A phase 1, open-label, dose escalation study of the safety and tolerability of T3011 in advanced cutaneous or subcutaneous malignancies.
Authors: Haydon Andrew Mark , Kichenadasse Ganessan , Kirkwood John M. , Kaufman Howard E. , Buchbinder Elizabeth Iannotti , Ganju Vinod , Barve Minal A. , Jiang Haifang , Xu Huinan , Zhou Xusha , Zhu Huan J. , Ni Dongyao , Niu Jiaxin 
Published: June 2021

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Background: T3011 is a genetically modified, next-generation oncolytic HSV-1 with 2 exogenous genes encoding the active heterodimer human interleukin 12 (IL-12) and the Fab fragment of an anti-human PD-1 antibody. Locally produced IL-12 induces the synthesis of interferon-gamma (IFN-γ) production, enhancing cytolytic activity of natural killer cells and cytotoxic T lymphocytes. The anti PD-1 antibody blocks checkpoint inhibition of T effector cells. Extensive preclinical studies demonstrate that T3011 (and murine equivalent T3855) has potent antitumor activities. Methods: This phase 1 multicenter, open-label, dose escalation study evaluates the safety of intratumoral (IT) T3011 given once every other week (Q2W) in patients (pts) with advanced cutaneous or subcutaneous malignancies. The primary objective is to determine the Recommended Phase 2 Dose of T3011 based on the overall safety, pharmacokinetic and pharmacodynamic profile. Eligible pts are ≥ 18 years, have cutaneous or subcutaneous advanced cancer that has progressed on standard treatment and at least 1 measurable tumor lesion (≥ 10 mm) suitable for T3011 IT injection. Part 1 of the study uses a 3+3 design to evaluate the safety and tolerability of T3011 monotherapy in 4 escalating doses (1 × 106, 1 × 107, 5 × 107, and 1 × 108 PFU/mL). Up to 4 mL of T3011 may be injected based on tumor size. Total enrollment will be determined by toxicities observed. Results: As of Feb. 14, 8 pts have received IT T3011 (Q2W): 3 in Cohort 1 (1 × 106), 3 in Cohort 2 (1 × 107), and 2 in Cohort 3 (5.0 × 107 PFU/ml). Maximum doses per pt was 11. Enrollment continues in Cohort 3. T3011 was well tolerated with no ≥ Grade 3 treatment-related adverse events (AEs), no DLTs or treatment-related SAEs reported to date. Common AEs were pain at injection site, leukopenia, anemia, hypocalcemia, nausea, fever, headache, dermatitis, and diaphoresis. Viral shedding was analyzed in blood, urine and saliva at various times during the study. No Viral DNA was detected in blood or urine samples (first 3 pts analyzed) to date. Biopsy samples taken from injected tumors from 2 melanoma pts (Cohort 1) revealed significant reduction of viable tumor cells after 4 injections (Week 9) compared with baseline. In particular, one post-treatment biopsy contained 45% tumor necrosis area with dramatic increases of CD8 + and NKT cells. CD3+ and CD4+ cells as well as PD-1 expression were increased in post-treatment biopsies of both pts. Conclusions: T3011 IT injection was well tolerated at the first 2 dose levels. Post treatment biopsies from 2 pts (Cohort 1) demonstrated significantly reduced tumor cell viability as well as increased lymphocyte infiltration indicating on-target anti-tumor activities of T3011. To date, 5 out of 6 evaluable pts had SD as best response and 6 enrolled pts remain on study. Dose escalation is continuing. Clinical trial information: NCT04370587.