Darovasertib + Crizotinib for Uveal Melanoma

Recruiting at 80 trial locations

Overseen By Hetal Patel, MD, MSHS, CHCQM

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: IDEAYA Biosciences

Must not be taking: PKC inhibitors, MET inhibitors

Disqualifiers: Concurrent malignant disease, CNS metastases, AIDS, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

420 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment options for individuals with metastatic uveal melanoma, a rare eye cancer that has spread to other body parts. Participants will receive either a combination of two drugs, IDE196 (Darovasertib) and crizotinib, or one of several other treatments selected by the study team, such as pembrolizumab or dacarbazine. The goal is to determine which treatment is most effective. This trial may suit those with metastatic uveal melanoma who are HLA-A*02:01 negative (a specific genetic profile) and have not undergone prior systemic therapy for their condition. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on certain treatments like PKC inhibitors, MET inhibitors, or GNAQ/11 inhibitors, you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of IDE196 (darovasertib) and crizotinib was safe in earlier studies involving people with metastatic uveal melanoma, a type of eye cancer. Importantly, this treatment combination helped patients live longer, indicating its potential effectiveness.

While detailed safety information from these studies remains limited, the treatment's progression to a later phase suggests confidence in its safety. Earlier phases typically ensure a treatment's safety before assessing its effectiveness. Thus, previous research likely found the IDE196 and crizotinib combination to be safe, with manageable side effects.

For those considering joining a trial with this treatment, it is reassuring that its safety has been studied in other patients. Always consult a healthcare professional to understand any potential risks or side effects specific to your situation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for uveal melanoma, like pembrolizumab or ipilimumab + nivolumab, the combination of IDE196 and crizotinib is unique because it targets specific genetic mutations associated with the disease. IDE196 is an oral drug that inhibits protein kinases linked to tumor growth, while crizotinib acts on a different pathway, potentially enhancing the treatment's effectiveness. Researchers are excited about this combination because it offers a more personalized approach, aiming directly at the molecular drivers of uveal melanoma, which could lead to better outcomes for patients.

What evidence suggests that this trial's treatments could be effective for metastatic uveal melanoma?

Research shows that combining darovasertib and crizotinib holds promise for treating metastatic uveal melanoma. In this trial, participants in the experimental arms will receive this combination. Studies have demonstrated that this combination extended patient survival to a median of 21.1 months, significantly longer than the usual median survival of about 12 months for this condition. This suggests that the treatment might extend life more effectively than traditional therapies. Such evidence strongly supports considering this treatment combination. ^{1 2 3 5 6}

Who Is on the Research Team?

Hetal Patel, MD, MSHS, CHCQM

Principal Investigator

IDEAYA Biosciences

Are You a Good Fit for This Trial?

This trial is for people with metastatic uveal melanoma who are HLA-A*02:01 negative and haven't had systemic therapy for advanced cancer. They should have measurable disease, be able to take the study drugs safely, have good organ function and physical status, and a life expectancy of at least 3 months.

Inclusion Criteria

I can safely take and absorb the study medication.

I haven't had systemic therapy for advanced or metastatic disease, but local treatments are okay.

I am fully active or can carry out light work.

Exclusion Criteria

You have had serious allergic reactions to other biologic drugs or antibodies in the past.

Has any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the opinion of the investigator, would make the participant inappropriate for entry into the study

My side effects from previous cancer treatments are mild or gone.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 2a Dose Optimization

Multiple doses of IDE196 will be tested in combination with a fixed dose of crizotinib to identify the optimal combination dose

Approximately 5 months

Phase 2b

The chosen combination dose of IDE196 + crizotinib will be tested in additional participants compared with the comparator arm

Approximately 2 years

Phase 3

Continued enrollment of the chosen combination dose of IDE196 + crizotinib compared with the comparator arm

Approximately 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Crizotinib
• Dacarbazine
• IDE196
• Ipilimumab + Nivolumab
• Pembrolizumab

Trial Overview The trial is testing IDE196 combined with crizotinib against other treatments like pembrolizumab or ipilimumab + nivolumab. It's an open-label study where patients are randomly chosen to receive either the combination or one of the standard therapies.

How Is the Trial Designed?

Group I: Phase 2b / 3 Chosen Combination dose of IDE196 + crizotinib Experimental Treatment 2 Interventions

Chosen combination dose of IDE196 + crizotinib will be tested in additional participants.

Group II: Phase 2a Dose Optimization of IDE196 + crizotinib Experimental Treatment 2 Interventions

Multiple doses of IDE196 will be tested in combination with fixed dose of crizotinib to identify the optimal combination dose.

Group III: Phase 2a / 2b / 3 Comparator Arm Active Control 4 Interventions

Participants will receive investigator's choice of Pembrolizumab, Ipilimumab + Nivolumab, or Dacarbazine.

Crizotinib is already approved in United States, European Union, Japan, Canada for the following indications:

Approved in United States as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Approved in European Union as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Approved in Japan as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Approved in Canada as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Who Is Running the Clinical Trial?

IDEAYA Biosciences

Lead Sponsor

Trials

6

Recruited

1,300+

Published Research Related to This Trial

A case report demonstrated that the combination of neoadjuvant darovasertib and crizotinib effectively reduced the size of a large uveal melanoma in a patient, allowing for vision-saving treatment instead of enucleation.

After 6 months of treatment, the tumor shrank significantly, enabling the use of plaque brachytherapy, which suggests that this combination therapy could improve visual outcomes for patients with primary uveal melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Globe Salvage and Vision Preservation by Neoadjuvant Darovasertib and Crizotinib in Uveal Melanoma. Hiong, A., O'Day, R., Fog, LS., et al.[2023]

In a study of 55 uveal melanoma specimens, 78.2% showed positive expression of the c-kit protein, indicating its potential role in this type of cancer.

Imatinib mesylate significantly reduced the proliferation and invasion of five human uveal melanoma cell lines in vitro, suggesting it could be an effective treatment option and warranting further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of c-kit and imatinib mesylate in uveal melanoma. Pereira, PR., Odashiro, AN., Marshall, JC., et al.[2020]

The SUMIT trial is a phase III study involving 128 patients with metastatic uveal melanoma, testing the combination of selumetinib (a MEK1/2 inhibitor) and dacarbazine, aiming to improve progression-free survival compared to dacarbazine alone.

Previous studies indicated that selumetinib showed antitumor effects in pre-clinical models and improved outcomes in a phase II trial, making this combination a promising approach for patients who have not received prior systemic therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study design and rationale for a randomised, placebo-controlled, double-blind study to assess the efficacy of selumetinib (AZD6244; ARRY-142886) in combination with dacarbazine in patients with metastatic uveal melanoma (SUMIT). Carvajal, RD., Schwartz, GK., Mann, H., et al.[2018]

Uveal melanoma, the most common eye cancer in adults, has a significant risk of metastasis, with up to 50% of patients developing metastases within 15 years after treatment of the primary tumor.

Current systemic therapies for uveal melanoma have limited efficacy, but ongoing research is exploring new candidate drugs, including bortezomib and MEK inhibitors, to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New therapeutic agents in uveal melanoma. Velho, TR., Kapiteijn, E., Jager, MJ.[2012]

The study evaluated the effectiveness of the MEK inhibitor selumetinib in combination with various drugs for treating metastatic uveal melanoma, finding that combining selumetinib with the chemotherapy drug DTIC did not enhance its antitumor effects, aligning with previous clinical trial results.

However, combinations of selumetinib with ERK and mTORC1/2 inhibitors showed promising efficacy in patient-derived xenograft models, suggesting these combinations may be more effective treatment strategies for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selumetinib-based therapy in uveal melanoma patient-derived xenografts. Decaudin, D., El Botty, R., Diallo, B., et al.[2019]

A 75-year-old woman developed drug-induced uveitis after 4 months of treatment with Dabrafenib and Trametinib for metastatic melanoma, leading to significant eye inflammation and visual impairment.

Switching her treatment to Nivolumab resulted in improvement of intraocular inflammation, although her visual acuity remained low due to an epiretinal membrane, highlighting the need for careful monitoring and management of ocular side effects in patients receiving these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bilateral Drug-Induced Uveitis and Epiretinal Membrane during the Treatment of a Metastatic Cutaneous Melanoma. Mozo Cuadrado, M., Tabuenca Del Barrio, L., Compains Silva, E.[2022]

Darovasertib, a new oral inhibitor of protein kinase C (PKC), has received orphan drug designation for treating uveal melanoma, a cancer with a high risk of metastasis and poor prognosis.

In clinical trials, darovasertib has shown greater potency and a better safety profile compared to other PKC inhibitors, and when combined with MEK inhibitors, it produces a synergistic effect, enhancing its potential efficacy in treating uveal melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Darovasertib, a novel treatment for metastatic uveal melanoma. Cao, L., Chen, S., Sun, R., et al.[2023]

In a phase II trial involving 52 patients with metastatic uveal melanoma, the combination of nivolumab and ipilimumab resulted in a 12-month overall survival rate of 51.9%, indicating a modest improvement compared to historical chemotherapy benchmarks.

The treatment demonstrated a manageable safety profile, with stable disease being the most common outcome (51.9%), and the median overall survival was 12.7 months, suggesting that this combination therapy could be a viable first-line option for patients not eligible for liver resection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Ipilimumab for Treatment-Naïve Metastatic Uveal Melanoma: An Open-Label, Multicenter, Phase II Trial by the Spanish Multidisciplinary Melanoma Group (GEM-1402). Piulats, JM., Espinosa, E., de la Cruz Merino, L., et al.[2021]

Citations

1. ir.ideayabio.com ir.ideayabio.com/2025-10-20-IDEAYA-Biosciences-Reports-Positive-Median-Overall-Survival-Data-from-Phase-2-Trial-of-the-Darovasertib-and-Crizotinib-Combination-in-First-line-Metastatic-Uveal-Melanoma-at-the-2025-Society-for-Melanoma-Research-Congress

News Releases Combination demonstrated median overall survival (OS) of 21.1 months, compared to reported historical mOS of approximately 12 months in ...

2. prnewswire.com prnewswire.com/news-releases/ideaya-biosciences-reports-positive-median-overall-survival-data-from-phase-2-trial-of-the-darovasertib-and-crizotinib-combination-in-first-line-metastatic-uveal-melanoma-at-the-2025-society-for-melanoma-research-congress-302588313.html

IDEAYA Biosciences Reports Positive Median Overall ... Combination demonstrated median overall survival (OS) of 21.1 months, compared to reported historical mOS of approximately 12 months in ...

3. ir.ideayabio.com ir.ideayabio.com/2025-08-29-IDEAYA-Biosciences-to-Present-First-Median-Overall-Survival-Data-from-Phase-2-Trial-of-the-Darovasertib-Crizotinib-Combination-in-Metastatic-Uveal-Melanoma-at-the-2025-Society-for-Melanoma-Research-Congress

News Releases The presentation will include data from over 40 patients in the trial, including the first reported median overall survival (OS) data for the ...

4. onclive.com onclive.com/view/frontline-darovasertib-plus-crizotinib-shows-clinical-efficacy-in-metastatic-uveal-melanoma

Frontline Darovasertib Plus Crizotinib Shows Clinical ... Darovasertib and crizotinib combination achieved a median overall survival of 21.1 months in metastatic uveal melanoma, surpassing historical ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05987332

Study Details | NCT05987332 | IDE196 (Darovasertib) in ... This study is designed as a multi-stage Phase 2 study within a Phase 3 study to evaluate the safety, tolerability, pharmacokinetics, dose-exposure relationship, ...

6. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)03661-5/fulltext

1139TiP IDE196 (darovasertib) in combination with ... The purpose of this study is to determine clinical and safety outcomes of IDE196 in combination with crizotinib in adult participants with HLA-A2 negative MUM.