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

Trial Summary

What is the purpose of this trial?

This is a single center Phase 0 "window of opportunity" trial for the treatment of newly diagnosed, PRC2 deficient, primary malignant peripheral nerve sheath tumors (MPNSTs) with a short course of the combination of mirdametinib and vorinostat prior to the most appropriate standard of care treatment for their specific tumor (typically localized radiation followed by surgical resection). Four to eight patients, 12 years of age or older and meeting the study's biomarker inclusion criteria, would be enrolled onto this trial. After voluntary written consent (assent with parent consent for minors) the patient undergoes MRI and PET imaging of the tumor and a needle biopsy to collect tumor is performed. Patients with histone H3K27 trimethylation deficient MPNST, as confirmed by immunohistochemistry, receive a single 28-day course of mirdametinib and vorinostat at standard oral dosing for each. At day 26, 27, or 28 the patient returns to clinic for a research visit repeating the baseline MRI and PET imaging and the needle biopsy for tumor tissue. This ends direct study participation. The patient goes on to the most appropriate standard of care treatment for their MPNST. Information about the subsequent standard of care treatment is collected for the purposes of this study.

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.

What data supports the effectiveness of the drug Mirdametinib Plus Vorinostat for cancer?

Research shows that vorinostat, one of the drugs in this combination, has been studied with other cancer drugs like bortezomib and sorafenib, showing potential in killing cancer cells. Additionally, a similar drug combination involving a MEK inhibitor like mirdametinib and vorinostat showed promise in preclinical models of colorectal cancer. ^{1 2 3 4 5}

What makes the drug Mirdametinib + Vorinostat unique for cancer treatment?

The combination of Mirdametinib and Vorinostat is unique because it combines a MEK inhibitor (Mirdametinib) with a histone deacetylase inhibitor (Vorinostat), potentially offering a novel approach by targeting different pathways in cancer cells, which may enhance treatment effectiveness compared to using each drug alone. ^{3 4 6 7 8}

Research Team

Christopher L Moertel, MD

Principal Investigator

University of Minnesota

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

References

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

Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. [2022]

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

A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies. [2021]

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

Vorinostat and sorafenib synergistically kill tumor cells via FLIP suppression and CD95 activation. [2022]

4. United States 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. [2021]

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

Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models. [2022]

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

Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study. [2021]

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

Vorinostat in acute myeloid leukemia and myelodysplastic syndromes. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Development of lipid nanoparticles for a histone deacetylases inhibitor as a promising anticancer therapeutic. [2018]