A first patient with advanced solid tumors with HER2 Expression was dosed in a phase I clinical trial with ADCT-502. The investigational drug being developed by ADC Therapeutics represents the company’s fourth proprietary Antibody-drug Conjugates (ADCs) programs in clinical six clinical trials and is designed to evaluate and provide data on safety, tolerability, pharmacokinetics and efficacy.
The clinical trial is a two stage, open-label Phase Ia/Ib clinical trial. The first stage (Phase Ia) is a dose escalation phase which will recruit patients at leading clinical centers across the United States and and Europe, and will seek to determine the recommended dose of ADCT-502. The second consecutive stage (Phase Ib), has the objective to confirm the safety and efficacy profile for ADCT-502 in expanded patient cohorts in multiple potential cancer indications.
Investigational agent
ADCT-502 combines a humanized monoclonal antibody trastuzumab targeting the human epidermal growth factor receptor 2 (HER2) with a pyrrolobenzodiazepine (PBD-based) linker-drug tesirine payload. Tesirine, a cathepsin B-cleavable valine-alanine PBD payload also known as SG3249, has been designed to combine potent anti-tumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. It is a potent and clinically validated PBD payload currently being employed in the clinic in a number of ADCs, including the CD25-targeted ADCT-301, the CD19-targeted ADCT-402, both for the treatment of lymphoma and leukemia, and the DDL3-targeted rovalpituzumab tesirine for the treatment of small cell lung cancer.
The antibody is site-specifically conjugated to the payload. Once bound to the HER2 receptor on the cell surface, ADCT-502 is internalized into the cell where enzymes release the PBD-based payload.The HER2 surface protein is expressed at high or low levels in a variety of different tumor types, including breast cancer, gastric and gastroesophageal cancers. It is also a well-established, clinically validated target.
Figure 1.0: Pyrrolobenzodiazepine dimers are an emerging class of payloads used in antibody-drug conjugates (ADCs). Tesirine also known as SG3249, is a N10 linked PBD dimer designed to combine potent anti-tumor activity with desirable physicochemical properties, including favorable hydrophobicity and improved conjugation characteristics.Clinical studies
Preclinical data presented during the 2017 annual meeting of the American Association for Cancer Research (AACR) shows superior in vivo anti-tumor activity of ADCT-502 compared to T-DM1 (ado-trastuzumab emtansine/Kadcyla®; Genentech/Roche) in various tumor xenografts with low HER2 levels. These results support the development of ADCT-502 not only in patients that have become resistant/refractory to T-DM1, but also in patients whose tumors express low levels of HER2, and are not eligible for treatment with T-DM1. [1]
Overall, the ADCT-502 has exhibited strong dose-dependent anti-tumor activity at low single doses against both low and high HER2 expressing tumors. Given the substantial prevalence of HER2 expression in a range of cancers, ADCT-502 will be evaluated in patients with non-small cell lung cancer (NSCLC), bladder, biliary tract, and ovarian cancer, for which HER2 targeted therapies are not yet approved.
“This is the fourth ADC we have put into the clinic in just over two years. Dosing the first patient in this trial with ADCT-502 is an important milestone for us and could pave the way for a better treatment regimen for patients,” said Jay M. Feingold, MD, Ph.D. , Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics.
“The trial will give us vital data on safety, tolerability and dosing. Our preclinical studies suggest ADCT-502 may provide significant clinical benefit for patients suffering from a variety of tumor types which are known to express HER2 in a significant proportion of patients. We are exploring this potential in lung, bladder and biliary tract cancers further within this study as well as in the more established indications of breast and gastric cancer,” Feingold added.
Eagerly expected
“Tremendous advances have been made in the treatment of HER2 expressing cancers, particularly gastroesophageal and breast cancers, in the past 20 years,” noted Kyriakos P. Papadopoulos, MD, Senior Clinical Investigator of the START Center for Cancer Care in San Antonio, Texas, and one of the investigators of the study.
“However, a significant portion of this patient population still fail to respond or relapse with currently available therapies. Having seen the effects of other pyrrolobenzodiazepine ADCs in various tumor types in recent years, we eagerly anticipate the results of this study,” Papadopoulos concluded.
