Darovasertib + Crizotinib for Uveal Melanoma

Recruiting in Palo Alto (17 mi)

+69 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: IDEAYA Biosciences

Must not be taking: PKC inhibitors, MET inhibitors

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

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug combination (IDE196 and crizotinib) on patients with a specific type of eye cancer that has spread. The goal is to see if this combination can stop or slow down the cancer better than other treatments. Crizotinib has been used in treating various cancers with ALK gene rearrangements, showing high response rates.

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.

What data supports the effectiveness of the drug combination Darovasertib and Crizotinib for treating uveal melanoma?

A study reported the effective use of darovasertib and crizotinib in preserving vision and saving the eye in a patient with a large uveal melanoma, suggesting potential benefits of this drug combination. ^{1 2 3 4 5}

Is the combination of Darovasertib and Crizotinib safe for humans?

Darovasertib, when combined with Crizotinib, has shown a good safety profile in early clinical trials for uveal melanoma, meaning it is generally well-tolerated by patients. ^{1 2 3 6 7}

What makes the drug combination of Darovasertib and Crizotinib unique for treating uveal melanoma?

The combination of Darovasertib and Crizotinib is unique because Darovasertib is a first-in-class oral drug that inhibits protein kinase C (PKC), which plays a crucial role in the development of uveal melanoma. This combination has shown a synergistic effect, meaning they work better together, and Darovasertib has a better safety profile compared to other PKC inhibitors. ^{1 2 3 6 8}

Research Team

Hetal Patel, MD, MSHS, CHCQM

Principal Investigator

IDEAYA Biosciences

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Crizotinib (Other)
• Dacarbazine (Chemotherapy)
• IDE196 (Other)
• Ipilimumab + Nivolumab (Checkpoint Inhibitor)
• Pembrolizumab (Monoclonal Antibodies)

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.

Participant Groups

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 Japan, Canada for the following indications:

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+

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Globe Salvage and Vision Preservation by Neoadjuvant Darovasertib and Crizotinib in Uveal Melanoma. [2023]

2. England 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). [2018]

3. Greece pubmed.ncbi.nlm.nih.gov

New therapeutic agents in uveal melanoma. [2012]

4. United States pubmed.ncbi.nlm.nih.gov

Selumetinib-based therapy in uveal melanoma patient-derived xenografts. [2019]

5. United States 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). [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Darovasertib, a novel treatment for metastatic uveal melanoma. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Bilateral Drug-Induced Uveitis and Epiretinal Membrane during the Treatment of a Metastatic Cutaneous Melanoma. [2022]

8. India pubmed.ncbi.nlm.nih.gov

The role of c-kit and imatinib mesylate in uveal melanoma. [2020]