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First Patient Dosed in Phase Ib Clinical Trial of Camidanlumab Tesirine in Patients with Advanced Solid Tumors

A first patient has been dosed in Phase Ib clinical trial of camidanlumab tesirine, also know ADCT-301, a proprietary antibody-drug conjugate or ADC being developed by ADC Therapeutics, for the treatment of patients with advanced solid tumors.[1]

The Phase Ib clinical trial is designed to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of camidanlumab tesirine in patients with selected solid tumors that are locally advanced or metastatic.

Camidanlumab tesirine is an antibody-drug conjugate composed of HuMax®-TAC (licensed from Genmab), conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin.

The HuMax-TAC monoclonal antibody targets the cell-surface antigen CD25 (the alpha chain of the Interleukin-2 receptor or IL2R-α) which is over-expressed on a variety of hematological tumors and shows limited expression on normal tissues.

IL2R-α [*], one of a heterotrimer that makes up the IL2R, has been recognized to play an important role in signal transduction pathways involved in the pathogenesis of autoimmunity and graft rejection. [2] Scientists have also confirmed the preponderance of CD25+ cells in hematological malignancies (malignant lymphomas including B-cell malignancies) [3] and the relationship between increased CD25 expression and poor prognosis [4] raising the possibility of using an anti-CD25 antibody to deliver a cytotoxin to these cells in vivo.

Once bound to a CD25-expresing cell, the investigational agent 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. In addition, the PBD payload will trigger immunogenic cell death, which in turn will strengthen the immune response against tumor cells.

Camidanlumab tesirine is already being evaluated in relapsed and refractory Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).[1][5]

American Society of Hematology
At the 2018 American Society of Hematology (ASH) Annual Meeting, ADC Therapeutics presented interim data on 113 patients dosed in its Phase Ia/Ib clinical trial in lymphoma. In hodgkin lymphoma patients with a median of five prior lines of therapy and no other approved therapy options, the overall response rate was 86.5%, including a 43% complete response rate, at the dose being considered for a pivotal Phase II clinical trial that the Company anticipates initiating in 2019.

“We continue to be very encouraged by the anti-tumor activity of [camidanlumab tesirine] in Hodgkin lymphoma and non-Hodgkin lymphoma,” said Jay Feingold, MD, Ph.D, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics/

“In addition, based on the immune-oncology potential [camidanlumab tesirine] has demonstrated in preclinical studies, we are excited to be starting this clinical trial for ADCT-301 in solid tumors to see if we can make an impact and improve patient outcomes in multiple difficult-to-treat solid tumor cancers,” Feingold added.

Solid Tumors
At the Society for Immunotherapy of Cancer’s (SITC) 33rd Annual Meeting, ADC Therapeutics presented preclinical data showing that an engineered version of camidanlumab tesirine demonstrated highly potent anti-tumor activity, both as a monotherapy and in combination with a checkpoint inhibitor, in multiple solid tumor models with infiltrating CD25-positive regulatory T cells (Tregs).

“[Camidanlumab tesirine] targets CD25, which is expressed on Tregs that infiltrate the local tumor environment,” noted Patrick van Berkel, PhD, Senior Vice President of Research and Development at ADC Therapeutics.

“In preclinical models, a single dose of the CD25-targeted ADC induced strong and durable anti-tumor activity against established CD25-negative solid tumors with infiltrating Tregs both as a monotherapy and in combination with a checkpoint inhibitor. Moreover, re-challenged mice did not develop new tumors indicating the CD25-targeted ADC was able to induce tumor-specific protective immunity,” Van Berkel, Ph.D, added.

The Phase Ib trial of camidanlumab tesirine in patients with advanced solid tumors has both dose escalation and cohort expansion parts. The dose escalation part is designed to establish a safe and tolerated dose and dosing schedule of camidanlumab tesirine in these patients.

The identified dose and dosing schedule will be studied in the dose expansion part. Approximately 50 patients will be enrolled in the trial.

Reference
[1] Study of ADCT-301 in Patients With Selected Advanced Solid Tumors – NCT03621982
[2] Burchill MA, Yang J, Vang KB, Farrar MA. Interleukin-2 receptor signaling in regulatory T cell development and homeostasis. Immunol Lett. 2007 Nov 30;114(1):1-8. Epub 2007 Sep 14.
[3] Srivastava MD, Srivastava A, Srivastava BI. Soluble interleukin-2 receptor, soluble CD8 and soluble intercellular adhesion molecule-1 levels in hematologic malignancies. Leuk Lymphoma. 1994 Jan;12(3-4):241-51.
[4] Yoshida N, Oda M, Kuroda Y, Katayama Y, Okikawa Y, Masunari T, Fujiwara M, Nishisaka T, et al. Clinical significance of sIL-2R levels in B-cell lymphomas. PLoS One. 2013 Nov 13;8(11):e78730. doi: 10.1371/journal.pone.0078730. eCollection 2013.
[5] Study of ADCT-301 in Patients With Relapsed or Refractory Hodgkin and Non-Hodgkin Lymphoma – NCT02432235 


[*] The interleukin-2 (IL-2) receptor includes three different IL-2 receptor chains: α, β, and γ. Among these, the α-chain (CD25) on the cell membrane is cleaved by proteolytic processing, and the cleaved α-chain is detected as sIL-2R. The ligand of IL-2R, IL-2, plays a critical role in the development of T and NK lymphocyte as a growth factor.


Last Editorial Review: January 7, 2019

Featured Image: working in the biosafety cabinet. Courtesy: © 2010 – 2019 Fotolia. Used with permission.

Copyright © 2019 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Interim Phase I Data from Camidanlumab Tesirine (ADCT-301) Shows Encouraging Preliminary Safety and Efficacy Results

Clinical data from two ongoing Phase I clinical trials evaluating camidanlumab tesirine, also known as ADCT-301* or “Cami-T”, in important subtypes of lymphoma and leukemia show encouraging, preliminary, safety and efficacy results.

The data from these clinical trials was presented at the 59th annual meeting of the American Society of Hematology (ASH), held December 9 – 12, 2017 in Atlanta, Georgia (USA).

Mode of Action
Camidanlumab tesirine is an antibody-drug conjugate or ADC, being developed by ADC Therapeutics, comprising a human monoclonal antibody against CD25 (HuMax®-TAC, licensed from Genmab), stochastically conjugated through a dipeptide cleavable linker to a potent pyrrolobenzodiazepine (PBD) dimer toxin with a drug-antibody ratio (DAR) of 2.3 [1][2]

Once bound to a CD25-expresing cell, camidanlumab tesirine is internalized into the cell where enzymes release the PBD-based payload. After internalizing, the released pyrrolobenzodiazepine (PBD) dimer payload, found among the most cytotoxic agents known, binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. [2] In turn, this eventually results in phosphorylation of histone H2AX, cell-cycle arrest in G2-M, and apoptosis.


Acute myeloid leukemia is the most common leukemia in the adult population in United States. Patients expressing CD25 on their leukemia cells have a particularly poor prognosis.

Camidanlumab tesirine … has shown an acceptable safety profile…


In vivo, single dose of camidanlumab tesirine leads to dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models.[2]

Attractive target
CD25, also known as interleukin-2 receptor alpha or IL2R-α, a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called interleukin-2 or IL-2, is an attractive target for an antibody-drug conjugate approach as it is expressed on the cell surface of a wide range of hematological malignancies, including Hodgkin lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and diffuse large B-cell lymphoma lymphoma. Interestingly, the expression of CD25 in healthy organs is restricted. [3][4]

To date, camidanlumab tesirine is being evaluated in two ongoing phase Ia/Ib clinical trials in patients with relapsed or refractory Hodgkin lymphoma and non-Hodgkin lymphoma, and in patients with relapsed or refractory CD25-positive acute myeloid leukemia and acute lymphoblastic leukemia. [5][6]

Poster 1.0: Presented at the 59th (2017) Annual Meeting of the American Society of Hematology. Interim results of a Phase I open label, single agent, dose-escalating study of ADCT-301 evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory B-cell Hodgkin’s or non-Hodgkin’s lymphoma. Click here to enlarge.

B-cell Hodgkin’s or non-Hodgkin’s lymphoma
The first poster presentation (1510) showed data from 86 evaluable, heavily pre-treated patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit. The median age of patients was 53 years and they had a median of 4 prior therapies.

Data were reported from Part 1 and Part 2 of the Phase I study as of November 1, 2017. In Part 1 (dose escalation), 71 patients were treated at dose ranges from 3-150 µg/kg every three weeks. In Part 2 (dose expansion), 15 Hodgkin Lymphoma patients were treated at 45 µg/kg every 3 weeks. [7]

“Despite considerable advances in the treatment of lymphoma, a significant number of patients still relapse or become refractory to existing therapies and need new treatment options. We are excited by the 77% overall response rate (ORR) in Hodgkin Lymphoma (HL), including a 44% complete response rate,” noted Steven M. Horwitz, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, and Principal Investigator of the study.

“We are also seeing emerging efficacy signals in T-cell lymphomas (ORR: 33%) and B-cell lymphomas (ORR: 19%). Although still early, we are very encouraged by a median duration of response for HL patients of over 5 months to-date. The safety profile appears consistent with what we expect with this target and warhead. We are now working to determine the best dosing regimen for Phase II,” Horwitz added.

Key findings included:

  • For the 27 response-evaluable patients with HL in Part 1, treated at doses greater than or equal to 45 µg/kg, the ORR was 77 percent (21/27 patients) with 12 patients achieving a complete response (44%) and 9 patients achieving a partial response (33%).
  • For the 12 response-evaluable patients with HL in Part 1 and Part 2, treated at the 45 µg/kg dose, the ORR was 100 percent (12/12) with 6 patients achieving a complete response (50 percent) and 6 patients achieving a partial response (50%).
  • For HL patients in Part 1 and Part 2, treated at doses greater than or equal to 45 µg/kg, a complete or partial response was achieved in 21 of 27 patients previously treated with brentuximab vedotin (77%), 13 of 18 patients previously treated with a checkpoint inhibitor (72%), 9 of 14 patients who had previously undergone a stem cell transplantation (64%), and 4 of 8 patients who had previously received all three of these treatments (50%).

Adverse events.
Camidanlumab tesirine has been reasonably well tolerated.

The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients in Part 1 and Part 2 were fatigue (30%), rash (26%), elevated gamma-glutamyltransferase (22%), and pyrexia (21%). The most common Grade 3 or 4 adverse events occurring in at least 5 percent of patients, regardless of attribution, were elevated gamma-glutamyltransferase (13%), reduced platelet count (9%), elevated alanine aminotransferase (6%), anemia (6%), and rash (6%). There were three heavily pre-treated patients diagnosed with auto-immune neurotoxicity, including two patients who developed Guillain-Barré syndrome.

Based on the encouraging preliminary safety and efficacy results, the researchers support further characterization of the dosing regime to optimize the therapeutic window in Hodgkin Lymphoma for a Phase II study.

Poster 2.0: Presented at the 59th (2017) Annual meeting of the American Society of Hematology. Interim results of a Phase I open label, single agent, dose-escalating study of ADCT-301 evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory B-cell acute myeloid leukemia or acute lymphoblastic leukemia. Click here to enlarge.

B-cell acute myeloid leukemia or acute lymphoblastic leukemia
Data were presented from 33 evaluable, heavily pre-treated, patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit.

The median age of patients was 67 years and they had a median of 3 prior therapies.[8]

In Part 1 (dose escalation), 33 patients were treated at dose ranges from 3-92 µg/kg every three weeks, or 30-37.5 µg/kg once weekly.

Key findings:

  • One patient achieved a complete response with incomplete blood count recovery;
  • Camidanlumab tesirine has shown an acceptable safety profile
  • The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients were fatigue (30%), nausea (24%), febrile neutropenia (21%), and pneumonia (21%). The most common Grade 3 or 4 adverse events occurring in at least 10 percent of patients, regardless of attribution, were febrile neutropenia (21%), thrombocytopenia (15%), fatigue (12%), reduced neutrophil count (12%), and pneumonia (12%);
  • Dose escalation will continue to investigate weekly dosing.

Earlier this year interim results from an ongoing Phase I, open label, dose-escalating study evaluating ADCT-301, for the treatment of relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma, were presented  at the 14th International Conference on Malignant Lymphoma (ICML), held June 14 – 17, 2017 the Lugano Convention Centre, Palazzo dei Congressi, in Lugano, Switzerland, confirming  favorable tolerability and efficacy.

These results were included in a poster showing tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma (r/r HL/NHL). [9]


* Also see: ADC Review | Antibody-drug Conjugates – Drug map

Last editorial review: December 16, 2017

Featured Image:  ADC Therapeutics Booth | 59th Annual Meeting of the American Society of Hematology. Courtesy: © 2017. Sunvalley Communication/Evan Wendt |Used with permission.

Copyright © 2017 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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