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Background: ADG126 is an anti-CTLA-4 fully human IgG1 SAFEbody® with a masking peptide blocking the antigen binding site. ADG126 is designed to be preferentially activated in the tumor microenvironment (TME), with the goal of limiting on-target off-tumor toxicities and promoting prolonged exposure to active drug in the TME. Activated ADG126 binds to a unique and conserved epitope of CTLA-4 with species cross-reactivity. Nonclinical studies have demonstrated that activated ADG126 potentiates T cell activation and depletes immunosuppressive Tregs through strong antibody-dependent cellular cytotoxicity (ADCC) specifically in the TME. We present interim results from our ongoing Phase 1b/2 study (ADG126-1001, NCT04645069) on dose escalation and expansion of ADG126 monotherapy as well as dose escalation of ADG126 + toripalimab (Tori). Method: Pts with advanced solid tumors received ADG126 monotherapy (0.1, 0.3, 1, 3, 10, and 20 mg/kg) Q3W IV or ADG126 (6 or 10 mg/kg) + Tori (240mg) Q3W IV. Primary endpoints are safety and tolerability. Secondary endpoints are PK, anti-drug antibody (ADA), as well as ORR, DCR, DOR and PFS per RECIST 1.1. Result: As of Dec. 26, 2022, 30 pts have received ADG126 monotherapy. The median number of treatment cycles was 2 (range: 1-24). The median age was 63.5 (39-84) years. 43% of pts had ≥ 3 prior lines of therapies, and 47% had been previously treated with anti-PD-(L)1 and/or anti-CTLA-4 therapies. ADG126 was well-tolerated with no dose-limiting toxicities (DLTs) observed, nor was the MTD reached. Only Grade (G) 1-2 TRAEs were reported; TRAEs ≥10% included diarrhea (17%), fatigue (17%), pruritus (13%), and rash (10%). Among 27 evaluable pts, DCR = 37%. One pt with ovarian serous carcinoma had a major CA125 response (90% reduction) and her disease was stable with ongoing treatment of ADG126 1 mg/kg at Cycle 24 (~16 months). In addition, 14 pts have received ADG126 + Tori in the dose escalation cohorts. The median age was 60 (36-85) years; 50% had ≥ 3 prior lines of therapies, and 43% received prior anti-PD-1 therapies. Both dose levels were well tolerated with no DLT. TRAEs (> 10%) included diarrhea (21%), fatigue (14%), pruritus (14%), rash (14%) and nausea (14%). After multiple cycles at 6 or 10 mg/kg Q3W, G3 TRAEs were observed in 21% (3/14) pts, including elevated liver function test/hepatitis, elevated lipase and diarrhea, which are immune-related, and sepsis. No G4/5 TRAEs have been reported. Among 12 evaluable pts, DCR = 58%, including 2 partial responses. Early efficacy signals were observed with continuous tumor shrinkage and stabilization in IO-resistant and cold tumors. Conclusion: The anti-CTLA-4 SAFEbody ADG126 shows favorable safety profiles in monotherapy up to 20 mg/kg and in combination with Tori up to 10 mg/kg. Furthermore, promising anti-tumor activity in heavily pre-treated patients was observed in the dose escalation phase. By enabling higher dose levels in combination with anti-PD-1 therapy, ADG126 may unleash the full therapeutic potential for proven and novel indications. Citation Format: Mihitha Ariyapperuma, John J. Park, Adnan Khattak, Gary Richardson, Anis Hamid, Michelle Morris, Anthony W. Tolcher, Boon Cher Goh, Justina Lam, Bartosz Chmielowski, Kristine She, Yanyan Zhang, Ai Li, Songmao Zheng, Guizhong Liu, Lvyu Zhu, Hongyan Wang, Xiaoxing Cui, Peter Luo, Jiping Zha. Interim results of a phase 1b/2 study of ADG126 (a masked anti-CTLA-4 SAFEbody®) monotherapy and in combination with toripalimab (an anti-PD-1 antibody) in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT227.

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Background Participation in early‐phase clinical trials has become a prominent part of medical oncology patient management. We examined the incidence and pattern of hospitalizations in early‐phase clinical trial patients and the associated clinical outcomes. Method We conducted a retrospective review of 194 patients with solid tumors treated on phase I clinical trials between July 2014 and October 2018 at a phase I trial unit. Unplanned hospitalizations occurring during the study period were characterized and correlated with treatment response and duration of trial participation. Results Among 194 patients, 104 hospitalizations were recorded involving 62 patients (31%). Nineteen percent of patients were hospitalized for cancer‐related complications and 8% for treatment toxicity. No significant correlation was seen between the hospitalization and age, sex, tumor type, or trial drug. Best response to trial therapy was complete response, partial response, stable disease, and progressive disease in 5%, 11%, 37%, and 47% of patients, respectively. Median duration on trial was 86 days (range 0–1,412). Twenty‐two patients (11%) remained on trial for more than 12 months. Overall, hospitalization did not impact treatment response or trial duration. However, cancer‐related hospitalization was associated with significantly lower response (p < 0.001) and early patient attrition (p < 0.001). Resolution of the hospitalization event was associated with improved response (p = 0.002) and longer duration on trial (p < 0.001). The treatment related mortality was 0.5% (n = 1). Conclusion Approximately one third of patients required hospitalization, most commonly for cancer‐related complications which correlated with poorer clinical outcomes. Hospitalizations related to treatment toxicity were infrequent. A significant proportion of patients derived significant therapeutic benefit. Phase I clinical trials provide a valuable treatment option for patients with cancer.

e14518 Background: New developments have rejuvenated anti-CTLA-4 therapies, yet dose-dependent adverse events remain a core challenge, leaving dose-dependent clinical efficacy on the table. ADG126 is an anti-CTLA-4 fully human IgG1 SAFEbody with a masking peptide blocking the antigen binding site, designed to be preferentially activated in the tumor microenvironment (TME). Activated ADG126 binds to a unique and conserved epitope of CTLA-4, allowing for cross-species demonstration of improved therapeutic window and prolonged exposure to active drug in the TME through preclinical imaging/pharmacokinetic (PK) studies. Activated ADG126 potentiates T cell activation and depletes immunosuppressive Tregs through strong antibody-dependent cellular cytotoxicity specifically in the TME. Clinical data are obtained from ongoing Phase 1b/2 studies of ADG126 mono or combination therapy with toripalimab (NCT04645069) and Phase 1 monotherapy study in China (CTR20220571), to inform on its therapeutic window and dose selection. Methods: ADG126 in intact and total (i.e. intact + cleaved) forms in plasma were measured. Physiologically based PK modelling was conducted, leveraging clinical PK and tumor tissue PK from tumor-bearing mice. Clinical data of its parental antibody (Ab) was integrated. Results: The cleaved ADG126 plasma PK showed ~3-fold observed mean accumulation at steady state (SS) versus cycle 1 with Q3W dosing or <2-fold simulated accumulation with Q6W dosing. Modeling demonstrated that SS is reached between TME and plasma after releasing cleaved ADG126 into circulation, and when the production of the cleaved ADG126 reaches equilibrium with its elimination. Simulated maximum SS cleaved ADG126 exposure (Cmax,ss) at 10mpk Q3W or Q6W dosing is less than Cmax,ss of its parental Ab dosed at 3mpk Q3W (e.g., with manageable safety when combined with anti-PD-1 mAbs). This is consistent with reduced circulating PD biomarkers, reflective of reduced whole-body immune activation and superior clinical safety profiles for ADG126 as mono or combination therapies. At 10mpk, model-predicted SS tumor cleaved ADG126 exposure is greater than its in vitro binding and functional EC90s, and is higher than the predicted tumor exposure of its parental Ab at 10mpk, consistent with 10mpk Q3W or Q6W as emerging efficacious dose/regimens of ADG126. Conclusions: The SAFEbody technology enables ADG126 to be dosed at 10mpk, >3-fold higher dose levels than its parental Ab at 3mpk in a combination setting with anti-PD-1. It was demonstrated through modeling that ADG126 has higher and sustained TME active drug exposure, and therefore greater target engagement than what tolerable doses of non-masked anti-CTLA-4 molecules can achieve. The increased therapeutic window and efficacious dose selection of ADG126 is informed by quantitative integration of available data. Clinical trial information: NCT04645069 .