First-in-human Study With the Antibody-drug Conjugate SYD985 to Evaluate Safety and Efficacy in Cancer Patients

A Two Part First-in-human Phase I Study (With Expanded Cohorts) With the Antibody-drug Conjugate SYD985 to Evaluate the Safety, Pharmacokinetics and Efficacy in Patients With Locally Advanced or Metastatic Solid Tumors

The purpose of this study is to evaluate the safety of a new medicinal drug SYD985 at different dose levels in patients with cancer, to understand how SYD985 is handled by the body and to evaluate the effect of SYD985 on the cancer.

Cancer cells can have different kinds of proteins on their cell surface; one of these is the protein HER2. HER2 plays an important role in the development of cancer. High expression of HER2 is related to poor prognosis. Although several cancer drugs are available that work via the HER2 protein, a substantial portion of these patients still does not benefit from these treatments.

The new cancer drug SYD985 is being developed by Synthon Biopharmaceuticals B.V. SYD985 is an antibody-drug conjugate and consists of two parts: an antibody and a linker-drug moiety containing a toxin. The antibody part binds to HER2 on the surface of the cancer cell. When SYD985 binds to this cancer cell, it will be internalized by the cell. After proteolytic cleavage of the linker, the toxin will be split off in the cell and the cancer cell will be killed. Thus, SYD985 can be considered as a form of targeted chemotherapy.

This is the first study in which SYD985 is administered to humans. The study consists of two parts:

Part I is the dose-escalation part in which a low dose of SYD985 is given to three cancer patients. If it is well tolerated, a higher dose of SYD985 will be given to 3 other cancer patients. This will continue until a further dose increase is not safe anymore.

In Part II of the study, several groups of patients with a specific type of cancer will receive the SYD985 dose which has been selected for further evaluation.

All patients from both parts of the study will receive SYD985 infusions every three weeks until progression of the cancer or unacceptable toxicity develops.

Main Inclusion Criteria:

1. Patient with histologically-confirmed, locally advanced or metastatic tumor who has progressed on standard therapy or for whom no standard therapy exists, with the following restriction:

   • Part I: solid tumors of any origin;
   • Part II: breast, gastric, urothelial and endometrial tumors;

2. For Part II: HER2 tumor status as defined in the protocol;

3. ECOG performance status ≤ 1;

4. Life expectancy > 12 weeks;

5. Adequate organ function;

6. For Part II: measurable disease.

Main Exclusion Criteria:

1. Anthracycline treatment within 3 months and/or abnormal cardiac biomarker values;
2. Other anticancer therapy (except for LHRH agonists) within 4 weeks (6 weeks for nitrosoureas and mitomycin C);
3. History of infusion-related reactions and/or hypersensitivity to trastuzumab or (ado-) trastuzumab emtansine;
4. Severe, uncontrolled systemic disease;
5. 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;
6. History of clinically significant CV disease;
7. Symptomatic brain metastasis, or therapy for brain metastasis (excluding PCI and dexamethasone treatment with stable or decreasing daily dose) within 4 weeks.