Naporafenib + Trametinib for Solid Tumors

(SEACRAFT-1 Trial)

Not currently recruiting at 42 trial locations

Overseen By Erasca Clinical Team

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Erasca, Inc.

Must not be taking: CYP3A inhibitors/inducers

Disqualifiers: CNS tumors, Retinal vein occlusion, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two drugs, naporafenib (ERAS-254 or LXH254) and trametinib (Mekinist), to evaluate their combined effectiveness on solid tumors with the RAS Q61X gene mutation. Researchers aim to determine if this combination can effectively treat these tumors and assess its safety and tolerability for patients. They also study how the body processes these drugs. Individuals with advanced or spreading tumors, who cannot be treated with standard therapies and have this specific mutation, might be suitable for the trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires that you do not take medications that strongly affect certain liver enzymes (CYP3A, CYP2C8, CYP2C9) or have a narrow safety margin. It's best to discuss your current medications with the trial team to see if any need to be stopped.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that using naporafenib and trametinib together has been tested for safety in studies with patients who have advanced solid tumors. These studies suggest that this combination is generally well-tolerated.

Naporafenib blocks certain proteins involved in tumor growth. It has been studied both alone and with other treatments, such as spartalizumab, in patients with specific genetic changes. These studies showed that patients handled the treatment well without major safety concerns.

Trametinib, already approved by the FDA for other uses, has passed thorough safety tests on its own. When combined with naporafenib, early studies showed it works well against tumors without unexpected safety issues.

Overall, while this trial is still in the early stages, past research suggests that the treatment is likely safe for most participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Naporafenib and Trametinib for solid tumors because they offer a new approach by targeting specific pathways involved in tumor growth. Naporafenib works by inhibiting the RAF protein, which plays a key role in cell division and survival, potentially slowing down or stopping the growth of cancer cells. Trametinib complements this by inhibiting the MEK protein, another crucial part of the same pathway, offering a one-two punch to prevent tumor progression. This combined approach could be more effective than existing treatments that target these pathways individually, providing a fresh hope for patients with solid tumors.

What evidence suggests that this treatment might be an effective treatment for RAS Q61X solid tumors?

Research has shown that the combination of naporafenib and trametinib, which participants in this trial will receive, may help treat solid tumors with a specific genetic change (RAS Q61X). Earlier studies found that this drug pair can reduce tumor activity. In some patients, tumors shrank or even disappeared, known as a partial or complete response. The treatment also increased immune cell activity, aiding the body in fighting cancer. These early results suggest that using naporafenib and trametinib together might be effective against certain difficult tumors. ^{1 2 3 6 7}

Who Is on the Research Team?

Joyce Antal, MS

Principal Investigator

Clinical Development

Are You a Good Fit for This Trial?

This trial is for patients aged 12 or older with advanced solid tumors containing a specific mutation (RAS Q61X). They must have at least one measurable tumor, be able to take oral medication, and not have standard treatment options available. Patients who've had certain prior treatments or suffer from conditions affecting drug absorption, heart function, or eye health are excluded.

Inclusion Criteria

Willing and able to provide written informed consent

Presence of at least 1 measurable lesion according to RECIST v1.1

My cancer has a RAS Q61X mutation.

Exclusion Criteria

My heart's pumping ability is below normal.

Corrected QT interval using Fridericia's formula (QTcF) at Screening >450 ms based on triplicate average

My cancer originated in the brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive naporafenib (ERAS-254) 200 mg twice daily and trametinib 1 mg once daily

24 months

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Naporafenib
• Trametinib

Trial Overview The study tests the effectiveness and safety of combining two drugs: Naporafenib and Trametinib in treating solid tumors with RAS Q61X mutations. It also aims to understand how these drugs behave in the body when taken together by patients with this genetic alteration.

How Is the Trial Designed?

Group I: Naporafenib + Trametinib Experimental Treatment 2 Interventions

Naporafenib (ERAS-254) 200 mg twice daily (BID) Trametinib 1 mg once daily (QD)

Who Is Running the Clinical Trial?

Erasca, Inc.

Lead Sponsor

Trials

8

Recruited

1,200+

Published Research Related to This Trial

In a phase 1 study involving 142 patients with advanced solid tumors, naporafenib was found to have a maximum tolerated dose of 600 mg twice daily, demonstrating an acceptable safety profile with common side effects including rash and nausea.

The combination of naporafenib with spartalizumab showed promising results, with partial and complete responses observed in patients with KRAS-mutated non-small cell lung cancer and NRAS-mutated melanoma, indicating potential efficacy in these specific tumor types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations. Janku, F., Kim, TM., Iyer, G., et al.[2023]

In the VEM-PLUS study, combining vemurafenib with other targeted therapies or chemotherapy did not significantly improve overall survival (OS) or progression-free survival (PFS) compared to vemurafenib alone in patients with BRAF V600E-mutant solid tumors, except for a notable inferior OS in the combination with carboplatin and paclitaxel.

Patients who had not previously received BRAF inhibitors showed significantly better outcomes, with a median OS of 12.6 months compared to 10.4 months for those who were refractory to BRAF therapy, highlighting the importance of treatment sequencing in managing resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAF v600E-mutant cancers treated with vemurafenib alone or in combination with everolimus, sorafenib, or crizotinib or with paclitaxel and carboplatin (VEM-PLUS) study. Nelson, BE., Roszik, J., Janku, F., et al.[2023]

The pediatric oral solution of trametinib showed improved bioavailability compared to the tablet formulation, with significant increases in key pharmacokinetic measures such as Cmax and AUC, indicating it may be more effective in delivering the drug to patients.

The safety profile of the trametinib pediatric oral solution was consistent with existing data, with no serious adverse events leading to withdrawal from the study, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. Cox, DS., Allred, A., Zhou, Y., et al.[2018]

In a study of 50 patients with BRAFV600mut metastatic melanoma, the combination of dabrafenib and trametinib resulted in a median progression-free survival (PFS) of 11.4 months and an overall response rate of 70%.

Higher trough concentrations of dabrafenib were associated with significantly improved PFS and duration of response, suggesting that monitoring drug levels could optimize treatment outcomes and manage adverse events effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib and trametinib exposure-efficacy and tolerance in metastatic melanoma patients: a pharmacokinetic-pharmacodynamic real-life study. Goldwirt, L., Louveau, B., Baroudjian, B., et al.[2022]

In a clinical trial involving 57 pretreated NSCLC patients, the combination of dabrafenib and trametinib showed a high overall response rate (ORR) of 68.4% and a median overall survival (OS) of 18.2 months, indicating its efficacy in treating BRAF V600E mutant non-small cell lung cancer.

The treatment was well tolerated, with manageable side effects such as pyrexia and nausea, leading to its approval for BRAF V600E metastatic NSCLC patients, regardless of prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAF Inhibitors in Non-Small Cell Lung Cancer. Sforza, V., Palumbo, G., Cascetta, P., et al.[2022]

A 52-year-old man with BRAF-mutated unresectable melanoma developed severe cardiac complications, including pericardial effusion and cardiac tamponade, after treatment with the combination of Dabrafenib and Trametinib, highlighting a significant risk of cardiovascular toxicity associated with this therapy.

This case report is the first to document such severe cardiac adverse effects from Dabrafenib and Trametinib, emphasizing the need for careful monitoring of patients on BRAF/MEK inhibitors for potential treatment-emergent cardiac issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac tamponade induced by dabrafenib and trametinib combination therapy for melanoma: Case report. Sundaram, VR., Abbas, T.[2023]

The combination of dabrafenib and trametinib significantly improves progression-free survival and overall survival in patients with unresectable or metastatic melanoma with a BRAF (V600E/K) mutation, compared to monotherapy with dabrafenib or vemurafenib, based on results from two large phase III studies.

This combination therapy is well-tolerated, showing no increase in overall toxicity compared to monotherapy, and results in fewer skin-related adverse events, likely due to reduced activation of the MAPK pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation. Dhillon, S.[2022]

Dabrafenib and trametinib have been approved for treating metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutations, showing an overall response rate of 63% in previously treated patients and 61% in treatment-naïve patients, indicating their efficacy in this specific cancer subset.

The combination of dabrafenib and trametinib is necessary to achieve a response rate greater than 40%, highlighting the importance of using both drugs together for optimal treatment outcomes, while common side effects include fatigue, nausea, and rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring BRAF V600E Mutations. Odogwu, L., Mathieu, L., Blumenthal, G., et al.[2019]

The combination of BRAF inhibitor dabrafenib and MEK inhibitor trametinib significantly improves outcomes for metastatic melanoma patients compared to single-agent therapies, with a manageable safety profile.

While 98% of patients experience at least one adverse event during combination therapy, these events are mostly mild to moderate and can be effectively managed, highlighting the importance of addressing even minor side effects to maintain patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. Knispel, S., Zimmer, L., Kanaki, T., et al.[2017]

The combination of trametinib and afuresertib was poorly tolerated at the starting dose, leading to dose-limiting toxicities, but an intermittent dosing schedule showed better tolerability, suggesting a potential for safer administration.

Among 20 patients with advanced solid tumors, the study reported one partial response and four cases of stable disease, indicating some efficacy, but the overall response rate was low, warranting further investigation into alternative dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Tolcher, AW., Patnaik, A., Papadopoulos, KP., et al.[2015]

In a long-term study of 60 Chinese patients with unresectable or metastatic BRAF V600-mutant melanoma, the combination of dabrafenib and trametinib resulted in a high objective response rate of 71.7% and a median duration of response of 7.5 months.

The 3-year overall survival rate was 28.8%, with better outcomes observed in patients with acral melanoma (35.7%), and factors like normal lactic dehydrogenase levels and fewer metastatic sites were linked to improved survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival of Patients With Unresectable or Metastatic BRAF V600-Mutant Acral/Cutaneous Melanoma Administered Dabrafenib Plus Trametinib: Long-Term Follow-Up of a Multicenter, Single-Arm Phase IIa Trial. Mao, L., Ding, Y., Bai, X., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05907304

NCT05907304 | A Study to Assess Naporafenib (ERAS- ... To evaluate the efficacy of naporafenib administered with trametinib in patients with rat sarcoma viral oncogene (RAS) Q61X solid tumors.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11380116/

First-in-human study of naporafenib (LXH254) with or ... Naporafenib reduced DUSP6 expression in tumors. Two partial responses (PRs) occurred in naporafenib escalation, and 1 complete response and 3 PRs in the ...

3. erasca.com erasca.com/wp-content/uploads/2024/05/TiP_SC-1_ASCO_poster_24-0506.pdf

(ERAS-254) administered with trametinib in ... naporafenib (200 mg, oral BID) + trametinib (1 mg, oral QD). 28-day cycles. Pts with solid tumors. (Age 12+). Post-available therapy. Confirm RAS Q61Xm. Safety ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0959804923007608

First-in-human study of naporafenib (LXH254) with or ... The combined treatment significantly boosted the infiltration of CD8+ T cells, and the improved inhibition of tumor growth was strongly associated with the ...

5. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.22.02018

Initial Evidence for the Efficacy of Naporafenib in ... Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma.

6. georgiacancerinfo.org georgiacancerinfo.org/clinical-trials/detail/5565

A Study to Assess Naporafenib (ERAS-254) Administered ... Summary. To evaluate the efficacy of naporafenib administered with trametinib in patients with rat sarcoma viral oncogene (RAS) Q61X solid tumors

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36947734/

Initial Evidence for the Efficacy of Naporafenib in ... Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma.