Earlier this week Lausanne, Switzerland-based ADC Therapeutics, an oncology drug discovery and development company specializing in the development of proprietary antibody-drug conjugates or ADCs designed to target major hematological malignancies and solid tumors, confirmed that the company has terminated its Phase I clinical trial program for ADCT-502 in patients with advanced solid tumors with HER2 expression.[1]

ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with a novel class of highly potent cytotoxic agents linked via a chemical linker.

Figure 1.0: Study evaluates ADCT-502 in patients with Advanced Solid Tumors with HER2 Expression. Patients will participate in a dose-escalation phase (Part 1) and dose expansion (Part 2). In Part 2, patients will receive the dose level identified in Part 1. This is the first clinical study with ADCT-502 in patients with Advanced Solid Tumors with HER2 Expression.

The investigational agent, targeting HER2 expressing solid tumors, did, based on data on safety, tolerability, pharmacokinetics and efficacy, not demonstrate sufficient patient benefit to justify further development.

While the single group assessment trial was planned to have two parts, the expected risk/benefit ratio had not been achieved by the end of part one.

Advertisement #2
 

In total, the study enrolled not more than 20 patients (278 were planned) with solid cancers, including breast cancer, non-small cell lung cancer, gastroesophageal, and bladder cancer.

In the first part of the trial, researchers tested the safety and tolerability of ascending ADCT-502 doses. Unfortunately, the initial results showed that anti-cancer responses were only seen at higher doses. These higher doses were not well-tolerated by patients. As a result, the trial failed to achieve its primary objective and was suspended.

PBD-based ADC programs
“We are very pleased with the efficacy and tolerability achieved with our lead hematological PBD-based ADC programs, but regrettably this has not been the case with our HER2 targeted ADC,” said Jay Feingold, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics,

Pyrrolobenzodiazepine dimers or PBD’s are extremely potent and have a well characterized safety profile that includes fluid retention and pulmonary edema. For most PBD-based ADCs this can be managed by selecting dosing regimens that are efficacious with manageable toxicities.

“However, during dose escalation in this trial we did not achieve the necessary efficacy at tolerated doses required for patient benefit. This was possibly due to the extensive expression of HER2 in pulmonary tissue,” Feingold explained.

Photo 1.0: ADC Therapeutic at the 2017 annual meeting of the American Society of Hematology in Atlanta, GA. Courtesy: © 2018. Sunvalley Communication / Evan Wendt. Used with permission.

“Our next two solid tumor ADCs progressing into the clinic over the next nine months incorporate site specific conjugation technology which based on pre-clinical models has the potential to substantially improve tolerability and efficacy in difficult to treat solid tumors. Preclinical data on these programs was presented at the recent American Association of Cancer Research conference,” he added.

“Patients with HER2 expressing tumors have multiple therapeutic options including novel therapies in clinical development that are producing encouraging data. ADC Therapeutic’s strategy is to progress a deep pipeline of ADCs into Phase I in order to assess their clinical and market potential based on actual human data, and only to progress into later stage development those ADCs that demonstrate the potential to be best in class in areas of high unmet medical need.We currently have three other ADC programs in the clinic, and we plan to commence clinical trials for three additional programs in the next 9 months, including a third hematological program,” Chris Martin, CEO at ADC Therapeutics said.

“Moreover, our two most advanced clinical programs are progressing into later stage development over 2018,” he added,

At this time, ADC Therapeutics is collecting and evaluating the study data from the ADCT-502 Phase I-trial, which will be presented for publication later this year.