A phase I/II safety study of tisotumab vedotin (HuMax®-TF-ADC) in patients with solid tumors

Abstract

Background: Tisotumab vedotin (Tv) is an antibody-drug conjugate composed of a Tissue Factor (TF) specific human IgG1 monoclonal antibody conjugated to a microtubule disrupting agent Monomethyl Auristatin E (MMAE). Tv is being tested in an ongoing Ph I/II dose-escalation study (NCT02001623) in patients (pts) with locally advanced and/or metastatic solid tumors known to express TF. Preliminary data were presented at ASCO 2015, abstract #2570; here, we present the full data set from the dose-escalation part. Methods: Key eligibility criteria include PS 0-1, normal organ function and no bleeding disorder or invasion of large vessels. Pts were treated with a classic 3+3 dose escalation regimen of Tv once every 3 weeks (q3Wk). The primary study objective was to assess tolerability of Tv. Safety was reported according to CTCAE 4.03. Responses were evaluated according to RECIST 1.1. Results: Twenty-seven pts were enrolled across 8 dose cohorts (0.3-2.2 mg/kg). Demography: mean age 61 yrs (range 43-73); gender 9 males and 18 females; median number of prior lines of therapy 3 (range 1-14). Three dose-limiting toxicities (diabetes mellitus type II, mucositis and neutropenic fever, all Gr 3) were seen in 3 pts in the 2.2 mg/kg dose cohort. The most common AEs seen in≥20%: epistaxis (48%), fatigue (48%), anemia (41%), alopecia (30%), constipation (30%), nausea (30%), pyrexia (30%), decreased appetite (26%), abdominal pain (22%) and diarrhea (22%). SAEs (all pts): 29 events in 15 pts (56%), 1 SCCHN pt in the 0.6 mg/kg cohort died from tumor related bleeding. AEs Gr≥3: 19 pts (70%) experienced 41 events. Efficacy: 14 pts (52%) achieved SD or better; 1 cervical cancer pt dosed 1.2 mg/kg with 2 prior treatment lines before trial entry achieved and maintained PR during entire study period. After study period, the pt was transferred to named patient use. Immunohistochemistry (IHC): Samples from 25 pts were evaluable. TF expression was present in 20 (80%) samples. Conclusions: Tisotumab vedotin demonstrated a manageable toxicity profile. Recommended Ph II dose was identified as 2.0 mg/kg q3Wk. Biological activity included SD in 13 pts and 1 pt with prolonged PR (cervical cancer). TF was found widely expressed across investigated indications by IHC. Data warrant further exploration in solid tumors.