A Phase I/II, multi-center, open label study of DYP688 in patients with MUM and other GNAQ/11 mutant melanomas (study CDYP688A12101)

Uveal melanoma is a malignant neoplasm of the eye and although it represents
only 3-5% of all melanomas, it is the most common primary intraocular malignant
tumor in adults.
Nearly 50% of patients with uveal melanoma develop metastatic disease within 15
years of their initial diagnosis. Frequent sites of metastasis are the liver,
lungs, bone, and skin. The median overall survival for patients with metastatic
disease ranges from 5-19 months with a one-year survival of approximately
10-15%. No standard of care exists and, due to the lack of available therapies,
outcome for patients with metastatic disease remains extremely poor. Despite
showing significant survival benefit in cutaneous melanoma, immunotherapies
have shown modest impact on modulating the course of disease in metastatic
uveal melanoma.
Most recently, clinical trial data with the bi-specific fusion protein
tebentafusp demonstrate that immunotherapies that are designed to redirect
T-cells to tumor cells can improve OS in patients with MUM.
Mutations in GNAQ/11 are the key drivers to the development of uveal melanoma,
targeted and specific inhibition of GNAQ/11 should result in robust and durable
anti-tumor activity. Melanomas that may be driven by GNAQ/11 mutations appear
biologically distinct from melanomas that typically harbor BRAF or NRAS
mutations and have low mutational burden.
DYP688 is an antibody-drug conjugate, a new type of biologic drug where an
anticancer drug is attached to an antibody. The antibody that is part of
DYP688 is designed to bind the protein PMEL17 that is present on GNAQ/11 mutant
cancer cells. After binding to PMEL17 on cancer cells, DYP688 is then able to
deliver the anticancer drug. Experiments in animal cancer models show that
DYP688 has the potential to be a promising therapy for patients with MUM and
other melanomas with GNAQ/11 mutations.
This Phase I/II, First-in-Human study has two parts: a dose escalation part
(for patients >=18 years with metastatic uveal melanoma) to identify the MTD
and RD and regimen for future studies as a single agent and a dose expansion
part (for patients >=12 years worldwide, in Netherlands >= 18 year, with other
GNAQ/11 mutant metastatic melanomas as well) to evaluate the anti-tumor
activity of DYP688 as a single agent.

This study has been transitioned to CTIS with ID 2023-509451-14-00 check the CTIS register for the current data.

Primary:
Phase I:
• To characterize the safety and tolerability and to identify the maximum
tolerated dose (MTD) and/or recommended dose (RD) and regimen for future
studies of DYP688 as a single agent.
Phase Il:
• To evaluate the anti-tumor activity of DYP688 as a single agent.

Secondary:
Phase I:
• To characterize the pharmacokinetics (PK) of DYP688 as a single agent.
• To assess the immunogenicity of DYP688 as a single agent.
• To evaluate the preliminary anti-tumor activity of DYP688 as a single agent.
Phase Il:
• To further evaluate the anti-tumor activity of DYP688 as a single agent.
• To evaluate overall survival of DYP688 as a single agent.
• To further characterize the safety and tolerability of DYP688 as a single
agent.
• To further characterize the PK of DYP688 as a single agent.
• To further assess the immunogenicity (IG) of DYP688 as a single agent

This is a First in Human, phase I/II, open label, multi-center single arm
study. Phase I will characterize the safety and tolerability of DYP688 in adult
patients with MUM and ether GNAQ/11 mutant melanomas After the determination of
the MTD/RD whichever occurs first, for DYP688, phase Il will access the
anti-tumor activity and further access the safety, tolerability, and PK/PO at
the MTD/RD.

Treatment with DYP688.

Risk: Adverse events of the study medication.
Burden:
• Visits: screening, week 1-8 (cycle 1 and 2) and week 1 and 3 of cycle 3 and
onwards.
• Physical examination: week 1 and 3 of every cycle.
• Tanner staging: twice.
• Blood draws: cycle 1, 3 visits, kuur 3 and onwards 2 visits, 10 to 73 mL
blood per occasion.
• Pregnancy tests: monthly in blood (during a study visit) or in urine (at home
if no study visit planned).
• ECG: 4 visits during treatment phase.
• Eye examination: 5 times in total.
• Scan chest, abdomen, pelvis: every 12 weeks.
• Bone marrow biopsy: <=once (only if not performed in the 2 months prior to
screening).
• Questionnaire: if pediatric formulation is used (e.g. taste).

Optional:
• Tumor biopsy: once
• Use of data and remaining body material for other research.