Phase 1 SCCHN. VTX-2337 with Cetuximab (VRXP-A103) This ongoing, single-center phase 1b protocol at Seattle Cancer Care Alliance (Seattle, WA) is being conducted as an Investigator Sponsored Trial, with Xxxxx Xxxx, MD as the Sponsor-Investigator. VRXP-A103 assesses the safety and tolerability of VTX-2337 in combination with cetuximab. Cetuximab is administered weekly and VTX-2337 is administered weekly for three weeks of a four-week cycle. Three dose levels of VTX-2337 will be evaluated in a standard dose-escalation schema: 2.5 mg/m2, 3.0 mg/m2 and 3.5 mg/m2. Ten subjects with recurrent or metastatic SCCHN have been enrolled. The study regimen has been safe and adequately tolerated to date. There have been no dose-limiting toxicities; no serious, unexpected drug-related adverse events; and no evidence of synergistic toxicities between cetuximab and VTX-2337. Clinical tolerability data indicate that long-term dosing at 3.0 mg/m2 will be better tolerated than 3.5 mg/m2. Preliminary translational medicine results are available from the first two cohorts of SCCHN subjects who received VTX-2337 (2.5 and 3.0 mg/m2) in combination with cetuximab. Consistent with the data from the Phase 1 VRXP-A101 study, serum biomarkers consistent with TLR8 activation were readily measured at both dose levels. In additional, ex vivo analysis of NK cells collected pre-dose and 24 hours after dosing demonstrate NK cell activation. Given the proposed mechanism of VTX-2337 enhancing ADCC with cetuximab in an NK-dependent manner, these data provide important correlative information and suggest the doses of 2.5 or
Phase 1 SCCHN. VTX-2337 with Cetuximab (VRXP-A103) This ongoing, single-center phase 1b protocol at Seattle Cancer Care Alliance (Seattle, WA) is being conducted as an Investigator Sponsored Trial, with Xxxxx Xxxx, MD as the Sponsor-Investigator. VRXP-A103 assesses the safety and tolerability of VTX-2337 in combination with cetuximab. Cetuximab is administered weekly and VTX-2337 is administered weekly for three weeks of a four-week cycle. Three dose levels of VTX-2337 are being evaluated in a standard dose- escalation schema: 2.5 mg/m2, 3.0 mg/m2, and 3.5 mg/m2. Enrollment is complete (n=13), and one subject remains on study. The study regimen has been safe and adequately tolerated. There have been no dose-limiting toxicities; no serious, unexpected drug-related adverse events; and no evidence of synergistic toxicities between cetuximab and VTX-2337. Clinical tolerability data indicate that long-term dosing at 3.0 mg/m2 will be better tolerated than 3.5 mg/m2. Translational medicine results are available from the first twelve subjects who received VTX-2337 (2.5, 3.0, or 3.5 mg/m2) in combination with cetuximab. As expected based on data from the Phase 1 VRXP-A101 study, serum biomarkers consistent with TLR8 activation were readily measured at both dose levels. In addition, ex vivo analysis of NK cells collected pre-dose and 24 hours after dosing demonstrate NK cell activation. Given the proposed mechanism of VTX-2337 enhancing ADCC with cetuximab in an NK-dependent manner, these data provide important correlative information and suggest the doses of 2.5, 3.0, and 3.5 mg/m2 are biologically active from a pharmacologic perspective. Based on preliminary efficacy data, 10 of the 13 subjects have been eligible for evaluation of tumor response: 2 subjects achieved a partial response, 4 subjects experienced disease stabilization, and 4 subjects had disease progression. One subject has not yet had a response assessment, and 2 subjects discontinued the study prematurely and were unevaluable for response assessment.[20]
