15th ICML: Camidanlumab Tesirine Shows High Overall Response Rate in R/R Classical Hodgkin Lymphoma

Featured Image: Close-up cityscape of Lugano city waterfront along Lugano Lake. Facades of historic houses in front of alp mountains. Courtesy: © 2017. Fotolia. Used with permission.
Featured Image: Close-up cityscape of Lugano city waterfront along Lugano Lake. Facades of historic houses in front of alp mountains. Courtesy: © 2017. Fotolia. Used with permission.

During the International Conference on Malignant Lymphoma (ICML), one of the must-attend events for the scientific community involved in the study and treatment of lymphoid neoplasms, held June June 18 – 22, 2019 in Lugano, Switzerland, data were presented from Phase I clinical trial subgroup analyses of response to camidanlumab tesirine (ADCT-301) in  patients with R/R classical Hodgkin lymphoma (cHL).[1]

The investigational drug, being developed by ADC Therapeutics, is an antibody drug conjugate (ADC) comprised of a monoclonal antibody that binds to CD25 (HuMax®-TAC, licensed from Genmab A/S), conjugated to the pyrrolobenzodiazepine (PBD) dimer payload tesirine (SG3249), which has the ability to form highly cytotoxic DNA interstrand cross-links, blocking cell division and resulting in cell death.

CD25, also known as Interleukin-2 receptor alpha chain is a protein that in humans is encoded by the IL2RA gene. The interleukin 2 (IL2) receptor alpha (IL2RA) and beta (IL2RB) chains, together with the common gamma chain (IL2RG), constitute the high-affinity IL2 receptor.

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Once bound to a CD25-expressing cell, camidanlumab tesirine is internalized into the cell where enzymes release the PBD-based payload. The intra-tumor release of its PBD payload may cause bystander killing of neighboring tumor cells.

Tesirine (SG3249) is a cathepsin B-cleavable valine-alanine pyrrolobenzodiazepine (PBD) dimer and an antibody-drug conjugate (ADC) payload. Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics.
Tesirine (SG3249) is a cathepsin B-cleavable valine-alanine pyrrolobenzodiazepine (PBD) dimer and an antibody-drug conjugate (ADC) payload. Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics.

In addition, the PBD payload triggers immunogenic cell death, which in turn strengthens the immune response against tumor cells.

Camidanlumab tesirine is being evaluated in ongoing Phase Ia/Ib clinical trials in patients with relapsed or refractory Hodgkin lymphoma and non-Hodgkin lymphoma (NCT02432235), as well as a Phase Ib clinical trial in solid tumors (NCT03621982). A pivotal Phase II clinical trial of camidanlumab tesirine in 100 patients with relapsed or refractory Hodgkin lymphoma is expected to start later this year.

The observed clinical success of tesirine (SG3199), a PBD dimer as a payload in antibody-drug conjugates, stems from its potent cytotoxicity, showing activity across a wide range of both solid tumor and hematological cancers. This high potency an important advantage in ADCs utilizing payload tesirine, allowing to treat tumors with low copy number antigen targets.
The observed clinical success of SG3199 stems from its potent cytotoxicity, showing activity across a wide range of both solid tumor and hematological cancers. This high potency an important advantage in ADCs utilizing payload tesirine, allowing to treat tumors with low copy number antigen targets.

Presented results
The results presented during the 15th ICML included an analysis of the safety and efficacy of camidanlumab tesirine in Relapsed/Refractory (R/R) Classical Hodgkin Lymphoma (cHL) (Abstract 055). In this trial, at the time of the data cutoff of April 14, 2019, 77 patients were evaluable for safety and 75 patients were evaluable for efficacy.

Key findings from the oral presentation include:

  • The Overall Response Rate (ORR) for camidanlumab tesirine 45 μg/kg was 86.5%.
  • The ORR was high across all subgroups, suggesting significant anti-tumor activity across the R/R cHL population
  • The recommended dose for the pivotal Phase II trial of camidanlumab tesirine in cHL is 45 μg/kg every three weeks (Q3W) dosed for two cycles, followed by 30 μg/kg Q3W to improve tolerability while maintaining anti-cancer activity
  • Previously reported cases of Guillain-Barré syndrome/radiculopathy did not appear related to prior checkpoint inhibitor exposure

Poster presentation
A poster presentation during the 15th ICML showed the results of a preclinical study evaluating activity of ADCT-301 as a single agent in 57 lymphoma cell lines and in combination with select drugs in T-cell lymphoma-derived cell lines. The findings support the continued clinical development of ADCT-301 in Hodgkin lymphoma, T-cell lymphomas and other types of non-Hodgkin lymphoma, and identify potential agents for future ADCT-301 combination clinical trials.

Key findings from the poster include:

  • Camidanlumab tesirine in vitro activity was highly correlated with CD25 expression at both the cell surface and RNA level
  • When tested in combination with other drugs, camidanlumab tesirine demonstrated strong synergy with the mTOR inhibitor everolimus (4/4 cell lines), PI3K inhibitor copanlisib (3/4 cell lines), BCL2 inhibitor venetoclax (3/4 cell lines) and HDAC inhibitor vorinostat (3/4 cell lines)

“Our presentations at 15-ICML represent the strong dataset we continue to amass for camidanlumab tesirine in difficult-to-treat patients, both young and old, with subtypes of relapsed or refractory lymphoma, including DLBCL and Hodgkin lymphoma. The clinical activity we have observed in these populations, which include heavily pretreated patients with unfavorable genetics and primary refractory disease, increases our enthusiasm for the potential utility of camidanlumab tesirine as single agents and in combination with other agents, if approved.”

Clinical Trials
Study of ADCT-301 in Patients With Relapsed or Refractory Hodgkin and Non-Hodgkin Lymphoma – NCT02432235
Study of ADCT-301 in Patients With Selected Advanced Solid Tumors  – NCT03621982

Reference
[1] Collins G, Horwitz S, Hamadani M, Samaniego F, Spira A, Caimi P, Davies A, et al. Analysis of Clinical Determinants Driving Safety and Efficacy of Camidanlumab Tesirine (ADCT301, Cami) in Relapsed/Refractory (R/R) Classical Hodgkin Lymphoma (cHL) (Abstract 055) [PowerPoint Presentation]
[2] Spriano F, Tarantelli C, Golino G ,Gaudio E, Scalise L, Cascione L, Zucca E, et al. The Anti-CD25 Antibody-Drug Conjugate Camidanlumab Tesirine (ADCT-301) Presents a Strong Preclinical Activity Both as Single Agent and In Combination in Lymphoma Cell Lines. Presented during the 15th International Conference on Malignant Lymphoma (ICML), held June 18 – 22, 2019, Lugano, Switzerland.[Poster 270]