First-in-human Trial With SYD985 Evaluates Safety and Efficacy in Cancer Patients
Published on 25th November
Earlier today an initial group of patients with metastatic solid tumors started treatment with an investigational anti-HER2 antibody-drug conjugate called SYD985 (Synthon Biopharmaceuticals). The open label clinical trial (NCT02277717)  includes breast cancer patients with low expression of HER2. These patients 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 is designed to recruit at least 76 patients who are at least 18 years old or older at the start of the study. More centers are expected to join the trial in 2015.
SYD985 is a HER2-targeting antibody-drug conjugate or ADC based on trastuzumab and a proprietary cleavable linker-duocarmycin (vc-seco-DUBA) payload developed by Synthon.
Trial design: Dose Escalation and Expanded Cohort
This trial is a two part first-in-human Phase I clinical study. In the dose escalation part of the trial, safety, pharmacokinetics and efficacy of SYD985 will be evaluated in patients with histologically-confirmed, locally advanced or metastatic solid tumors of any origin. These are patients who have progressed on standard therapy or for whom no standard therapy exists. In this part of the trial a low dose of SYD985 is given to three cancer patients. If the trial drug is well tolerated, a higher dose of SYD985 will be given to 3 other cancer patients. This process will continue until a further dose increase is no longer considered safe.
In the expanded cohort part of the trial, only patients with a specific form of breast cancer and gastric tumors with demonstrated HER2 expression and measurable disease lesions, as per protocol defined criteria, will be enrolled. The expanded cohorts also includes 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.
Other inclusion criteria include ECOG performance status ≤ 1, a life expectancy > 12 weeks and adequate organ function.
Exclusion criteria include: a history of infusion-related reactions and/or hypersensitivity to trastuzumab or (ado-) trastuzumab emtansine, aevere, uncontrolled systemic disease, a LVEF < 55%, or a history of absolute decrease in LVEF of ≥ 10% points to < 50% during previous treatment with trastuzumab or (ado-)trastuzumab emtansine, or a history of decrease in LVEF to < 40% during previous treatment with trastuzumab or (ado-)trastuzumab emtansine, a history of clinically significant CV disease and symptomatic brain metastasis, or therapy for brain metastasis (excluding PCI and dexamethasone treatment with stable or decreasing daily dose) within 4 weeks.
Patients from both parts of the study receive SYD985 infusions every three weeks until progression of the cancer or unacceptable toxicity develops.
Antibody-drug conjugates are designed to combine the specificity of antibodies directed against tumor-associated targets with potent cytotoxicity. Upon internalization of the antibody-drug conjugate, 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 unique and 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, are members of a small group of natural products that are notable for their extreme cytotoxicity and thus represent a class of exceptionally potent antitumour antibiotics. First isolated from Streptomyces bacteria in the 1970s, they 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. 
The cytotoxin is 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, the 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.
To date, 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+).
Preclinical in vitro and in vivo findings in a head-to-head comparison of SYD985 and ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche, also known as T-DM1). In one trial, Wim Dokter, Ruud Ubink, Miranda van der Lee, and their colleagues at Synthon studied both in vitro, SYD985 and ado-trastuzumab emtansine in a panel of eight cell lines expressing different levels of HER2. Results of this trial showed that in cell lines with high HER2 expression, which was characterized as HER2 3+, SYD985 and ado-trastuzumab emtansine 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 ado-trastuzumab emtansine. 
HER2 status of tumor tissue is determined by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). IHC measures the level (0, 1+, 2+, or 3+) of HER2 protein expression on the surface of cancer cells. FISH, on the other hand, indicates whether the HER2 gene is amplified, meaning that the cancer cells have more copies of the gene than is normal. For breast cancer to be considered HER2+, the cells must have an IHC expression score of 3+ or gene amplification must be detected.
In vivo anti-tumor activity was also 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 ado-trastuzumab emtansine 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 ado-trastuzumab emtansine 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.
“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,” noted Jacques Lemmens, CEO of Synthon.
“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.”
Synthon believes this Phase I clinical trial will validate its ADC technology as potentially best-in-class.
Featured Image Courtesy: Synthon Biopharmaceuticals BV, Nijmegen, The Netherlands.
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