Trial Watch: Genmab & Seattle Genetic’s Potential Trojan Horse-like Cancer Killer

Feb 14, 2019 | Monoclonal Antibody, Oncology, Positive Results

Odysseus devised the mythical trojan horse to enter Troy and ultimately defeat the mighty Trojans. Beating Troy with the Trojan horse required creative thinking and ingenuity, team work and importantly—subterfuge.  Cancerous solid tumors represent the walled fortress city of Troy in this analogy. Odysseus is represented by Seattle Genetics and Genmab A/S. They intelligently combined forces to design an investigational drug that acts as a Trojan horse—entering the tumor via subterfuge and releasing toxins to kill it. Tisotumab vedotin (TV) represents the Trojan horse. It is an antibody-drug conjugate (ADC) targeted to tissue factor (TF)—a protein involved in tumor signaling and angiogenesis. The drug is made up with Genmab’s proprietary human monoclonal antibody (mAb) that binds to TF (the horse) and Seattle Genetics’ ADC technology (the weapons) that utilizes a cleavable linker and the cytotoxic drug monomethyl (l auristatin E (MMAE). TF is a transmembrane protein that is the main physiological initiator of coagulation and is involved in angiogenesis, cell adhesion, motility and cell survival. The UK’s Institute for Cancer Research was the lead research site for the initial clinical trial. Officially titled “First-in-human, Dose-escalating Safety Study of Tissue Factor Specific Antibody Drug Conjugate Tisotumab Vedotin (HuMax® TF ADC) in Patients with Locally Advanced and/or Metastatic Solid Tumors Known to Express Tissue Factor,” the study was conducted in two parts. The dose escalation portion of the trial subjects are enrolled into cohorts at increasing dose levels of HuMAX-TF-ADC in 21-day treatment cycles. In the Cohort Expansion part of the trial, the sponsors further explored the recommended phase 2 dose of the investigational drug from part 1 of the study.

The trial ran between December 2013 and May 2015, and initially included 27 eligible patients. During the dose expansion phase from October 2015 to April 2018, 147 eligible patients were enrolled. 67 (46%) of the 147 patients had a treatment-emergent serious event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. The sponsors concluded that Tisotumab vedotin a manageable safety profile with encouraging preliminary anti-tumor activity across multiple tumor types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumors.  

The study’s Principal Investigator, Professor Johann de Bono with the UK’s Institute of Cancer Research, noted, “What is so exciting about this treatment is that its mechanism of action is completely novel—it acts like a Trojan horse to sneak into cancer cells and kill them from the inside. Our early study shows that it has the potential to treat a large number of different types of cancer, and particularly some of those with very poor survival rates.”

The investigation continues. A brief check in reveals six ongoing tisotumab vedotin clinical trials—five of them are actively recruiting. We include a summary of a Phase 2 study sponsored by Danish Genmab.

The Phase 2 study was sponsored by Genmab. The study director is Genmab’s Reshma Rangwala. They are investigating tisotumab vedotin in the context of several cancers including ovary cancer, cervix cancer, bladder cancer, prostate cancer, non-small cell squamous cancer, head and neck cancer and others. Involving 25 patients and centers in the U.S. and UK, the following Principal Investigators/sites are involved:

Brian Slomovitz, University of Miami Health System

Johann de Bono, The Institute of Cancer Research

Fionna Thistlewaite, NHS, The Christie, UK Beatson Cancer Center


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