Neoadjuvant Evaluation of Darovasertib in Patients with Localized Uveal Melanoma
- Trial ID
- 2023-506683-14-00
- Protocol
- IDE196-009
- Sponsor
- Ideaya Biosciences Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **tolerability** and safety of IDE196 (Darovasertib) when administered in the neoadjuvant setting for patients with localized **uveal melanoma**. Additionally, the study aims to assess the clinical utility of tumor shrinkage in response to neoadjuvant IDE196 in primary uveal melanoma. These objectives are clinically relevant as they address the potential of IDE196 to improve surgical outcomes and reduce tumor burden prior to definitive treatment.
Secondary objectives include:
- Evaluating the antitumor activity of IDE196 as neoadjuvant therapy.
- Assessing visual acuity loss after PLT in both cohorts.
- Determining the rate of local disease recurrence.
- Exploring the impact of multiple-dose administration of IDE196 on the pharmacokinetics (PK) of a single dose of metformin.
- Exploring the impact of multiple-dose administration of IDE196 on the PK of a single dose of norethindrone (NE) and ethinyl estradiol (EE).
Participants
The clinical trial involves a total of **119 participants** diagnosed with **Uveal Melanoma**. The study population includes both male and female subjects, aged 18 years and older, who are in generally good health as indicated by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participants were selected based on their ability to provide informed consent and comply with study requirements, as well as having a primary diagnosis of localized Uveal Melanoma without evidence of distant or extraocular disease. The trial does not include a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria require participants to have adequate organ function and the ability to safely swallow orally administered medication. Female participants of childbearing potential must have a negative pregnancy test and agree to use effective contraception. The trial aims to evaluate the tolerability and safety of IDE196 in a neoadjuvant setting, as well as the clinical utility of tumor shrinkage in response to the treatment.
Plans and Procedures
The clinical trial is designed to evaluate the **tolerability** and safety of the investigational drug **darovasertib** in patients with localized **uveal melanoma**. This study is a Phase 4, randomized, double-blind, controlled trial, with an estimated duration extending until April 2029. The trial involves the administration of **darovasertib** in tablet form, with a maximum daily dose of 600 mg and a total treatment period of up to 12 months. Participants will be randomly assigned to receive either the investigational drug or a control, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the study.
The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed, including age, ability to provide informed consent, and a confirmed diagnosis of localized **uveal melanoma**. Following successful screening, participants will undergo regular follow-up visits to monitor safety, efficacy, and any adverse events. These visits will include assessments such as ocular ultrasound and color fundus photography to measure tumor size and proximity to vital eye structures. The primary endpoints focus on the incidence of adverse events leading to dose modification or discontinuation, and the percentage of patients converting from planned enucleation to eye-preserving therapy. Secondary endpoints include changes in tumor size and visual acuity.
The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of the treatment's impact on the disease and any long-term effects. Participant involvement is expected to last up to 12 months, with conditions for early termination including the occurrence of severe adverse events or the participant's inability to comply with study requirements. The trial aims to provide valuable insights into the clinical utility of **darovasertib** in reducing tumor size and preserving vision in patients with **uveal melanoma**.
Treatment
The clinical trial involves the administration of the experimental medication **IDE196 (LXS196)**, which contains the active substance **darovasertib**. This medication is provided in the form of a **tablet** and is intended for oral administration. The maximum daily dose of IDE196 is 600 mg, with a total maximum dose of 219,000 mg over a treatment period of up to 12 months. The medication is produced by IDEAYA BIOSCIENCES INC. and is classified as a chemical substance. The trial aims to evaluate the tolerability and safety of IDE196 in the neoadjuvant setting for patients with localized ocular melanoma, as well as its clinical utility in tumor shrinkage.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of the experimental drug IDE196. Participants' compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not include any pediatric formulations, and the medication is not classified as an orphan drug. The study is designed to assess the effects of IDE196 in a controlled clinical setting, with careful monitoring of patient outcomes and safety.
Efficacy
Efficacy in the clinical trial of IDE196 (Darovasertib) for patients with localized ocular melanoma will be assessed using both primary and secondary endpoints. The primary endpoints include the incidence of adverse events (AEs) leading to dose interruption, modification, and discontinuation during neoadjuvant therapy, as well as the incidence of Grade 3 or 4 AEs and clinically significant laboratory abnormalities. Additionally, for Cohort 1, the percentage of patients converted from planned enucleation to eye-preserving therapy will be evaluated. For Cohort 2, the percentage of patients with a reduction in radiation dose to the fovea, optic disc center, or optic nerve, as determined by independent central dosimetry modeling, will be assessed.
Secondary endpoints will focus on tumor measurements and visual acuity. These include a decrease in tumor apical height or bidirectional measurements that encompass the apical height and largest basal diameter. The loss of 15 or more letters in the Early Treatment Diabetic Retinopathy Study (ETDRS) Best-Corrected Visual Acuity (BCVA) letter score will also be monitored. Additionally, the local disease recurrence rate will be tracked. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to determine the clinical utility of IDE196 in the neoadjuvant setting for ocular melanoma.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Must be at least 18 years of age.
- Is able to provide written, informed consent before initiation of any study-related procedures, and is able, in the opinion of the Investigator, to comply with all the requirements of the study.
- Has an initial primary diagnosis of localized UM (no evidence of distant and/or extraocular disease) as clinically determined by the treating Investigator, with a plan to undergo either enucleation or plaque brachytherapy. (Note: Patients with local relapse after prior primary therapies are excluded.) Tumor must be able to be completely imaged by ocular ultrasound and color fundus photography for accurate tumor measurements and distance to vital eye structures, such as the fovea and optic disc. • Cohort 1: o Clinically diagnosed uveal (not iris) melanoma in which enucleation is recommended and meets the following criteria: > 10 mm in thickness (or in regions where non-I125 plaque is standard of care, > 6 mm for non-I125 plaques) Tumor must not exceed 16 mm in LBD to be considered eligible. o NOTE: The cancer cannot have attributes that necessitate enucleation regardless of response to therapy (e.g., extraocular disease, hemorrhage; blind painful eye; evidence of optic nerve invasion to an extent that despite tumor shrinkage eye preservation is not reasonably expected; etc.) • Cohort 2: o Clinically diagnosed uveal (not iris) melanoma in which plaque brachytherapy is recommended, meets the following criteria, and places the patient at significant risk of loss of useful vision in the affected eye: 4-10 mm in thickness (or in regions where non-I125 plaque is standard of care, 4-6 mm for non-I125 plaques) Tumor must not exceed 16 mm in LBD to be considered eligible. • Cohort 2: o Clinically diagnosed uveal (not iris) melanoma in which plaque brachytherapy is recommended, meets the following criteria, and places the patient at significant risk of loss of useful vision in the affected eye: 4-10 mm in thickness (or in regions where non-I125 plaque is standard of care, 4-6 mm for non-I125 plaques) Tumor must not exceed 16 mm in LBD to be considered eligible. o NOTE: Sub-foveal or > 180-degree optic nerve involved tumors are excluded. At least 10 subjects from Cohort 2 will participate in the PK substudy. • Cohort 3: o Clinically diagnosed uveal (not iris) melanoma that is < 4 mm in thickness requiring treatment Tumor must not exceed 12 mm in LBD to be considered eligible. o NOTE: at least half the subjects must have a tumor that is ≤ 3 mm in thickness. Approximately 10 subjects in Cohort 3 will participate in the PK substudy. Lesions that are indeterminate or are nevi are excluded.
- Able to safely swallow orally administered medication.
- Has available prognostication results assessed by local standards, or patient must be willing to submit sample(s) (prior to neoadjuvant therapy or at the time of PLT) for local or central laboratory prognostication testing. If prognostication results are not available and sample(s) cannot be collected, a patient may be enrolled only after approval by the Medical Monitor.
- Has Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix 4, [Section 14.4]) (or Karnofsky ≥70%).
- No evidence of progressive secondary underlying ocular disease in either eye that will confound longitudinal visual acuity assessments (e.g., macular degeneration, diabetic retinopathy, neovascular glaucoma, etc.).
- Has adequate organ function: • Absolute neutrophil count ≥1500/mm3 without the use of hematopoietic growth factors • Platelet count ≥100,000/mm3 (must be at least 2 weeks post-platelet transfusion and not receiving platelet-stimulating agents) • Hemoglobin ≥9.0 g/dL (must be at least 2 weeks post-red blood cell transfusion and not receiving erythropoietic-stimulating agents) • Total bilirubin ≤1.5 × the upper limit of normal (ULN). For patients with documented Gilbert's disease, total bilirubin ≤3.0 mg/dL is allowed • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN • Serum albumin ≥3.0 g/dL • Creatinine clearance ≥45 mL/min by Cockroft-Gault equation (Appendix 1, [Section 14.1]). Patients with creatine clearance between 30 and 45 mL/min can be considered for eligibility in discussion with the Medical Monitor.• Prothrombin time/International Normalized Ratio (INR) or partial thromboplastin time test results at screening ≤1.5 × ULN (this applies only to patients who do not receive therapeutic anticoagulation)
- Female patients of childbearing potential must be non-pregnant, non-lactating, and have a negative serum human chorionic gonadotropin pregnancy test result within 28 days prior to the first IDE196 administration. • Females of childbearing potential who are sexually active with a non-sterilized male partner agree to use effective methods of contraception from screening (see Appendix 5 [Section 14.5]), throughout the study period and agree to continue using such precautions for 30 days after the final dose of IDE196 as a monotherapy. Systemically acting hormonal contraceptives should always be combined with a barrier method (preferably male condom). • Non-sterilized males who are sexually active with a female of childbearing potential must agree to use effective methods of contraception, including condom, from Day 1 throughout the study period and for 90 days after the final dose of IDE196 as a monotherapy treatment.
Exclusion Criteria
- Has received previous treatment with a PKC inhibitor.
- Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to the study treatment; completely resected basal cell and squamous cell skin carcinomas; any malignancy considered to be indolent and that has never required systemic therapy; and completely resected carcinomas in situ of any type.
- Has uncontrolled human immunodeficiency virus (HIV).
- Has active infection requiring therapy, positive tests for hepatitis B surface antigen (HBsAg) with detected hepatitis B virus (HBV) DNA or positive hepatitis C antibody with detected hepatitis C virus (HCV) ribonucleic acid (RNA).
- Has a malabsorption disorder that would interfere with absorption of IDE196.
- Requires any medication that cannot be discontinued prior to study entry and that is considered to be any of the following: • Known to be strong inducers or inhibitors of cytochrome P450 (CYP)3A4/5 • Known to be substrates of CYP3A4/5 with a narrow therapeutic index (NTI) • Known to be a sensitive substrate of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) with an NTI.
- Women of childbearing potential planning to become pregnant during the study.
- Has 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); patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac exclusion criteria • Unstable angina or acute myocardial infarction ≤6 months prior to starting IDE196 treatment • Other clinically significant heart disease (e.g., symptomatic congestive heart failure; uncontrolled arrhythmia or history of labile hypertension or poor compliance with an antihypertensive regimen) • Corrected QT interval using Fridericia’s formula (QTcF) >480 msec on baseline electrocardiogram (ECG) (mean of baseline values). Abnormal electrolytes at Screening such as low potassium or magnesium, which may cause QT prolongation, can be corrected and then the baseline ECG repeated. (Appendix 2, [Section 14.2]).
- Has any other condition or circumstances that may increase the risk associated with study participation or may interfere with the interpretation of study results and/or, in the opinion of the Investigator, would make the patient inappropriate for entry into the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 30 Nov 2023 | 4 |
 Germany | Not Recruiting | 30 Nov 2023 | 8 |
 Italy | Not Recruiting | 30 Nov 2023 | 18 |
 The Netherlands | Not Recruiting | 30 Nov 2023 | — |
| Netherlands | — | — | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
NORETHISTERONE AND ETHINYLESTRADIOL | Other | PHF00082MIG | ORAL USE | 1 | 2 | SCP133490 |
IDE196LXS196 | Test | TABLET | ORAL | 600 | 12 | PRD10390877 |
IDE196LXS196 | Test | TABLET | ORAL | 600 | 12 | PRD10390878 |
METFORMIN HYDROCHLORIDE | Other | — | ORAL USE | 500 | 2 | SUB03200MIG |