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Background Micvo (PYX-201) targets extra domain-B of fibronectin, an extracellular matrix protein highly expressed in tumors compared to normal tissues. It has a protease-cleavable linker conjugated to an Aur0101 payload. In animal models, micvo demonstrated compelling antitumor activity across patient-derived xenograft models including HNSCC. A mouse analog of micvo induced T-cell infiltration and increased PD-L1 expression in a syngeneic tumor model. The combination of micvo with a mouse analog of anti-PD-L1 resulted in sustained tumor regression. In the ongoing first-in-human study ( NCT05720117), micvo monotherapy showed encouraging antitumor activity in heavily pretreated patients across multiple tumor types, particularly HNSCC, with a manageable safety profile. Therefore, exploring the combination of micvo with pembrolizumab in HNSCC is of strong interest.Methods PYX-201-102 is a dose-escalation and expansion study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of micvo in combination with pembrolizumab in select solid tumors. As the micvo starting dose of 3.6 mg/kg Q3W is considered therapeutically active in recurrent/metastatic (R/M) HNSCC based on data from the monotherapy study (confirmed partial response in HNSCC at this dose), the focus of the combination therapy dose-escalation part is first line (1L) therapy in R/M HNSCC with PDL1 CPS ≥1. Eligible primary tumor sites include oropharynx (regardless of HPV status), oral cavity, hypopharynx, and larynx. Additionally, 2L+ HNSCC (including platinum-refractory disease or recurrence/progression ≤6 months from concurrent chemoradiation) and other tumor types that progressed on standard therapies are eligible during dose escalation. The primary objective of dose escalation is to determine MTD and RP2D. Pembrolizumab (200 mg IV) will be given with micvo at escalating doses starting at 3.6 mg/kg IV Q3W following a BOIN design. During dose escalation, additional participants with 1L HNSCC will be enrolled in 1 or more dose levels determined to be safe and tolerable (i.e., backfill enrollment). Approximately 60 participants across HNSCC and other tumor types will be enrolled in dose escalation to accurately characterize RP2D. For dose expansion, participants with 1L R/M HNSCC PD-L1 CPS≥1 will be enrolled first, with other indications added based on emerging data. The primary objective of dose expansion is to assess objective response rate per RECIST v1.1. The study opened for enrollment in January 2025. Clinical Trial Information: NCT06795412Ethics Approval The study obtained Ethics Approval from the IRB board at each institution and all participants signed an informed consent before taking part in the study. Approval number for 4 active sites are as follows: • 2024-1995 • 25-075 • NXVIR24.61 • Pro00084051