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A082 - A Phase 1, First-In-Human, dose-escalation study of ADG106, a fully human anti-CD137 agonistic antibody, in subjects with advanced or metastatic solid tumors and/or relapsed/refractory non-Hodgkin lymphoma

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Author(s): Anthony Tolcher1, Raghad Karim1, Christina Rosas1, Guizhong Liu2, Yi Zhu2, Liming Liu2, Felix Fangyong Du2, Feng Roger Luo2, Peter Luo2

1Next Oncology and Texas Oncology; 2Adagene Inc.

Background:  Ligation of CD137 induces a co-stimulatory signal on activated CD8+ T cells and natural killer (NK) cells, resulting in proliferation, increased pro-inflammatory cytokine secretion and cytolytic function.  ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody; ADG106 targets a unique epitope of CD137 with novel mechanism of actions for CD137 agonism, CD137 antagonism and potent cross-linking via FcgRIIb.  The broad cross-reactivity of ADG106 with mouse, rats, monkey and human enables robust translational studies using syngeneic tumor models with intact immune system.  Preclinical studies demonstrated the anti-tumor activities of ADG106 for both single agent and combination therapy in multiple syngeneic mouse models including liver, breast, and colon cancers. There were no observable adverse findings in GLP toxicity studies at doses up to 100 mg/kg in rats and 200 mg/kg in monkey with a weekly repeat-dosing for one month. Method: This phase 1 first-in-human study was initiated to evaluate the safety and tolerability of ADG106, as well as the pharmacokinetics, immunogenicity and preliminary clinical activities. The dose escalation includes accelerated titration (0.03, 0.1 and 0.3 mg/kg) and conventional dose escalation (1, 3, and 10 mg/kg).  ADG106 was administered by intravenous infusion every 3 weeks and the patients with advanced or metastatic solid tumors and/or non-Hodgkin lymphoma who are refractory or relapsed and exhausted all available therapies were enrolled and received treatment until disease progression, intolerable toxicity, withdraws with consent, or for a maximum of 24 months. Result:  As of July 11, 2019, 10 patients/5 cohorts were enrolled for treatment, DLT evaluation of 4 cohorts was completed (1 patient each at 0.03, 0.1, 0.3 mg/kg and 4 patients at 1 mg/kg, respectively), safety evaluation at 3 mg/kg is ongoing.  Among 7 patients at doses up to 1 mg/kg, medium treatment duration was 3 cycles (1-8 cycles).  Neither drug related SAE nor DLTs occurred, the most common treatment emergent adverse events (TEAEs) (≥20%, regardless of causality) were arthralgia (43%), decreased appetite (29%), diarrhea (29%), hypothyroidism (29%) and vomiting (29%).  Most of TEAEs were Grade 1 or 2, and there was no ≥Grade 4 TEAEs.  Total of 7 Grade 3 TEAEs occurred in 4 patients, none of them were drug-related except that 1 case of anorexia at 0.03 mg/kg was considered related to the study drug.  There was only one case of SAE, which was Grade 3 tachycardia at 1mg/kg and was not drug related. Tumor shrinkage and decline in SUV scores on PET CT image was observed in one patient with stage IV Follicular Lymphoma (FL) who was refractory to multiple prior therapies including Rituximab. Conclusion: ADG106 demonstrated excellent safety and tolerability profiles at doses up to 1 mg/kg and currently 3 mg/kg is being explored.  Preliminary clinical activity was seen in a patient with FL, which warrants further evaluation. Clinical trial information: NCT03707093.