On June 21, 2019 ADC Therapeutics, an oncology drug discovery and development company that specializes in the development of antibody drug conjugates (ADCs), presented data from subgroup analyses of its 183-patient Phase I clinical trial of ADCT-402 (loncastuximab tesirine) and 128-patient Phase I trial of ADCT-301 (camidanlumab tesirine), as well as preclinical data demonstrating the potential of both product candidates in combination with other therapies, at the 15th International Conference on Malignant Lymphoma (15-ICML) in Lugano, Switzerland (Press release, ADC Therapeutics, JUN 21, 2019, View Source [SID1234596059]).
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"The ADCT-402 data presented at 15-ICML demonstrate its signficant anti-tumor activity and manageable tolerability profile at doses greater than or equal to 120 μg /kg in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL)," said John Radford, MD, FRCP, FMedSci, Professor of Medical Oncology at The University of Manchester and Director of Research at The Christie NHS Foundation Trust, Manchester, UK. "It is particularly encouraging to see the responses in older patients and patients with transformed or primary refractory disease, as in many cases these are very frail and sick patients who have not responded to multiple previous therapies. I believe ADCT-402 has the potential to become an important part of the treatment paradigm for patients with relapsed or refractory DLBCL, if approved, and look forward to the forthcoming interim results of the pivotal Phase II trial."
Regarding the ADCT-301 data, Graham P. Collins, MB, BS, DPhil, Consultant and Lymphoma Lead, Oxford University Hospitals, said, "The response rates we have observed in patients with relapsed or refractory Hodgkin lymphoma in the Phase I trial of ADCT-301 are very encouraging, as these patients have been heavily pretreated with a median of five prior therapies, including stem cell transplantation and highly active agents like brentuximab vedotin and checkpoint inhibitors. The data support further evaluation of ADCT-301 in a pivotal Phase II trial in relapsed or refractory Hodgkin lymphoma."
Chris Martin, PhD, Chief Executive Officer of ADC Therapeutics, added, "On the heels of these encouraging data, we look forward to completing enrollment in the pivotal 140-patient Phase II trial of ADCT-402 in patients with relapsed or refractory DLBCL and, if successful, preparing to file a potential Biologics License Application in the second half of 2020. In addition, based on the compelling data from our 128-patient Phase I trial of ADCT-301 and recent end of Phase I meeting with the U.S. Food and Drug Administration, we plan to start a pivotal Phase II trial in 100 patients with relapsed or refractory Hodgkin lymphoma in the coming months."
ADCT-402 Oral Presentations at ICML
Analysis of Efficacy and Safety of Loncastuximab Tesirine (ADCT-402) by Demographic and Clinical Characteristics in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (Abstract 054)
Data were presented from Phase I clinical trial subgroup analyses of response to ADCT-402 at doses ≥120 μg/kg in 129 patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). As of the October 16, 2018 data cutoff, 129 patients were evaluable for safety and 127 patients were evaluable for efficacy.
Key findings from the oral presentation include:
Older patients had a higher overall response rate (ORR) than younger patients (≥ 75 years: 59.1%; 65-74 years: 52.8%; <65 years: 33.3%)
Patients with transformed disease had a higher ORR than those with de novo DLBCL (54.8% vs 39.6%)
Median duration of response (DoR) was longer for refractory patients than relapsed patients, and median DoR was comparable for patients to their most recent therapy vs relapsed patients
No difference in ORR was observed between patients who had received ≤3 lines vs >3 lines of prior therapy
The most common grade ≥3 treatment-emergent adverse events were: gamma-glutamyltransferase increased (20.2%), neutropenia (17.8%), neutrophil count decreased (14%), anaemia (11.6%), thrombocytopenia (11.6%) and platelet count decreased (10.9%)
The Antibody-Drug Conjugate (ADC) Loncastuximab Tesirine (ADCT-402) Targeting CD19 Shows Strong In Vitro Anti-Lymphoma Activity Both as Single Agents and In Combination (Abstract 084)
This preclinical study evaluated the activity of ADCT-402 as a single agent and in combination with approved drugs in lymphoma cell lines. The findings support the continued evaluation of ADCT-402 in ongoing clinical trials in patients with R/R DLBCL and other types of non-Hodgkin lymphoma.
Key findings from the oral presentation include:
ADCT-402 demonstrated significant activity in vitro in a wide panel of lymphoma cell lines and sensitivity to ADCT-402 was higher in B-cell lymphomas than T-cell lymphomas
ADCT-402 in vitro activity correlated with CD19 expression at both the cell surface and RNA level
When tested in combination with other drugs, ADCT-402 demonstrated strong synergy with BCL2 inhibitor venetoclax (4/4 cell lines), PI3K-delta inhibitor idelalisib (4/4 cell lines) and chemotherapy agent bendamustine (3/4 cell lines)
ADCT-301 Oral Presentation and Poster at ICML
Analysis of Clinical Determinants Driving Safety and Efficacy of Camidanlumab Tesirine (ADCT301, Cami) in Relapsed/Refractory (R/R) Classical Hodgkin Lymphoma (cHL) (Abstract 055)
Data were presented from Phase I clinical trial subgroup analyses of response to ADCT-301 in patients with R/R classical Hodgkin lymphoma (cHL). 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:
ORR for ADCT-301 45 μg/kg was 86.5% and 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 ADCT-301 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
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 (Poster 270)
This preclinical study evaluated 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:
ADCT-301 in vitro activity was highly correlated with CD25 expression at both the cell surface and RNA level
When tested in combination with other drugs, ADCT-301 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)
Jay Feingold, MD, PhD, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics, said, "Our presentations at 15-ICML represent the strong dataset we continue to amass for ADCT-402 and ADCT-301 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 ADCT-402 and ADCT-301 as single agents and in combination with other agents, if approved."
The three oral presentations and one poster will be available after 15-ICML under "Posters & Presentations" in the News & Media section of ADC Therapeutics’ web site at www.adctherapeutics.com.
About ADCT-402
ADCT-402 (loncastuximab tesirine) is an antibody drug conjugate (ADC) comprised of a humanized monoclonal antibody that binds to human CD19, conjugated through a linker to a pyrrolobenzodiazepine (PBD) dimer toxin. Once bound to a CD19-expressing cell, ADCT-402 is internalized into the cell where enzymes release the PBD-based warhead. CD19 is a clinically validated target for the treatment of B-cell malignancies. The PBD-based warhead has the ability to form highly cytotoxic DNA interstrand cross-links, blocking cell division and resulting in cell death. ADCT-402 is being evaluated in a pivotal Phase II clinical trial in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (NCT03589469), a Phase Ib trial in combination with ibrutinib in patients with R/R DLBCL or mantle cell lymphoma (MCL) (NCT03684694) and a Phase Ib trial in combination with durvalumab in patients with R/R DLBCL, MCL or follicular lymphoma (NCT03685344). The U.S. Food and Drug Administration granted orphan drug designation to ADCT-402 for the treatment of relapsed or refractory DLBCL and MCL.
About ADCT-301
ADCT-301 (camidanlumab tesirine) 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. Once bound to a CD25-expressing cell, ADCT-301 is internalized into the cell where enzymes release the PBD-based warhead. The intra-tumor release of its PBD warhead may cause bystander killing of neighboring tumor cells. In addition, the PBD warhead will trigger immunogenic cell death, which in turn will strengthen the immune response against tumor cells. ADCT-301 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 ADCT-301 in 100 patients with relapsed or refractory Hodgkin lymphoma is expected to commence in 2019.