Phase 1 Trial of Darovasertib Monotherapy Enrolls First Patient With Uveal Melanoma

A patient enrolled in the phase 1 NADOM trial of darovasertib alone in non-metastatic uveal melanoma shows early signs of clinical efficacy.

The first patient has been enrolled in the phase 1 NADOM clinical trial (NCT05187884) evaluating darovasertib (IDE196) as a monotherapy in patients with both neoadjuvant and adjuvant, primary, non-metastatic uveal melanoma, according to IDEAYA Biosciences, Inc.1

"We are excited to be leading this ground-breaking clinical study treating patients with darovasertib in the neoadjuvant and adjuvant settings. The concept for this study originated from anecdotal observations in a metastatic uveal melanoma patient treated with darovasertib who also had an intact primary lesion in the eye, where a reduction in the eye lesion was observed at an initial scan with improvement in visual symptoms," said Anthony Joshua, MBBS, PhD, FRACP, professor, head of the Department of Medical Oncology, Kinghorn Cancer Center, St. Vincent's Hospital Sydney, in a press release.

Darovasertib is a potent, potential first-in-class protein kinase C inhibitor.In April 2022, the FDA granted darovasertib an orphan drug designation for patients with uveal melanoma.

In the NADOM study, investigators will evaluate darovasertib alone in adult patients with ocular melanoma to determine the feasibility and tolerability of (neo)adjuvant treatment.

The study aims to enroll 12 patients who will undergo 4 weeks of treatment with darovasertib administered orally at a dose of 300 mg twice a day.2 Eligible patients will undergo adjuvant treatment for 6 months based on their initial response.

According to Mark Shackleton MBBS, PhD, FRACP, professor, director of oncology at Alfred Health and professor of oncology at Monash University, an early signal of clinical activity is already being observed in this first patient who has enrolled in the NADOM study.

"We are observing an early signal of clinical activity in the first patient enrolled in the NADOM study. Our coordinated patient care with eye specialists at the Royal Victorian Eye and Ear Hospital on this trial has enabled a potential paradigm-shifting approach to reduce the size of ocular tumors prior to primary treatment, which we hope will lead to better outcomes for patients," said Shackleton in the press release.

The primary end point of the study is to determine the safety of a 28-day course of darovasertib by clinical assessment through using CTCAE v5.0 guidelines for adverse events (AEs) and the percentage of participants that complete the 28-day treatment period. Secondary end points of the trial include to determine the effect of neoadjuvant darovasertib on tumor size in uveal melanoma as measured by ocular ultrasound and to explore time to recurrence and disease-specific survival in patients on adjuvant darovasertib as assessed by standard of care imaging measured using RECIST 1.1.

To be eligible for the trial, patients must be at least 18 years of age with a primary diagnosis of uveal melanoma, life expectancy > 3 months, ECOG performance status of 0-1, and adequate organ function at screening. Those with a prior history of or clinically stable concurrent malignancy are eligible for enrollment as long as the malignancy is clinically insignificant, no treatment is required, and the patient is clinically stable. Additionally, patients with a history of squamous or basal cell carcinoma of the skin or carcinoma in the situ of the cervix may be enrolled along with patients with prostate cancer who have an elevated prostate specific antigen not requiring treatment.

Patients who have had previous treatment with a PKC inhibitor, have adverse events from prior anti-cancer therapy that have not resolved or are equal to grade 1, excluding alopecia, prior peripheral neuropathy, or anemia, will be excluded from the trial.

Further, those who have untreated or symptomatic malignant lesions in the central nervous system, known human immunodeficiency virus or acquired immunodeficiency syndrome related illness, prior gastrointestinal disorders or defects that would interfere with absorption of darovasertib, and patients receiving treatment with medications that cannot be discontinued prior to study entry will be excluded. Females who are pregnant or breastfeeding, patients with impaired cardiac function or clinically significant cardiac diseases, and those who have previously received darovasertib are also ineligible to enroll.

Overall, this study aims to determine the safety and tolerability of darovasertib and document the pharmacodynamic and pharmacokinetic effects of darovasertib in this patient population. The estimated study completion date is November 1, 2024.

"There are currently limited treatment options for patients with uveal melanoma in the pre-metastatic setting. We are pleased to be collaborating with St. Vincent's Hospital in Sydney and with Alfred Health and Royal Victorian Eye and Ear Hospital in Melbourne to explore the potential for darovasertib monotherapy to be impactful for patients with primary uveal melanoma," said Matthew Maurer, MD, vice president, head of clinical oncology and medical affairs at IDEAYA Biosciences, in the press release.

References:
  1. IDEAYA announces first-patient-in for phase I clinical trial to evaluate darovasertib monotherapy in (neo)adjuvant uveal melanoma. News release. IDEAYA Biosciences, Inc. September 6, 2022. Accessed September 6, 2022. https://prn.to/3elczFX
  2. Neoadjuvant/adjuvant trial of darovasertib in ocular melanoma (NADOM). ClinicalTrials.gov. Updated May 5, 2022. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT05187884