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PEER-REVIEWED ARTICLES

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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First Patient with Advanced Solid Tumors with HER2 Expression Dosed in a Phase I Clinical Trial of ADCT-502

A first patient with advanced solid tumors with HER2 Expression was dosed in a phase I clinical trial with ADCT-502. The investigational drug being developed by ADC Therapeutics represents the company’s fourth proprietary Antibody-drug Conjugates (ADCs) programs in clinical six clinical trials and is designed to evaluate and provide data on safety, tolerability, pharmacokinetics and efficacy.

The clinical trial is a two stage, open-label Phase Ia/Ib clinical trial. The first stage (Phase Ia) is a dose escalation phase which will recruit patients at leading clinical centers across the United States and and Europe, and will seek to determine the recommended dose of ADCT-502. The second consecutive stage (Phase Ib), has the objective to confirm the safety and efficacy profile for ADCT-502 in expanded patient cohorts in multiple potential cancer indications.

Investigational agent
ADCT-502 combines a humanized monoclonal antibody trastuzumab targeting the human epidermal growth factor receptor 2 (HER2) with a pyrrolobenzodiazepine (PBD-based) linker-drug tesirine payload. Tesirine, a cathepsin B-cleavable valine-alanine PBD payload also known as SG3249, has been designed to combine potent anti-tumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. It is a potent and clinically validated PBD payload currently being employed in the clinic in a number of ADCs, including the CD25-targeted ADCT-301, the CD19-targeted ADCT-402, both for the treatment of lymphoma and leukemia, and the DDL3-targeted rovalpituzumab tesirine for the treatment of small cell lung cancer.

The antibody is site-specifically conjugated to the payload. Once bound to the HER2 receptor on the cell surface, ADCT-502 is internalized into the cell where enzymes release the PBD-based payload.The HER2 surface protein is expressed at high or low levels in a variety of different tumor types, including breast cancer, gastric and gastroesophageal cancers. It is also a well-established, clinically validated target.


Figure 1.0: Pyrrolobenzodiazepine dimers are an emerging class of payloads used in antibody-drug conjugates (ADCs). Tesirine also known as SG3249, is a N10 linked PBD dimer designed to combine potent anti-tumor activity with desirable physicochemical properties, including favorable hydrophobicity and improved conjugation characteristics.

Clinical studies
Preclinical data presented during the 2017 annual meeting of the American Association for Cancer Research (AACR) shows superior in vivo anti-tumor activity of ADCT-502 compared to T-DM1 (ado-trastuzumab emtansine/Kadcyla®; Genentech/Roche) in various tumor xenografts with low HER2 levels.  These results support the development of ADCT-502 not only in patients that have become resistant/refractory to T-DM1, but also in patients whose tumors express low levels of HER2, and are not eligible for treatment with T-DM1. [1]

Overall, the ADCT-502 has exhibited strong dose-dependent anti-tumor activity at low single doses against both low and high HER2 expressing tumors. Given the substantial prevalence of HER2 expression in a range of cancers, ADCT-502 will be evaluated in patients with non-small cell lung cancer (NSCLC), bladder, biliary tract, and ovarian cancer, for which HER2 targeted therapies are not yet approved.

“This is the fourth ADC we have put into the clinic in just over two years. Dosing the first patient in this trial with ADCT-502 is an important milestone for us and could pave the way for a better treatment regimen for patients,”  said Jay M. Feingold, MD, Ph.D. , Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics.

“The trial will give us vital data on safety, tolerability and dosing. Our preclinical studies suggest ADCT-502 may provide significant clinical benefit for patients suffering from a variety of tumor types which are known to express HER2 in a significant proportion of patients. We are exploring this potential in lung, bladder and biliary tract cancers further within this study as well as in the more established indications of breast and gastric cancer,” Feingold added.

Eagerly expected
“Tremendous advances have been made in the treatment of HER2 expressing cancers, particularly gastroesophageal and breast cancers, in the past 20 years,” noted Kyriakos P. Papadopoulos, MD, Senior Clinical Investigator of the START Center for Cancer Care in San Antonio, Texas,  and one of the investigators of the study.

“However, a significant portion of this patient population still fail to respond or relapse with currently available therapies. Having seen the effects of other pyrrolobenzodiazepine ADCs in various tumor types in recent years, we eagerly anticipate the results of this study,” Papadopoulos concluded.


Last Editorial Review: May 19, 2017

Featured Image: Older Patient and Nurse. Courtesy: © 2017 Fotolia. Used with permission.

Copyright © 2017 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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Encouraging Data for Novel ADC Presented at ESMO 2016

During the annual meeting of the European Society for Medical Oncology (ESMO) being held October 7 – 11, 2016 in Copenhagen, Denmark, preliminary data for PF-06647020 in advanced solid tumors was presented as part of a Late Breaking Abstract/Poster Discussion Session (Abstract LBA35). [1]

The study was initially designed as a dose-escalation study to evaluate safety, pharmacokinetics and antitumor activity for patients with advanced solid tumors. A pre-planned expansion for ovarian cancer included 27 patients that received PF-06647020.

esmo_2016_logoClinical trial data also confirms that the use of PTK7-targeted therapy resulted in a response of approximately 50% in the case of breast cancer and an almost Complete Response (CR) for ovarian cancer. These early-stage results underline the strong efficacy profile of PF-06647020. The early-stage trials have further demonstrated that PF-06647020, given its low toxicity, is well-tolerated with an acceptable safety profile.

Trial results
To date, 76 patients have been treated with PF-06647020. A total of 60 of which were treated at 2.8 mg/kg once every 3 weeks (Q3W)/cycle in escalating doses from 0.2 – 3.7 mg/kg until progression.

Most adverse events have grade 1-2 with the majority being self-limiting and nor requiring medical intervention. Most commonly (≥10%) reported drug related adverse events included nausea (46%), alopecia (34%), headache (32%), fatigue (30%), neutropenia (26%), vomiting (22%), decreased appetite (17%), myalgia (15%), arthralgia (11%), and diarrhea (11%).

Fourteen patients (18%) experienced Grade ≥3 drug related neutropenia and 3 patients (4%) discontinued due to drug related adverse events.

Twenty-nine recurrent ovarian cancer patients with ECOG Performance Status 0-1 (median age 58.5 yrs [42-77]) were treated at  2.1 mg/kg (1 pt).  Twenty-two patients currently evaluable in this heavily pre-treated group of patients with platinum-resistant ovarian cancer, the trial results showed Complete Response (CR) in 1 patient, 5 patients had Partial Response (PR) with Objective Response Rate (ORR) of 27% (95% CI: 13%, 48%), 12 patients (55%) had Stable Disease (SD), and 4 patients  (18%) had Progressive Disease. Median duration of treatment was 3 cycles (range 1–13). A total of 10 patients remained on treatment.

The investigational drug targets PTK7,  a catalytically inactive protein tyrosine kinase which functions in developmental biology and is over expressed in a variety of human cancers. Exploratory immunohistochemistry staining by a validated assay on archival tumors showed that all ovarian cancer (OVCA) patients in this had PTK7 expression.

Novel approach
PF-06647020 is an anti-PTK7 Antibody-drug Conjugate being developed by Pfizer in collaboration with Stemcentrx (now part of AbbVie). The novel ADC is comprised of a humanized monoclonal antibody directed against PTK7, which is also expressed in many tumor types, linked to an auristatin microtubule inhibitor payload via a cleavable dipeptide linker.

Advanced Solid Tumors
In the phase I study PF-06647020 showed an acceptable safety profile in patients with advanced malignancies, including triple negative breast cancer (TNBC), advanced ovarian cancer and non-small cell lung cancer (NSCLC). PF-06647020 also showed early indication of anti-tumor activity in an unselected patient population. [2]

In data presented during the ESMO/ECCO meeting in 2015, PF-06647020 showed some responses at doses above 2.1mg/kg in patients with advanced triple negative breast cancer and platinum resistant ovarian cancer. At that time, no dose-limiting toxicities (DLTs) were reported with dose escalation continuing to 3.7mg/kg. [2]

“Both triple negative breast cancer and platinum resistant ovarian cancer are difficult to treat, and novel approaches are urgently needed,” noted Markus Joerger, MD, attending medical oncologist at the St. Gallen Cancer Centre (Kantonsspital St.Gallen) in St. Gallen, Switzerland, after reviewing the trial results presented at the annual meeting of the European Society for Medical Oncology. “The clinical activity shown with PF-06647020, is indeed encouraging,” he continued.

“Clinically relevant benefits can be confirmed with some novel targeted agents such as PF-06647020 and it is hoped that their early promise will be confirmed in larger studies,” Joerger concluded.


Last Editorial Review: October 14, 2016

Featured Image: Woman Having Chemotherapy With Nurse Using Digital Tablet Courtesy: © Fotolia. Used with permission. Illustration 1.0: Schematic of PF-06647020 an investigational antibody-drug conjugates targeting PTK7. Courtesy: © Pfizer. Used with permission.

Copyright © 2016 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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