Lifirafenib + Mirdametinib for Cancer

Not currently recruiting at 5 trial locations

Overseen By BeiGene

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: BeiGene

Must not be taking: CYP3A inhibitors, Glucocorticoids

Disqualifiers: CNS metastasis, Cardiac disease, HIV, Liver disease, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, lifirafenib and mirdametinib, for individuals with advanced or spreading tumors. The goal is to determine the optimal dose and assess how effectively these medicines work together against cancer. The trial specifically targets tumors with an NRAS mutation, a gene change that can influence cancer growth. Individuals with advanced tumors that cannot be surgically removed and have not responded to other treatments may be suitable candidates. 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 treatment combination.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including chemotherapy, immunotherapy, biologic therapy, hormonal, or molecular targeted therapy within 2 weeks before starting the study. You also cannot take certain other medications like strong CYP3A inhibitors or systemic glucocorticoid therapy within 2 weeks before the trial.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including chemotherapy, immunotherapy, biologic therapy, hormonal, or molecular targeted therapy within 2 weeks before starting the trial. Additionally, you cannot take systemic or glucocorticoid therapy within 2 weeks or medicines that are strong CYP3A inhibitors.

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

Research has shown that the combination of lifirafenib and mirdametinib is generally safe. Previous studies found that many patients tolerated the treatment well, with few experiencing severe side effects. This suggests the combination is relatively safe for people, although further research is needed to confirm this. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Lifirafenib and Mirdametinib for treating NRAS-mutated solid tumors because these drugs target specific pathways often involved in cancer growth. Unlike traditional chemotherapy that attacks rapidly dividing cells indiscriminately, Lifirafenib specifically inhibits BRAF mutations, while Mirdametinib targets the MEK1/2 pathway. This targeted approach could potentially result in fewer side effects and more effective treatment outcomes. By combining these two drugs, the treatment aims to tackle cancer growth from multiple angles, offering hope for improved responses in patients with these genetic mutations.

What evidence suggests that this trial's treatments could be effective for cancer?

This trial will investigate the combination of lifirafenib and mirdametinib for cancer treatment. Research has shown that this combination can help fight tumors in patients with specific genetic changes in their cancer, such as KRAS, NRAS, and BRAF mutations. Lifirafenib blocks certain proteins that aid cancer cell growth, while mirdametinib targets other pathways involved in cancer progression. Early studies indicate that this combination is generally safe and typically does not cause severe side effects. Although still under investigation, these findings suggest the treatment could be effective for certain solid tumors with these mutations. ^{1 2 3 6 7}

Who Is on the Research Team?

Katie Wood

Principal Investigator

BeiGene

Are You a Good Fit for This Trial?

Adults with advanced solid tumors who can provide a tumor sample and consent, have a life expectancy over 12 weeks, measurable disease per RECIST 1.1, good performance status (ECOG ≤1), adequate organ function, and agree to use contraception can join. Exclusions include CNS metastasis, certain heart conditions, abnormal QT interval on ECG, active liver disease or infections like HIV/Hepatitis B/C.

Inclusion Criteria

My cancer has spread, cannot be surgically removed, and is getting worse.

I can carry out all my self-care but cannot do heavy physical work.

My organs are working well and I haven't had a transfusion in the last 2 weeks.

Exclusion Criteria

I haven't had severe bleeding in the last 28 days.

My heart's pumping ability is below normal.

Underlying medical conditions in investigator's opinion to be unfavorable to be a part of the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive combination doses of Mirdametinib and lifirafenib to determine optimal dosing

Varies

Expansion

Approximately 20 participants with NRAS mutated solid tumors receive treatment at the determined dose

Varies

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Lifirafenib
• Mirdametinib

Trial Overview The trial is testing the combination of two drugs: Lifirafenib (BGB-283) and Mirdametinib (PD-0325901) in adults with various types of advanced solid tumors. It's designed to assess safety and how the body processes these drugs.

How Is the Trial Designed?

Group I: Part B: Expansion Experimental Treatment 2 Interventions

Approximately 20 participants with NRAS mutated solid tumors will be enrolled

Group II: Part A: Dose Escalation/Dose finding Dose Level Cohorts ranging in dose levels and dose regimens. Experimental Treatment 2 Interventions

Combination doses of, Mirdametinib at once a day and lifirafenib at once a day And Mirdametinib at twice a day and lifirafenib at once a day

Who Is Running the Clinical Trial?

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

SpringWorks Therapeutics, Inc.

Industry Sponsor

Trials

14

Recruited

900+

Published Research Related to This Trial

Lifirafenib, a new drug targeting B-RAF and other kinases, was found to be safe and tolerable at a maximum dose of 40 mg/day, with common side effects including hypertension and fatigue.

The drug showed promising antitumor activity in patients with B-RAF mutations, achieving complete and partial responses in various solid tumors, while also demonstrating efficacy in some K-RAS-mutated cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors. Desai, J., Gan, H., Barrow, C., et al.[2021]

Vemurafenib is associated with a higher incidence of acute kidney injury compared to dabrafenib, with 132 reported cases during the study period, particularly affecting male patients.

Both drugs can cause electrolyte imbalances, such as hypokalemia and hyponatremia, indicating the importance of monitoring renal function and electrolyte levels in patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nephrotoxicity of the BRAF Inhibitors Vemurafenib and Dabrafenib. Jhaveri, KD., Sakhiya, V., Fishbane, S.[2022]

This phase I/II clinical trial is investigating the safety and efficacy of a combination treatment involving selumetinib, tremelimumab, and durvalumab in 40 patients with previously treated, unresectable non-small-cell lung cancer (NSCLC).

The study aims to determine the maximum tolerated dose and progression-free survival, while also exploring biomarkers of response and resistance, which could help tailor future treatments for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II Trial of Immunotherapy With Durvalumab and Tremelimumab With Continuous or Intermittent MEK Inhibitor Selumetinib in NSCLC: Early Trial Report. Gaudreau, PO., Lee, JJ., Heymach, JV., et al.[2021]

In a subgroup of 109 patients with EGFR-mutant NSCLC from the MARQUEE study, the combination of erlotinib and tivantinib significantly improved progression-free survival, with a median of 13.0 months compared to 7.5 months for erlotinib alone.

The combination therapy also showed a trend towards improved overall survival, with a median of 25.5 months for erlotinib plus tivantinib versus 20.3 months for erlotinib plus placebo, although the results were not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tivantinib in Combination with Erlotinib versus Erlotinib Alone for EGFR-Mutant NSCLC: An Exploratory Analysis of the Phase 3 MARQUEE Study. Scagliotti, GV., Shuster, D., Orlov, S., et al.[2019]

The combination of tivantinib and sorafenib was found to be safe and tolerable in 87 patients with advanced solid tumors, with the most common side effects being rash, diarrhea, and anorexia, but no unexpected toxicities were reported.

Preliminary results showed a 12% overall response rate, with higher efficacy in specific cancers: 26% in melanoma, 15% in renal cell carcinoma, and 10% in hepatocellular carcinoma, indicating potential therapeutic benefits for these tumor types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 trial of tivantinib in combination with sorafenib in adult patients with advanced solid tumors. Puzanov, I., Sosman, J., Santoro, A., et al.[2021]

In a phase I trial, BGB-283 was shown to be safe and well-tolerated in patients with solid tumors that have mutations in BRAF, KRAS, and NRAS.

The trial demonstrated that BGB-283 is effective in treating these tumors, indicating its potential as a targeted therapy for specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BGB-283 Deemed Effective in Phase I Study. [2018]

The combination of sorafenib and gefitinib is well tolerated in patients with advanced non-small cell lung cancer, with most side effects being mild (grade 1/2), although some patients experienced more severe effects like diarrhea and elevated liver enzymes.

Out of 31 patients treated, 65% achieved stable disease for at least 4 months, indicating promising efficacy, while the recommended dose for further studies was established as sorafenib 400 mg twice daily with gefitinib 250 mg once daily.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of sorafenib in combination with gefitinib in patients with refractory or recurrent non-small cell lung cancer. Adjei, AA., Molina, JR., Mandrekar, SJ., et al.[2018]

In a study of 43 patients with BRAF V600-mutant metastatic colorectal cancer, the combination of dabrafenib and trametinib showed activity, with 12% of patients achieving a partial response and one patient achieving a complete response lasting over 36 months.

All patients evaluated during treatment showed a significant reduction in phosphorylated ERK levels, indicating effective inhibition of the mitogen-activated protein kinase signaling pathway, although the response was less pronounced than in BRAF-mutant melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer. Corcoran, RB., Atreya, CE., Falchook, GS., et al.[2022]

The maximum tolerated doses (MTDs) for the combination of pembrolizumab and trametinib were established, with concurrent dosing showing a lower objective response rate (0%) compared to intermittent dosing (27%).

While the combination treatment had manageable safety profiles, with 31% of patients experiencing grade 3/4 treatment-related adverse events in the concurrent group, the overall antitumor activity was limited, suggesting that this combination may not be highly effective for solid tumors and BRAF wild-type melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation. Maio, M., Carlino, MS., Joshua, AM., et al.[2022]

Citations

1. ir.springworkstx.com ir.springworkstx.com/news-releases/news-release-details/springworks-and-beigene-present-clinical-data-lifirafenib/

Press Release Details The combination showed antitumor activity in patients with various KRAS, NRAS, and BRAF mutations across several solid tumor types, including ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03905148

NCT03905148 | Study of the Safety and Pharmacokinetics ... This is a 2-part Phase 1b study of BGB-283 (lifirafenib) and PD-0325901 (mirdametinib) combination in participants with tumors.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32182156/

Phase I, Open-Label, Dose-Escalation/Dose-Expansion ... Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAF V600 ...

4. cancer.gov cancer.gov/clinicaltrials/NCI-2020-08109

Study of the Safety and Pharmacokinetics of BGB-283 ... This is a 2-part Phase 1b study of BGB-283 (lifirafenib) and PD-0325901 (mirdametinib) combination in participants with tumors. Eligibility Criteria ...

5. targetedonc.com targetedonc.com/view/lifirafenib-plus-mirdametinib-shows-tolerable-safety-in-braf-kras-mutant-advanced-solid-tumors

Lifirafenib Plus Mirdametinib Shows Tolerable Safety in ... The investigational combination of lifirafenib (BGB-283) and mirdametinib (PD-0325901) has shown a favorable safety profile, as well as few dose-limiting ...

6. clin.larvol.com clin.larvol.com/trial-detail/NCT03905148

Study of the Safety and Pharmacokinetics of BGB-283 ... Study of the Safety and Pharmacokinetics of BGB-283 (Lifirafenib) and PD-0325901 (Mirdametinib) in Participants With Advanced or Refractory Solid Tumors. P1.

7. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03905148/

Clinical Trial: NCT03905148 This is a 2-part Phase 1b study of BGB-283 (lifirafenib) and PD-0325901 (mirdametinib) combination in participants with tumors.