The trial will include breast cancer patients with low expression of HER2.
Synthon Biopharmaceuticals (‘Synthon’) today announced that the first patients with metastatic solid tumors have commenced treatment with its investigational anti-HER2 antibody-drug conjugate (ADC), SYD985.
First patients for this trial are being enrolled in leading European oncology centers Radboud University Medical Center (Nijmegen, the Netherlands), the Jules Bordet Institute (Brussels, Belgium) and the Institute of Cancer Research at The Royal Marsden Hospital (London, United Kingdom). The trial will recruit at least 76 patients and more centers are expected to join the trial in 2015.
This trial is a two part first-in-human Phase I study. In the dose escalation part of the trial, safety and efficacy of SYD985 will be evaluated in patients with locally advanced or metastatic solid tumors of any origin. In the expanded cohort part of the trial, only patients with breast and gastric cancer will be enrolled. The expanded cohorts will include patients currently indicated for HER2-targeted treatment as well as patients with HER2 2+ and HER2 1+ breast cancer for whom there currently is no effective anti-HER2 therapy available.
SYD985 is a HER2-targeting ADC based on trastuzumab and Synthon’s proprietary cleavable linker-duocarmycin (vc-seco-DUBA) payload. SYD985 is the most advanced candidate in Synthon’s ADC portfolio, and has demonstrated unprecedented anti-tumor activity in preclinical breast and gastric cancer models with low expression of HER2 (HER2 2+ and HER2 1+). See Notes to Editors for further information.
Jacques Lemmens, CEO of Synthon, said: “Entering this phase of clinical evaluation is another significant development milestone for SYD985. The dose-escalation part of the trial will determine the start of expanded patient cohorts to further evaluate safety and explore preliminary efficacy of this new and promising ADC.”
“We believe SYD985 has the potential to at least double the current breast cancer population eligible for HER2-based ADC treatment. If successful, it could provide new treatment options for cancer patients with a high unmet medical need, including triple negative breast cancer patients.”
Trial SYD985.001 is a two part first-in-human Phase I study with the anti-HER2 ADC SYD985 to evaluate the safety, pharmacokinetics and efficacy in patients with histologically-confirmed, locally advanced or metastatic tumors. These are patients who have progressed on standard therapy or for whom no standard therapy exists.
During part I (dose escalation) patients with solid tumors of any origin will be enrolled. For part II (expanded cohorts) enrollment is limited to patients with breast or gastric tumors with demonstrated HER2 expression and measurable disease lesions as per protocol defined criteria.
This trial is registered in ClinicalTrials.gov with identifier NCT02277717.
In vitro, SYD985 and T-DM1 (Kadcyla®) were studied in a panel of eight cell lines expressing different levels of HER2.
In cell lines with high HER2 expression (characterized as HER2 3+) SYD985 and T-DM1 showed similar potencies. However, in cell lines with low or moderate HER2 expression (characterized as HER2 1+ and HER2 2+), SYD985 was substantially more potent than T-DM1.
In vivo anti-tumor activity was assessed in a series of xenograft models using tumor cell lines and patient-derived breast-cancer tissues with varying HER2 expression levels (HER2 3+, HER2 2+ and HER2 1+).
Both SYD985 and T-DM1 showed anti-tumor activity in the HER2 3+ models. SYD985 demonstrated very potent anti-tumor activity in the FISH-negative models that were either HER2 2+ or HER2 1+, contrary to T-DM1 which was completely inactive. In these moderate- or low-expressing HER2 tumor models, SYD985 was even able to induce complete tumor remission after a single dose of 3 mg/kg.
For more information refer to Wim Dokter, Ruud Ubink, Miranda van der Lee, et al. Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform. Mol Cancer Ther 13(11);2618-2629, 2014.
* Kadcyla® is a registered trademark of Genentech, Inc. (U.S.) / F. Hoffmann-La Roche AG (EU)
Antibody-drug conjugates are designed to combine the specificity of antibodies directed against tumor-associated targets with potent cytotoxicity. Upon internalization of the ADC, the antibody-bound cytotoxins are released intracellularly, leading to programmed tumor cell death.
While the cytotoxins used in the majority of advanced programs in the field prevent tubulin polymerization during cell division, Synthon’s differentiating linker-drug technology − applying valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA) − is based on synthetic duocarmycin analogs, which have a unique mechanism of action. Duocarmycins, first isolated from Streptomyces bacteria in the 1970s, bind to the minor groove of DNA and subsequently cause irreversible alkylation of DNA. This disrupts the nucleic acid architecture, which eventually leads to tumor cell death.
Duocarmycins are able to exert their mode of action at any phase in the cellular cycle, whereas tubulin binders will only attack tumor cells when they are in a mitotic phase. Growing evidence suggests that DNA damaging agents, such as duocarmycins, are more efficacious in tumor cell killing than tubulin binders, particularly in solid tumors.
Although based on natural products, Synthon’s proprietary ADC linker-drug technology uses fully synthetic duocarmycin analogs. The unique design of the selectively cleavable linker connecting the antibody to the duocarmycin drug leads to high stability in circulation, and induces efficient release of the cytotoxin in the tumor.
Synthon, with headquarters in Nijmegen, the Netherlands, is an international pharmaceutical company and a leader in the field of generic medicines. The company started its biopharmaceutical franchise in 2007 and is building a promising portfolio of next generation medicines. Synthon is developing rapidly into a specialty pharmaceutical company, focusing on the therapeutic areas of oncology and autoimmune diseases. Synthon products are currently approved by regulatory agencies in over 80 countries worldwide and marketed through strategic partnerships and – in dedicated areas – through direct sales. Synthon employs about 1,400 staff worldwide, and in 2013 it recorded a turnover of EUR 215 million.