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.
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.
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.
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.
Clinical trial identification
NCT02001623, release date November 14, 2013
Legal entity responsible for the study
D.S. Hong: Research/Grant Funding: Bayer, Lilly, Genentech, LOXO, Pfizer, Amgen, Mirati, Ignyta, Merck, Daichi-Sanko, Eisai Travel, Accommodations, Expenses: MiRNA, LOXO Consulting Role: Bayer, Baxter, Guidepoint Global Other: Oncoreseponse (founder). R. Coleman: Member of Genmab\'s Advisory Board for Tisotumab vedotin. J. de Bono: Employee of The institute of Cancer Research, Served on Genmab Advisory Board, have served as advisor on advisory boards for multiple industry partners incl. AstraZeneca, Daiichi-Sankyo, Genentech, GSK, Merck, Pfizer, Sanofi, Taiho a.o. S. Lisby, L. Basse: Employee of Genmab and hold stocks in the company. All other authors have declared no conflicts of interest.