Mirdametinib + Vorinostat for Cancer

Overseen By Kris Beatrez

Age: Any Age

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Minnesota

Disqualifiers: Pregnant, Cardiac disease, Eye disease, others

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

Compensation: Varies

Number of Visits: 3

Duration: 4 weeks

8 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how a combination of two drugs, mirdametinib and vorinostat, can help treat malignant peripheral nerve sheath tumors (MPNSTs), a rare type of cancer. The study specifically targets tumors lacking a protein called H3K27 trimethylation. Participants will take the medication for 28 days and undergo imaging and biopsies to assess tumor response before resuming their usual cancer treatment. Suitable candidates include those with Neurofibromatosis type 1, a genetic disorder that causes tumors, and suspected MPNSTs confirmed by scans. As an Early Phase 1 trial, this 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 information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that mirdametinib is already approved for treating neurofibromatosis type 1, indicating its safety is well-established for that condition. However, this trial tests mirdametinib with another drug, vorinostat, to evaluate their combined effect on a different type of tumor. As an early phase study, the primary goal is to understand the safety and effects of using these drugs together for the first time. While the safety of mirdametinib alone is better understood, the combination with vorinostat remains under investigation. Participants might experience common side effects, and researchers aim to understand these better. Those considering joining the trial will be closely monitored to manage any side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of Mirdametinib and Vorinostat for treating newly diagnosed, PRC2 deficient, primary malignant peripheral nerve sheath tumors (MPNSTs) because these drugs target the cancer cells in unique ways. Mirdametinib is a MEK inhibitor, which means it blocks a specific pathway that cancer cells use to grow and divide. Vorinostat is an HDAC inhibitor, which helps reactivate suppressed genes that can control cancer growth. By combining these two mechanisms, the treatment aims to attack the cancer from multiple angles, potentially offering more effective results than standard chemotherapy, which is the usual go-to for this condition.

What evidence suggests that mirdametinib plus vorinostat might be an effective treatment for MPNST?

Research has shown that both mirdametinib and vorinostat have potential in treating certain cancers. Mirdametinib successfully reduced tumor size by about 41-42% in patients with neurofibromatosis type 1. Vorinostat slows or stops cancer cell growth. In this trial, participants will receive a combination of these drugs to target malignant peripheral nerve sheath tumors (MPNSTs), especially those lacking PRC2 function. Although limited data exist on using these drugs together for MPNSTs, the positive effects of each drug individually offer hope for their combined use. ^{1 2 3 5 6}

Who Is on the Research Team?

Christopher L Moertel, MD

Principal Investigator

University of Minnesota

Are You a Good Fit for This Trial?

This trial is for individuals aged 12 or older with Neurofibromatosis type 1 (NF-1) and a specific tumor called MPNST that lacks a certain protein marker. Participants must have normal blood, liver, and kidney function tests, be able to swallow capsules, and provide consent. Women who can get pregnant and men with partners who can get pregnant must use effective contraception.

Inclusion Criteria

I am using or willing to use effective birth control during and after the study.

I have been diagnosed with Neurofibromatosis type 1.

My scans suggest I might have a malignant peripheral nerve sheath tumor.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive a single 28-day course of mirdametinib and vorinostat at standard oral dosing

4 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with information collected about subsequent standard of care treatment

48 months

What Are the Treatments Tested in This Trial?

Interventions

• Mirdametinib Plus Vorinostat

Trial Overview The trial studies the combination of two drugs, mirdametinib and vorinostat, given before standard care for MPNST tumors. Patients will take these drugs orally for one month then undergo imaging and biopsy before proceeding to typical treatments like radiation or surgery.

How Is the Trial Designed?

Group I: Experimental group Experimental Treatment 1 Intervention

newly diagnosed, PRC2 deficient, primary malignant peripheral nerve sheath tumors (MPNSTs)

Who Is Running the Clinical Trial?

University of Minnesota

Lead Sponsor

Trials

1,459

Recruited

1,623,000+

Published Research Related to This Trial

The combination of the MEK inhibitor selumetinib and the HDAC inhibitor vorinostat showed synergistic effects in inhibiting the growth of KRAS-mutant colorectal cancer (CRC) cell lines in vitro, leading to increased apoptosis and reduced cell migration.

In vivo studies demonstrated that this combination resulted in additive tumor growth inhibition and significant metabolic changes, particularly in membrane phospholipid turnover, suggesting a potential new therapeutic approach for advanced CRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models. Morelli, MP., Tentler, JJ., Kulikowski, GN., et al.[2022]

In a phase I trial involving 23 patients with relapsed/refractory multiple myeloma, the combination of vorinostat and bortezomib showed a promising overall response rate of 42%, including partial responses in patients who were previously resistant to bortezomib.

The maximum tolerated dose of vorinostat was determined to be 400 mg daily for 8 days in a 21-day cycle, with some dose-limiting toxicities observed, such as prolonged QT interval and fatigue, but no drug-related deaths were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Badros, A., Burger, AM., Philip, S., et al.[2022]

In a study of 16 patients with relapsed non-small cell lung cancer (NSCLC) treated with vorinostat, no objective tumor responses were observed, but 8 patients achieved stable disease for a median of 3.7 months.

Vorinostat demonstrated a median time to progression of 2.3 months and a median overall survival of 7.1 months, suggesting it may have similar efficacy to other targeted therapies, although safety concerns included serious adverse events like neutropenia and a possible treatment-related stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study. Traynor, AM., Dubey, S., Eickhoff, JC., et al.[2021]

Vorinostat, an HDAC inhibitor, has a generally acceptable safety profile, primarily causing gastrointestinal and constitutional side effects, making it a potentially safer option for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

While vorinostat alone shows limited efficacy, combining it with conventional chemotherapy or investigational agents has yielded promising results, suggesting it may enhance treatment outcomes for AML and MDS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vorinostat in acute myeloid leukemia and myelodysplastic syndromes. Prebet, T., Vey, N.[2022]

The combination of low doses of sorafenib and vorinostat synergistically kills hepatic, renal, and pancreatic adenocarcinoma cells, as shown in both short-term and long-term viability assays.

This treatment reduces levels of antiapoptotic proteins and activates the CD95 apoptotic pathway, indicating that the suppression of c-FLIP-s is crucial for triggering cell death in these cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vorinostat and sorafenib synergistically kill tumor cells via FLIP suppression and CD95 activation. Zhang, G., Park, MA., Mitchell, C., et al.[2022]

In a phase I study involving 17 patients, the combination of sorafenib and vorinostat was found to be poorly tolerated in patients with advanced renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC), leading to dose reductions and interruptions due to side effects like hand-foot syndrome.

While no confirmed responses were observed, some patients with RCC experienced minor responses, suggesting that lower doses may be necessary for better tolerability and potential efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of sorafenib and vorinostat in patients with advanced solid tumors with expanded cohorts in renal cell carcinoma and non-small cell lung cancer. Dasari, A., Gore, L., Messersmith, WA., et al.[2021]

Vorinostat (VRS) was successfully incorporated into nanostructured lipid carriers (NLCs), resulting in nanoparticles with ideal properties such as a small size of approximately 150 nm and high entrapment efficiency of about 99%.

The VRS-NLCs demonstrated significantly higher cytotoxicity against cancer cell lines (A549, MCF-7, and SCC-7) compared to the free drug, and improved oral bioavailability, with an area under the curve (AUC) enhancement of approximately 4.4 times.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of lipid nanoparticles for a histone deacetylases inhibitor as a promising anticancer therapeutic. Tran, TH., Chu, DT., Truong, DH., et al.[2018]

The maximum-tolerated dose (MTD) for the combination of vorinostat and bortezomib was determined to be vorinostat 400 mg daily and bortezomib 1.3 mg/m², indicating a safe dosing regimen for patients with advanced solid tumors.

The treatment was generally well-tolerated, with some patients experiencing grade 3 toxicities like fatigue and hyponatremia, while showing partial responses in patients with non-small cell lung cancer and treatment-refractory soft tissue sarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies. Schelman, WR., Traynor, AM., Holen, KD., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06693284

Study Details | NCT06693284 | A Window of Opportunity ... This is a single center Phase 0 "window of opportunity" trial for the treatment of newly diagnosed, PRC2 deficient, primary malignant peripheral nerve sheath ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2025-01026

Mirdametinib and Vorinostat for the Treatment of ... This early phase I trial tests the safety and side effects of mirdametinib and vorinostat and evaluates how well they work in treating patients with ...

3. trialx.com trialx.com/clinical-trials/listings/311355/a-window-of-opportunity-trial-of-mirdametinib-plus-vorinostat-for-nf1-associated-h3k27-trimethylation-deficient-malignant-peripheral-nerve-sheath-tumor-mpnst/

A Window of Opportunity Trial of Mirdametinib Plus ... Clinical trial for Primary Malignant Peripheral Nerve Sheath Tumors , A Window of Opportunity Trial of Mirdametinib Plus Vorinostat for NF1 ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S3050461925000140

Mirdametinib approval for neurofibromatosis type 1 with ... The primary endpoint, objective response rate, was achieved in 41% of adults and 52% of children, with median tumor volume reductions of 41% and 42%, ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11763529/

A Sequencing Overview of Malignant Peripheral Nerve ... Malignant peripheral nerve sheath tumors (MPNSTs) are rare but aggressive malignancies with a low 5-year survival rate despite current ...

6. esmorarecancers.org esmorarecancers.org/article/S3050-4619(25)00014-0/fulltext

Mirdametinib approval for neurofibromatosis type 1 with ... Neurofibromatosis type I (NF-1) is an autosomal dominant genetic disorder, regularly accompanied by plexiform neurofibroma.