Dose escalation of a phase 1b/2 study of modakafusp alfa, an immune-targeting attenuated cytokine, in patients (pts) with metastatic solid tumors.

2503 Background: Modakafusp alfa (TAK-573) is a first-in-class immune-targeting attenuated cytokine designed to deliver attenuated interferon alpha-2b (IFNα2b) moieties to CD38-expressing cells. It consists of two attenuated IFNα2b molecules genetically fused to the Fc portion of a humanized, anti-CD38, IgG4 monoclonal antibody. Specificity for CD38 and reduced IFN receptor binding affinity of the attenuated IFNα2b molecules significantly reduces the potential for off-target binding and toxicity. Modakafusp alfa has demonstrated immune cell activation and antitumor activities in preclinical mouse models, including tumor models that do not express CD38, and has shown strong clinical responses and immune activation in pts with refractory/relapsed multiple myeloma. The dose-escalation phase of this phase 1b/2 study (NCT04157517) investigated safety, pharmacokinetics, immunogenicity, pharmacodynamics (PD), and preliminary efficacy of modakafusp alfa in metastatic solid tumors. Methods: Adult pts with advanced/metastatic solid tumors received modakafusp alfa IV on day 1 of a 21-day cycle (Q3W). Dose escalation started at 0.1 mg/kg and proceeded based on cycle 1 safety data via a Bayesian model with overdose control principles. Results: Twenty-one pts were dosed in the escalation phase at 0.1 (n = 3), 0.2 (n = 3), 0.4 (n = 3), 0.75 (n = 3), 1.0 (n = 3), and 1.5 mg/kg (n = 6) Q3W; median age 63 y (range 42–80); male 57.1%; GI malignancies 71.4%; median prior lines of therapy 3 (range 2–7). Two pts had dose-limiting toxicities in cycle 1 at 1.5 mg/kg; 1 pt with baseline bone infiltration had grade 4 thrombocytopenia and 1 pt had grade 3 confusion. As of Nov 2021, across all doses, pts received a median of 2 treatment cycles (range 1–11). Modakafusp alfa treatment-related adverse events (TRAEs) reported in 81% of pts included infusion-related reactions (52.4%), chills (47.6%), and nausea (33.3%). Grade ≥3 TRAEs reported in 42.9% of pts included neutropenia (14.3%) and hypertension (9.5%). There was a greater than dose proportional exposure increase in the dose range 0.1–1.5 mg/kg, with no exposure accumulation after Q3W dosing. Incidence rate of post-treatment anti-drug antibody (ADA) was 100%. PD data suggested saturation of peak IFN pathway modulation at ≥0.2 mg/kg in the peripheral blood with duration of modulation increasing with dose. Among the 14 response-evaluable pts, 7 had best response of stable disease, including 1 with cutaneous melanoma who had 21% target lesion reduction. Conclusions: Modakafusp alfa had a manageable safety profile in the dose range 0.1–1.5 mg/kg in pts with solid tumors. Proof of mechanism was validated. The recommended phase 2 dose was determined as 1.0 mg/kg Q3W based on assessment of holistic data and will be tested in combination with a checkpoint inhibitor in selected tumor types. Characterization of ADA and its impact is ongoing. Clinical trial information: NCT04157517.