were enrolled. One patient in the 300 mg cohort experienced dose limited toxicity (DLT), a grade 3 hyperthyroidism. The top 3 most common treatment-related adverse events of ≥ grade 3 were transaminases increased (17.9%), hypertension (14.3%) and blood bilirubin increased (10.7%). No treatment-related death or treatment discontinuation was identified. The RP2D was determined to be surufatinib 250 mg QD plus toripalimab 240 mg Q3W. Overall objective response rate was 22.2% [95% confidential interval (CI) 8.6‒42.3], and disease control rate reached 81.5% (95% CI 61.9‒93.7). ConclusionsSurufatinib plus toripalimab was well-tolerated, with no unexpected safety signals, and showed promising antitumor activity in patients with advanced solid tumors. Trial registrationclinicaltrials.gov, NCT03879057; Registered March 18, 2019, https://clinicaltrials.gov/ct2/show/NCT03879057

Trial in progress: A phase 1-2 multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABN401 in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3157-TPS3157
Author(s):  
Dae Ho Lee ◽  
Aflah Roohullah ◽  
Byoung Chul Cho ◽  
Charlotte Rose Lemech ◽  
Paul L. de Souza ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Locally Advanced ◽  
Local Therapy ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Open Label

TPS3157 Background: c-MET (hepatocyte growth factor (HGF) receptor) overexpression, either by gene amplification, or mutation is associated with oncogenic transformation in numerous malignancies including lung, gastric, skin, renal, colorectal, and pancreatic cancers. ABN401 inhibits the activation of c-MET by reversibly interfering with the binding of c-Met tyrosine kinase to adenosine triphosphate (ATP) and blocking the receptor's downstream signaling that has demonstrated efficacy in NSCLC and gastric cancer in mouse xenograft and PDx models. This clinical trial is in progress in patients with advanced cancers. Methods: ABN401 is being evaluated in an open-label, non-randomized, dose-escalation (phase 1) study in patients with advanced solid tumors, and dose-expansion (phase 2) in patients with targeted indications and c-MET biomarker expression (NCT04052971). The phase 1 explores ascending daily doses of oral ABN401 monotherapy in 21-day cycles to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). A preplanned extension (pilot expansion) study has been initiated based on predefined positive efficacy signals at intermediate doses up to 10 NSCLC patients who have c-MET alteration. Once RP2D is determined, the phase 2 expansion of up to 10-29 patients in four specific tumor-type cohorts is planned, utilizing a Simon's optimal two-stage design to evaluate the clinical activity of ABN401. ABN401-001 study began enrolling patients in August 2019 and is ongoing in Korean and Australia. Dose escalation up to cohort 4 has been completed, enrollment to cohort 5 began in November 2020. AEs are assessed according to CTCAE v5. Tumor response is determined according to RECIST 1.1 criteria and safety findings reviewed by the DRC, which will determine the RP2D and MTD. Key Phase 1 eligibility criteria include 1) histological or cytological diagnosis of melanoma or any type of carcinoma or sarcoma and 2) refractory metastatic disease, or refractory locally advanced disease not amenable to local therapy. For the extension (pilot expansion) study, patients must have NSCLC with MET exon 14 skipping, MET amplification and/or c-MET overexpression. An exploratory study is being conducted for co-development of a companion diagnostic (CDx) system including a CTC device and ddPCR kit through liquid biopsy. Clinical trial information: NCT04052971.

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.

288 A phase 1 study of IMC-001, a PD-L1 blocker, in patients with metastatic or locally advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A315-A315
Author(s):  
Bhumsuk Keam ◽  
Tae Min Kim ◽  
Do-Youn Oh ◽  
Chan-Young Ock ◽  
Won Ki Kang ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Dose Range ◽  
Locally Advanced ◽  
Evaluation Criteria ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Tract Cancer

BackgroundIMC-001 is a fully human IgG1 monoclonal antibody that binds to human PD-L1 and mediate the antibody-dependent cell-mediated cytotoxicity. The main objectives of this study were to evaluate the safety, pharmacokinetics, and pharmacodynamics of IMC-001 in patients with advanced solid tumors. Here, we report final result of the phase 1 study of IMC-001.MethodsThis open-labeled phase 1 study used standard 3+3 dose-escalation design, dose ranging from 2 to 20 mg. IMC-001 was administered intravenously every two weeks until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) window was defined as 21 days from the first dose. Adverse events (AEs) were assessed using CTCAE v4.03, and tumor response was assessed by and the Response Evaluation Criteria In Solid Tumors (RECIST) version v1.1.ResultsFifteen subjects (8 Male, 7 Female; Median age : 58 [range 39–69]) were included in 5 dose escalation cohorts. No DLT was observed and the maximum tolerated dose was not reached. Most common AEs were general weakness, decreased appetite, fever, and cough. No Grade 4 or 5 treatment emergent AEs (TEAEs) were reported during the study and no TEAE or serious AE led to treatment discontinuation or death. There were no infusion-related reactions during this study. Grade 2 immune-induced thyroiditis and diabetes mellitus suspected to be related to IMC-001 were seen in one subject at 2 mg/kg cohort. Over the dose range of 2 to 20 mg/kg IMC-001, AUC 0-14d, AUC 0—∞, and Cmax generally appeared to increase in a dose proportional manner for each step of dose escalation. Of the 15 enrolled patients, one subject with colon cancer showed partial response, and disease control rate was 33.3%. There were total 3 biliary tract cancer patients (1 GB cancer, 2 Cholangiocarcinoma) who received ≥3 lines of systemic therapies prior to this trial. They all had stable disease during IMC-001 treatment, and one cholangiocarcinoma subject received the treatment for 434 days.ConclusionsIMC-001 demonstrated a favorable safety profile up to 20 mg/kg given IV every 2 weeks and showed encouraging preliminary efficacy in patients with advanced solid tumors. Based on PK and PD data, 20 mg/kg was selected as recommended Phase 2 dose (RP2D).Ethics ApprovalThis study was approved by Institutional Review Board; approval number SMC 2018-01-007-001 and H-1801-042-913.

Phase 1 and phase 2a, first-in-human (FIH) study, of DRP-104, a broad glutamine antagonist, in adult patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3149-TPS3149
Author(s):  
Melissa Lynne Johnson ◽  
Deborah Blythe Doroshow ◽  
Tanguy Y. Seiwert ◽  
Michael K. Gibson ◽  
Vamsidhar Velcheti ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Primary Objective ◽  
Adult Patients ◽  
Glutamine Metabolism ◽  
Advanced Solid Tumors

TPS3149 Background: Dependence of cancer cells on glutamine has made glutaminolysis an attractive therapeutic target in cancer. Prior clinical trials evaluating glutamine analogues for the treatment of cancer were abandoned due to lack of efficacy and/or tolerability. DON (6-Diazo-5-oxo-L-norleucine) is an irreversible inhibitor of several enzymes that utilize glutamine as a metabolic substrate. In addition to direct anti-tumor efficacy, inhibition of glutamine metabolism in the tumor microenvironment has been shown to improve T-cell activation and tumor infiltration, increasing anti-tumor immune responses. As such, combining DON with an immune checkpoint inhibitor (ICI), has strong preclinical rationale. The investigational product DRP-104 (sirpiglenastat) is an inactive prodrug of DON designed to limit systemic DON exposure while targeting glutamine dependence in tumor cells. Methods: A phase 1/2a, FIH, multi-center, non-randomized, multi-cohort, open-label study of DRP-104 is currently open to accrual for patients with advanced solid tumors. This study will be conducted in 4 parts: A) Dose Escalation of IV and subQ DRP-104 (Run-In phase followed by modified Continual Reassessment Method) to define MTD/RP2D. Primary objective of dose escalation is to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of DRP-104 as a single agent; B) Dose Expansion of IV and subQ DRP-104 for safety assessment while primary objective is to select and recommend phase 2 DRP-104 route of administration; C) Phase 2a at recommended MTD/RP2D of selected route of DRP-104 in 2 patient cohorts: patients with locally advanced/metastatic NSCLC with KEAP1, NFE2L2 and/or STK11 mutation and patients with unresectable or metastatic SCCHN, in order to assess the safety, tolerability and preliminary antitumor activity of DRP-104 as a single agent; D) Phase 2a at recommended MTD/RP2D of selected route of DRP-104 in combination with atezolizumab in adult patients with advanced solid tumors previously treated with an ICI, in order to assess the safety, tolerability and preliminary antitumor activity of DRP-104 in combination with atezolizumab; DRP-104 IV is infused TIW over 1 hour infusion for 2 consecutive weeks followed by 1 week off. DRP-104 subQ is administered BIW weekly. Study is currently open with 6 IV patients (Run-In Phase completed and at Dose Level 4) and 3 subQ patients at Dose Level 1 at time of submission. Clinical trial information: NCT04471415.

scholarly journals 532 First-in-human phase 1 trial of SRK-181: a latent TGFβ1 inhibitor, alone or in combination with anti-PD-(L)1 treatment in patients with advanced solid tumors (DRAGON trial)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A563-A563
Author(s):  
Timothy Yap ◽  
Minal Barve ◽  
Justin Gainor ◽  
Bruno Bockorny ◽  
Yawen Ju ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Solid Tumors ◽  
Transforming Growth Factor ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Human Study ◽  
Mouse Tumor ◽  
Advanced Solid Tumors ◽  
Link Type ◽  
Best Response

BackgroundTransforming growth factor-beta 1 (TGFβ1) plays an important role in mediating the primary resistance to PD-1/PD-L1 [PD-(L)1] blockade. SRK-181 is a fully human monoclonal antibody that selectively inhibits latent TGFβ1 activation. Mouse tumor models (bladder, melanoma, and breast cancer) demonstrated that treatment with SRK-181+anti-PD-1 overcame primary anti-PD-1 resistance. Four-week GLP nonclinical toxicology studies showed that SRK-181 has improved safety profile (no cardiotoxicities) compared to broad TGFβ pathway inhibition.MethodsThe DRAGON trial (NCT04291079) is an ongoing open-label, phase 1 study. Part A of the study follows a standard 3+3 dose escalation design to determine the dose for Part B. Part B (expansion phase) evaluates combination treatment in patients with non-small cell lung cancer (NSCLC), urothelial carcinoma, melanoma, or other advanced solid tumors. SRK-181 is administered IV every 3 or 2 weeks (Q3W/Q2W) alone in patients with advanced solid tumors (Part A1), or in combination with anti-PD-(L)1 in patients who did not respond to prior anti-PD-(L)1 therapy (Part A2/B).ResultsAs of 7 June 2021, 25 patients have enrolled to Part A; median 4 prior lines of therapies (range 1–9). Cancer types: colorectal, ovarian, prostate, and unknown primary (Part A1); liver, melanoma, NSCLC, oropharynx, renal cell carcinoma (RCC) and uterine (Part A2). In Part A1, 15 patients were treated with SRK-181 monotherapy at doses of 80, 240, 800, 1600, 2400, 3000mg Q3W, with no dose limiting toxicity (DLT) observed. The last cohort (2000mg Q2W) remains under evaluation. The most common treatment-related AEs (TRAE, >10%) of any grade were decreased appetite and fatigue (each: 13.3%, n=2). Six patients had stable disease (SD) as best response (2/colorectal cancer, 1/prostate cancer, and 3/ovarian cancer). Three ovarian cancer patients were stable ≥153 days with tumor regressions. In Part A2, 10 patients were treated with SRK-181 at doses of 240, 800 and 1600mg Q3W+pembrolizumab. No DLT was observed up to 800mg. 1600mg Q3W is under evaluation. No TRAE (>10%) of any grade were observed. One confirmed RECIST1.1 partial response (PR) was observed (800mg) in a patient with anti-PD-1 resistant RCC and 2 patients had best response of SD (1/oropharynx cancer, 1/liver cancer). The half-life of SRK-181 ranged from 3.9 to 19.3 days across the doses tested.ConclusionsAs of 7 June 2021, SRK-181 has been well tolerated as monotherapy and in combination with anti-PD-(L)1. One RECIST1.1 PR (800mg) was observed in a patient with anti-PD-1 resistant RCC. Next planned dose in Part A2 will be 2400mg Q3W.Trial RegistrationDRAGON trial (NCT04291079)Ethics ApprovalThe human study was approved by the Massachusetts General Hospital and Beth Israel Deaconess Medical Center (20–286), Sarah Cannon Research Institute (1276118), Mary Crowley Cancer Research (20–06), MD Anderson Cancer Center (2020–0110) Institutional Review Boards with written informed consent obtained from each participant and/or their legal representative, as appropriate.

AdvanTIG-105: Phase 1 dose-escalation study of anti-TIGIT monoclonal antibody ociperlimab (BGB-A1217) in combination with tislelizumab in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2583-2583
Author(s):  
Sophia Frentzas ◽  
Tarek Meniawy ◽  
Steven Chuan-Hao Kao ◽  
Ruihua Wang ◽  
Yunxia Zuo ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Group Performance ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Study Objective

2583 Background: Anti-programmed death 1 (PD-1) therapy has improved clinical outcomes for patients (pts) with advanced solid tumors but unmet needs remain. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) is a co-inhibitory, immune checkpoint receptor. Ociperlimab (OCI; BGB-A1217) is a novel, humanized, monoclonal antibody that binds to TIGIT with high affinity and specificity. OCI has demonstrated competent binding with C1q and all Fcγ receptors and induces antibody-dependent cellular cytotoxicity. Preclinical studies demonstrated dual targeting with OCI and tislelizumab (TIS), an anti-PD-1 antibody, produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-105 is a phase 1, open label, multicenter, dose-escalation study (NCT04047862) that assessed the safety and preliminary antitumor activity of OCI plus TIS in pts with advanced, metastatic, unresectable solid tumors, for which standard therapy was ineffective or unavailable. Eligible pts had an Eastern Cooperative Oncology Group performance score ≤1 and no prior therapy targeting TIGIT. Pts received OCI intravenously (IV) on Day 1 of Cycle 1 and TIS 200 mg IV on Day 8. Pts were monitored for dose-limiting toxicities (DLTs) until Day 28. If tolerated, OCI and TIS were administered sequentially on Day 29 and every 3 weeks (Q3W) thereafter. Pts received escalating doses of OCI (50-900 mg) plus TIS 200 mg. The study objective was determination of recommended phase 2 dose (RP2D) of OCI plus TIS. Study endpoints included assessment of adverse events (AEs), pharmacokinetics and antitumor activity. Data cut-off was October 12 2020. Results: 24 pts with various advanced solid tumors received OCI plus TIS. At baseline, pts had undergone a median of 2 prior treatment regimens; 9/24 (37.5%) pts had received prior immunotherapy. Median follow-up time was 17 weeks. No DLTs were observed. 20 pts had ≥1 treatment emergent AE (TEAE) and most TEAEs were grade ≤2; fatigue (6 pts) and diarrhea (4 pts) were most commonly reported. No pts had grade ≥4 TEAEs or TEAEs leading to death. There were 2 grade 3 immune related AEs (colitis and low cortisol). One pt on OCI 450 mg achieved partial response and 9 pts had stable disease. The longest duration of stable disease was 36 weeks (1 pt on OCI 150 mg). After administration, serum concentration of OCI decreased in a biphasic manner. Exposure to OCI increased proportionally with dose, and TIGIT receptor occupancy was sustained at ≥50 mg doses. Conclusions: OCI in combination with TIS was well tolerated across all doses in pts with advanced solid tumors. The RP2D was OCI 900 mg plus TIS 200 mg Q3W. Clinical trial information: NCT04047862.

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