Featured Image: ADC Therapeutics Booth at AACR 2018 Courtesy: © 2017 – 2018. Sunvalley Communication, LLC / Evan Wendt. Used with permission.
Featured Image: ADC Therapeutics Booth at AACR 2018 Courtesy: © 2017 – 2018. Sunvalley Communication, LLC / Evan Wendt. Used with permission.

Swiss-base ADC Therapeutics, an oncology drug discovery and development company specializing in the development of proprietary antibody-drug conjugates (ADCs) targeting hematological malignancies and solid tumors, confirmed that a first patient with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) has been dosed with loncastuximab tesirine, also known as ADCT-402.

Diffuse Large B-Cell Lymphoma (DLBCL) Non-Hodgkin lymphoma (NHL) is the seventh most common type of cancer in the U.S., and accounted for an estimated 4.3% of new cancer cases in 2017. [1] The disease accounts for nearly one-third (32.5%) of NHL.

Pivotal trial
The patient received the treatment as part of a pivotal phase II clinical trial (Clinical trial identifier NCT03589469) evaluating efficacy and safety of the CD19-targeting antibody-drug conjugate intended to support a submission of a Biologics License Application (BLA) of loncastuximab tesirine to the U.S. Food and Drug Administration (FDA) [2]

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Top-line data is expected to be available in third quarter of 2019.

At the 2017 American Society of Hematology (ASH) Annual Meeting, ADC Therapeutics presented interim Phase I data on loncastuximab tesirine in 138 evaluable, heavily pre-treated lymphoma patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit, with a median of three prior therapies. At the time, for the 49 response-evaluable patients in the dose escalation part of the study with DLBCL who received loncastuximab tesirine at doses greater than or equal to 120 μg/kg, the overall response rate (ORR) was 55% (27/49), with 18 patients achieving a complete response (37%) and 9 patients achieving a partial response (18%).

The primary endpoint of the Phase II, multi-center, open-label, single-arm trial is the ORR in patients treated with loncastuximab tesirine, as confirmed by central review. Secondary endpoints include assessments of duration of response, complete response rate, relapse-free survival, progression-free survival and overall survival, as well as safety, pharmacokinetics and related quality of life. The trial will enroll approximately 140 patients with relapsed or refractory DLBCL at multiple centers in the USA and Europe.

“We are pleased to have dosed the first patient in our registrational Phase II clinical trial evaluating ADCT-402 in patients with DLBCL who have relapsed and have refractory disease after two or more multi-agent treatment regimens,” said Jay Feingold, MD, PhD, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics.

“Our Phase I clinical trial of ADCT-402 in non-Hodgkin lymphoma showed significant
activity in patients with DLBCL and an acceptable safety profile,” he added.

Unmet medical need
“Unfortunately, there is no effective treatment for patients with multiple relapsed and refractory DLBCL, so we are excited about the potential to improve outcomes in these patients with ADCT-402 in a single-arm trial. We anticipate reporting results from the Phase II trial in the third quarter of 2019 and are
hopeful that the data will support our submission of a BLA to the FDA,” Feingold concluded.

Alex Spira, MD, PhD, FACP, Director of Virginia Cancer Specialists Research Institute and Clinical Assistant Professor of Oncology at Johns Hopkins School of Medicine, added, “Patients with DLBCL who
have relapsed or are refractory after second-line chemotherapy face a very poor prognosis. There is a significant unmet need for an effective new treatment option for this patient population, and we believe loncastuximab tesirine has the potential to help impact patient outcomes in this disease.”

ADC Therapeutics also plans to initiate multiple combination studies with loncastuximab tesirine in the fourth quarter of 2018.

Current treatment
The most common initial treatment for patients with DLBCL is chemo-immunotherapy. Response to initial treatment is high, but more than half of patients do not have long-term disease control. [3]

The current standard of care for relapsed DLBCL is additional chemotherapy, which can be followed by stem cell transplantation (SCT). The prognosis for relapsed patients is poor, especially for those with chemotherapy-refractory disease with a short interval between remission and relapse or those who relapse after high-dose therapy and SCT. There is a significant unmet need for an effective treatment for patients with relapsed or refractory DLBCL.

Mechanism of Action
Loncastuximab tesirine is composed of a humanized monoclonal antibody which is stochastically conjugated via a valine-alanine cleavable, maleimide linker to the cytotoxic anticancer) pyrrolobenzodiazepine (PBD) dimer.

The antibody binds to CD19, a protein which is highly expressed on the surface of B-cell hematological tumors, including diffuse large B-cell lymphoma (DLBCL).

After binding to the tumor cells the antibody is internalized after which the cytotoxic drug PBD is released and the cancer cells are killed. PBD dimers are generated out of PBD monomers, a class of natural products produced by various actinomycetes. They work by crosslinking specific sites of the DNA, blocking the cancer cells’ division that cause the cells to die. As a class of DNA-crosslinking agents they are significantly more potent than systemic chemotherapeutic drugs.