Darovasertib before Surgery or Radiation Therapy to Treat Early-stage Eye Cancer (Uveal Melanoma)

Prior treatment

• Previous treatment for UM
• 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.
• 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.)
• 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
• History of stroke ≤ 6 months before trial enrollment
• 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.

Other illness

• 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.
• Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection as diagnosed by institutional protocol.
• Asymptomatic persistent heart rate < 55 bpm, unless discussed with and agreed to enroll by the IDEAYA Medical Monitor
• Allergy to mammalian meat products or gelatin
• Sub-retinal or vitreous bleeding that prevents monitoring of treatment effect
• 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)

Lab values

• 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.
• 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].

Age

• 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)

Other

• Evidence of metastatic UM or extraocular involvement
• Tumor originating from the iris
• UM that is subfoveal in location and abutting the optic disc , or require a notched ruthenium plaque (Cohort 1 only)
• Inability to visualize all tumor dimensions on imaging studies for tumor measurements

• 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.