A RANDOMIZED, PHASE 3, OPEN-LABEL STUDY OF NEOADJUVANT DAROVASERTIB IN SUBJECTS WITH PRIMARY NON-METASTATIC UVEAL MELANOMA (OptimUM-10)

Trial ID: 2025-522387-32-00
Protocol: IDE196-010
Sponsor: Ideaya Biosciences Inc.

Trial statistics

science

test molecules

location_city

research sites

public

countries

medical_information

disease

person_search

investigators

handshake

vendors

Diseases & Conditions

Uveal melanoma

Objectives

This study evaluates darovasertib as neoadjuvant therapy in patients with primary non-metastatic uveal melanoma. The primary objective in Cohort 1 is to demonstrate that the proportion of subjects with vision loss is lower in the treatment arm compared to the control arm receiving immediate plaque brachytherapy. In Cohort 2, the primary objective is to demonstrate the ability to salvage the eye and prevent enucleation in the treatment arm. These objectives address critical clinical outcomes related to visual preservation and eye-sparing approaches in uveal melanoma management.

The secondary objectives include:

• Evaluation of neoadjuvant darovasertib treatment with respect to objective response rate (ORR) per uveal melanoma response criteria by Blinded Independent Central Review (BICR) in both cohorts.

• Comparison of neoadjuvant darovasertib to immediate plaque brachytherapy or enucleation with respect to event-free survival (EFS) in both cohorts.

• Assessment of safety and tolerability of darovasertib in the neoadjuvant setting in both cohorts.

• Evaluation of treatment response per uveal melanoma response criteria with respect to ORR by investigator assessment and disease control rate (DCR) by investigator assessment and BICR in both cohorts.

• Assessment of best-corrected visual acuity (BCVA) improvement in treatment arms relative to baseline during the neoadjuvant treatment period in both cohorts.

• Demonstration of reduction in the proportion of subjects with clinically significant macular edema (ME) in the treatment arm versus control arm in Cohort 1.

• Assessment of severe visual acuity (VA) loss for subjects in the treatment arm versus control arm in Cohort 1.

• Evaluation of the effect of neoadjuvant darovasertib treatment on radiation dose reduction by comparing baseline predicted radiation dose to post-treatment dose by central simulation in Cohort 1 treatment arm.

• Demonstration of reduction in the proportion of subjects with optical coherence tomography (OCT) findings consistent with macular edema by BICR in the treatment arm versus control arm in Cohort 1.

• Determination of whether neoadjuvant darovasertib can reduce radiation-related ocular complications in subjects in the treatment arm compared to control arm in Cohort 1.

Participants

The clinical trial enrolled a total of **295 participants** diagnosed with **uveal melanoma** who were at high risk of metastasis. The study population included both **male and female subjects** aged **18 years and older**. Participants were required to have an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0 or 1, indicating good general health and functional capacity. The trial was divided into two cohorts based on treatment approach: Cohort 1 consisted of subjects being considered for **plaque brachytherapy** with specific tumor characteristics including thickness between 4 mm and 6 mm or 4 mm and 10 mm depending on the type of brachytherapy used (ruthenium or iodine), basal diameter up to 16 mm, at least 20/80 vision in the affected eye, and projected radiation dose of at least 30 Gy to the macula or optic disc/nerve. Cohort 2 included subjects being considered for **enucleation** with tumor thickness greater than 6 mm up to 10 mm or greater than 10 mm up to 15 mm depending on regional standard of care, and basal diameter up to 16 mm. High risk of metastasis was defined by the presence of **monosomy 3**, **Class 2 gene expression profile (GEP)**, or **Stage 3 by AJCC** classification. Participants were required to be able to safely swallow orally administered medication and to have adequate organ function. The study included vulnerable populations and required strict contraception measures for subjects of childbearing potential throughout the treatment period and for specified periods following the final dose.

Plans and Procedures

This is a randomized, Phase 3, open-label clinical trial evaluating neoadjuvant darovasertib in subjects with primary non-metastatic uveal melanoma. The study is designed to assess the efficacy and safety of darovasertib administered before definitive local therapy in patients at high risk of metastasis. The trial consists of two distinct cohorts based on the planned local treatment approach. Cohort 1 includes subjects being considered for plaque brachytherapy, while Cohort 2 includes subjects being considered for enucleation. The investigational medicinal product, darovasertib (IDE196), is administered as an oral tablet and has been designated as an orphan drug (EU/3/25/3122). The maximum treatment period is 168 weeks.

The primary objective for Cohort 1 is to demonstrate that the proportion of subjects with vision loss is lower in the treatment arm compared to the control arm. For Cohort 2, the primary objective is to demonstrate the ability to salvage the eye and prevent enucleation in the treatment arm. The primary endpoint for Cohort 1 is the proportion of moderate to high risk of visual impairment subjects with loss of Best Corrected Visual Acuity (BCVA) of ≥ 15 letters using Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA measured from the time of randomization and completion of plaque brachytherapy. For Cohort 2, the primary endpoint is the eye preservation rate. Secondary endpoints for both cohorts include objective response rate (ORR_UM), defined as the rate of best overall response (complete response or partial response), event-free survival (EFS), and the incidence of treatment-emergent adverse events, serious adverse events, and clinically significant laboratory test abnormalities.

Principal inclusion criteria require subjects to be at least 18 years of age and at high risk of metastasis, defined by at least one of the following: monosomy 3, Class 2 gene expression profiling (GEP), or Stage 3 by American Joint Committee on Cancer (AJCC) staging. For Cohort 1, subjects must have a diagnosis of primary uveal melanoma being considered for treatment with plaque brachytherapy, with specific tumor thickness and basal diameter criteria depending on the geographic region and type of brachytherapy used. Subjects must have at least 20/80 vision in the affected eye and a projected radiation dose of ≥ 30 Gy to the macula or optic disc/nerve. For Cohort 2, subjects must have a diagnosis of primary uveal melanoma being considered for enucleation, with tumor thickness and basal diameter criteria also varying by geographic region. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and adequate organ function. Women of childbearing potential must use highly effective contraception during study treatment and for 6 months after the final dose, while male subjects must use double-barrier contraception methods for 3 months following the last dose.

The estimated recruitment start date is March 31, 2026, and the estimated end date is May 31, 2031. The expected length of participant involvement extends through the treatment period and follow-up assessments, with specific timepoints for evaluation of ocular outcomes and safety parameters. Subjects may be withdrawn from the study early due to treatment failure, including disease progression, local or distant recurrence, or death. Additional reasons for early termination may include withdrawal of consent, unacceptable toxicity, or investigator decision based on safety concerns. The study will monitor for radiation-related ocular toxicities at 6, 12, 18, 24, 30, and 36 months post plaque brachytherapy in Cohort 1, and will assess the proportion of subjects with macular edema on optical coherence tomography (OCT) and other vision-related outcomes throughout the follow-up period.

Treatment

The experimental medication utilized in this clinical trial is **IDE196** (also known as **LXS196**), which contains the **active substance darovasertib**. This investigational medicinal product is manufactured by IDEAYA Biosciences Inc. and has been designated as an **orphan drug** under the designation number EU/3/25/3122. Darovasertib is a chemical substance with the European substance number SUB218613.

IDE196 is formulated as an **oral tablet** for administration by the **oral route**. The product is supplied in tablet form for neoadjuvant treatment in subjects with primary non-metastatic **uveal melanoma**. The maximum treatment period specified for this investigational medicinal product is **168 weeks**. The medicinal product identification number assigned is IMP11566/00001, and the sponsor product code is IDE196.

The trial employs a randomized, open-label design with two cohorts. Cohort 1 includes a Treatment Arm receiving darovasertib and a Control Arm for comparison, with the objective of demonstrating a lower proportion of subjects with vision loss in the Treatment Arm versus the Control Arm. Cohort 2 focuses on the Treatment Arm with the objective of demonstrating the ability to salvage the eye and prevent **enucleation**. The study design allows for evaluation of the experimental medication against standard management approaches in this patient population.

Efficacy

Efficacy will be assessed through distinct primary endpoints for each cohort. In Cohort 1, the primary endpoint is the proportion of moderate to high risk of visual impairment subjects with loss of Best Corrected Visual Acuity of ≥ 15 letters using Early Treatment Diabetic Retinopathy Study BCVA measured from the time of randomization and completion of plaque brachytherapy. In Cohort 2, the primary endpoint is eye preservation rate.

Secondary efficacy endpoints for both cohorts include overall response rate in uveal melanoma, defined as the rate of best overall response (complete response or partial response). Complete response is defined as complete regression of tumor by ultrasound and fundus photography. Partial response is defined as decrease in product of diameters by ultrasound and/or fundus photography by ≥ 20% or decrease in thickness by ultrasound by ≥ 20% from baseline. Event-free survival will be measured as the time from randomization to the first documented date of treatment failure, including disease progression, local/distant recurrence, or death, whichever occurs first. Disease control rate, defined as the proportion of complete response, partial response, or stable disease, will also be assessed. The proportion of subjects with improvement in Early Treatment Diabetic Retinopathy Study BCVA letters and/or Snellen lines will be evaluated.

Additional secondary endpoints specific to Cohort 1 include the proportion of subjects with clinically significant macular edema (defined by optical coherence tomography finding, vision loss, and initiation of vascular endothelial growth factor inhibitor administration) measured from the time of randomization and completion of plaque brachytherapy. The proportion of subjects with 20/200 vision or worse from the time of randomization and completion of plaque brachytherapy will be assessed. The proportion of subjects with significant reduction of radiation dose (defined as a ≥ 20% reduction) delivered to key eye structures including the macula, optic disc/nerve, and lens will be evaluated. The proportion of subjects with macular edema on optical coherence tomography from the time of completion of plaque brachytherapy, defined as the presence of intraretinal fluid (cystoid edema) on optical coherence tomography, will be measured. The proportion of subjects with radiation-related ocular toxicities at 6, 12, 18, 24, 30, and 36 months post plaque brachytherapy, including the incidence and severity of radiation induced ocular toxicities, will be assessed.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

Be at least 18 years of age
Able and willing to provide written, informed consent before initiation of any trial-related procedures, and in the opinion of the Investigator, to comply with all trial requirements
At high risk of metastasis defined by at least one of the following: • Monosomy 3 • Class 2 GEP • Stage 3 by AJCC (Appendix 1 [Section 15.1]) , Tumor with largest basal diameter > 12 mm NOTE: Monosomy 3 as determined by karyotyping, chromogenic or fluorescence in situ hybridization (CISH or FISH), Next-Generation Sequencing (NGS), chromosomal microarray analysis (CMA), multiplex ligation-dependent probe amplification or array Comparative Genomic Hybridization (aCGH). Other methodologies may be acceptable after discussion with the IDEAYA Medical Monitor. Class 2 GEP as determined by Castle Decision Dx-UM® when this testing has been performed as part of local standard of care practice. Molecular testing is preferred to determine high risk for metastasis status; however, AJCC stage 3 is considered qualifying if molecular testing is not completed per local standard of care practice.
For Cohort 1 (PB): • Have a diagnosis of primary UM and being considered for treatment with PB and with the following tumor characteristics: o In geographic regions where ruthenium PB is standard of care therapy  Tumor thickness ≥ 4 mm and ≤ 6 mm  Tumor basal diameter up to 16 mm o In geographic regions where iodine PB is standard of care therapy  Tumor thickness ≥ 4 mm and ≤ 10 mm  Tumor basal diameter up to 16 mm o Have at least 20/80 vision in the affected eye o Projected radiation dose of ≥ 30 Gy to the macula or optic disc/nerve based on central dosimetry calculations
For Cohort 2 (enucleation): • Have a diagnosis of primary UM and being considered for treatment with enucleation and with the following tumor characteristics: o In geographic regions where ruthenium PB is standard of care therapy  Tumor thickness > 6 mm and ≤ 10 mm  Tumor basal diameter up to 16 mm o In geographic regions where iodine PB is standard of care therapy  Tumor thickness > 10 mm and ≤ 15 mm  Tumor basal diameter up to 16 mm
Able to safely swallow orally administered medication
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Have adequate organ function at the time of the Screening assessments.
Agree to the following contraception while receiving darovasertib and for the period defined after the final dose: • Women of childbearing potential, defined as women physiologically capable of becoming pregnant, who are sexually active with a non-sterilized male partner, must use, or continue to use if already using, highly effective methods of contraception during study drug/investigational medicinal product (IMP) and for 180 days after the final dose of study drug/IMP (Appendix 4 [Section 15.4]). Cessation of birth control after this point should be discussed with the participant's physician. NOTE: Systemically acting hormonal contraceptives should always be combined with a barrier method (preferably male condom). • Male participants: Are surgically sterile or must agree to use double-barrier contraception methods from the time of informed consent, throughout the treatment period, and for 90 days following administration of the last dose of study drug/IMP.

cancel

Exclusion Criteria

Previous treatment for UM
Evidence of metastatic UM or extraocular involvement
Tumor originating from the iris
Sub-retinal or vitreous bleeding that prevents monitoring of treatment effect
UM that is subfoveal in location and abutting the optic disc , or require a notched ruthenium plaque (Cohort 1 only)
Attributes that necessitate enucleation regardless of response to therapy (e.g., neovascular glaucoma, extraocular involvement, hemorrhage, blind painful eye, tumor involvement of the anterior chamber, or evidence of optic nerve invasion)
Inability to visualize all tumor dimensions on imaging studies for tumor measurements
Pre-planned (i.e., prophylactic) use of VEGFi and/or corticosteroids for radiation induced ocular toxicities (Cohort 1 only)
Previous, current, or anticipated administration of intravitreal VEGFi and/or corticosteroids for diabetic retinopathy or another ocular disorder (Cohort 1 only) NOTE: Use of corticosteroids at the time of PB placement and/or removal is allowed if considered local standard of care practice.
Evidence of progressive secondary underlying ocular disease in either eye that would confound longitudinal VA assessments (e.g., macular degeneration, neovascular age-related macular degeneration, central retinal vein occlusion, pre-existing glaucoma, or neovascular glaucoma)
Moderate to severe diabetic retinopathy or proliferative diabetic retinopathy as follows (Appendix 5 [Section 15.5]) • Moderate diabetic retinopathy is defined by at least 1 hemorrhage or microaneurysm and/or at least one of the following: retinal hemorrhages, hard exudates, cotton wool spots, or venous beading. • Severe diabetic retinopathy is defined by any of the following but no signs of proliferative diabetic retinopathy: > 20 intraretinal hemorrhages in each of the 4 quadrants, definite venous beading in 2 or more quadrants, or prominent intraretinal microvascular abnormality in one or more quadrants. • Proliferative diabetic retinopathy is defined by either neovascularization or vitreous/preretinal hemorrhage.
Presence of a malignant disease, other than the one being treated in this trial, with the following exceptions: malignancies that were treated curatively and have not recurred within 2 years prior to study drug/IMP, completely resected basal cell and squamous cell skin cancers, any malignancy considered to be indolent and never required systemic therapy, and any type of completely resected carcinoma in situ.
Known acquired immunodeficiency syndrome (AIDS)-related illness NOTE: Human immunodeficiency virus (HIV) seropositive participants who are healthy and have a low risk for AIDS-related outcomes may be considered eligible. Participants with known HIV, cluster of differentiation 4 (CD4) counts ≥200/μL and undetectable viral loads who are stable on antiretroviral regimen may be included after discussion with the IDEAYA Medical Monitor regarding current and past CD4 and T cell counts, history of any AIDS-defining conditions, and status of HIV treatment. The potential for drug-drug interactions (DDIs) will also be taken into consideration.
Active infection requiring systemic anti-microbial therapy (participants requiring systemic antimicrobial therapy for infection must have completed therapy at least 1 week prior to the first dose of study drug/IMP for participants in the Treatment Arms or PLT for participants in the Control Arms.)
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection as diagnosed by institutional protocol.
Major surgery within 4 weeks prior to trial entry (Minimally invasive procedures, such as bronchoscopy or tumor biopsy are not considered major surgery.)
Inability to discontinue medications belonging to any of the following categories prior to and while receiving darovasertib: • Known strong inducers or inhibitors of CYP3A4/5 • Known substrates of CYP3A4/5 with a narrow therapeutic index (NTI; Appendix 8 and Appendix 9 [Section 15.8 and Section 15.9, respectively]) • Known substrates of P-gp or BCRP with an NTI (Appendix 8 and Appendix 9 [Section 15.8 and Section 15.9a narrow therapeutic index, respectively]) NOTE: a wash-out period is required
Pregnant or breastfeeding prior to and while receiving darovasertib
Impaired cardiac function or clinically significant cardiac diseases, including any of the following: • History or presence of ventricular tachyarrhythmia • Presence of unstable atrial fibrillation (ventricular response > 100 beats per minute [bpm]); participants with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac exclusion criteria. • Presence of angina pectoris or acute myocardial infarction ≤ 6 months prior to study drug/IMP • Presence of congestive heart failure requiring treatment; (For New York Heart Association Class 1, inclusion can be considered upon discussion and agreement with the IDEAYA Medical Monitor.) • Presence of other clinically significant heart disease (e.g., uncontrolled arrhythmia or hypertension, history of labile hypertension or poor compliance with an antihypertensive regimen, and/or symptomatic bradycardia) Presence of a drug eluting stent for cardiovascular purposes placed ≤ 2 months prior to study drug/IMP • A corrected QT interval of > 470 msec per Fridericia’s formula (QTcF) on baseline ECG (mean of baseline values) (Appendix 6 [Section 15.6]) NOTE: If electrolytes are abnormal, they may be corrected, and baseline ECGs should be repeated. NOTE: For participants with a significantly prolonged QRS complex (> 110 msec) due to a bundle branch block or an intraventricular conduction delay, an “adjusted” QTcF for the QRS widening will be used to evaluate trial eligibility. “Adjusted QTcF” = measured QTcF – [measured QRS – 90 msec].
Asymptomatic persistent heart rate < 55 bpm, unless discussed with and agreed to enroll by the IDEAYA Medical Monitor
History of stroke ≤ 6 months before trial enrollment
Allergy to mammalian meat products or gelatin

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Recruiting	31 Mar 2026	24
Belgium	Recruiting	31 Mar 2026	10
Czechia	Recruiting	31 Mar 2026	7
Denmark	Recruiting	31 Mar 2026	8
France	Recruiting	31 Mar 2026	48
Germany	Recruiting	31 Mar 2026	72
Italy	Recruiting	31 Mar 2026	56
The Netherlands	Not Yet Recruiting	31 Mar 2026	—
Poland	Not Yet Recruiting	31 Mar 2026	24
Spain	Recruiting	31 Mar 2026	40