Mirdametinib + Sirolimus for Multiple Myeloma

Overseen By Elizabeth M Hill, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, BCRP inhibitors

Disqualifiers: Plasma cell leukemia, Amyloidosis, Heart failure, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 4

54 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Multiple myeloma (MM) is a type of blood cancer that affects a person s immunity. MM returns after treatment (relapse) in almost all people; MM may also not respond to initial treatment (refractory). Many people with relapsed refractory MM (RRMM) also have changes in their KRAS and NRAS genes. Researchers want to try a new drug treatment that targets cancer with these changed genes. Objective: To test 2 drugs (mirdametinib and sirolimus) in people with RRMM. Eligibility: People aged 18 and older with RRMM who have changes in their KRAS or NRAS genes. Design: Participants will be screened. They will have blood tests and imaging scans. They will have an eye exam and a test of their heart function. They will need to provide proof of their disease status and of their KRAS or NRAS status. If neither is available, the tests will be repeated. Participants will have a bone marrow biopsy: A needle will be inserted into a hipbone to draw out some soft tissue. This study will be done in two parts. In the first part of this study, we will find a safe dose of mirdametinib combined with sirolimus. In the second part, we will learn more about how mirdametinib combined with sirolimus may work against RRMM. Mirdametinib (capsules) and sirolimus (tablets) are taken by mouth. Participants will take both drugs at home on a 4-week cycle. They will take mirdametinib twice a day for the first 3 weeks of each cycle. They will take sirolimus once a day, every day, during each cycle. Participants will have study visits once a week during the first cycle, and then on the first day of subsequent cycles. Blood, heart, imaging scans, and other tests will be repeated. Treatment with the study drugs will go on for 1 year. Then participants will have follow-up visits every 3 months for 4 more years.

Will I have to stop taking my current medications?

The trial requires participants to stop other myeloma-directed therapy (except for radiation) at least 14 days before starting the study treatment. Additionally, participants must not take certain medications that strongly interact with specific enzymes (CYP3A4 and BCRP) within 14 days prior to starting the trial.

What data supports the effectiveness of the drugs Mirdametinib and Sirolimus for treating multiple myeloma?

Research shows that combining mTOR inhibitors like Sirolimus with other drugs can effectively target pathways involved in multiple myeloma cell growth and survival. Additionally, similar combinations have shown the ability to overcome drug resistance and improve patient outcomes in multiple myeloma. ^{1 2 3 4 5}

How does the drug combination of Mirdametinib and Sirolimus differ from other treatments for multiple myeloma?

The combination of Mirdametinib and Sirolimus is unique because it targets specific molecular pathways involved in cell growth and survival, potentially offering a new approach for patients who are resistant to existing treatments. Sirolimus, an mTOR inhibitor, has shown promise in combination with other drugs, suggesting that this new combination could enhance treatment effectiveness by targeting the AKT/mTOR pathway. ^{2 6 7 8 9}

Research Team

Elizabeth M Hill, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for adults over 18 with relapsed refractory multiple myeloma (RRMM) who have specific genetic changes (KRAS or NRAS mutations). Participants must provide proof of their disease and mutation status, undergo various screenings including blood tests, imaging scans, an eye exam, heart function test, and a bone marrow biopsy.

Inclusion Criteria

Participants must have measurable disease per International Myeloma Working Group (IMWG) criteria

Participants must agree to use contraception as specified if of childbearing potential or able to father a child

Participants seropositive for HIV, HCV, or HBV must meet specific criteria related to their infection status

Exclusion Criteria

Positive beta-HCG serum or urine pregnancy test performed in IOCBP at screening

I haven't taken certain medications or substances in the last 14 days.

Participant has abnormal QT interval corrected by Fridericia's formula

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Dose Finding (Phase 1b)

Determine the recommended phase 2 dose (RP2D) of mirdametinib in combination with sirolimus using a standard 3 + 3 design

4 weeks

Weekly visits during the first cycle

Treatment (Phase 2)

Evaluate the efficacy of mirdametinib at RP2D in combination with sirolimus for 12 cycles (1 year)

12 months

Weekly visits during the first cycle, then monthly

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months

Treatment Details

Interventions

• Mirdametinib and Sirolimus

Trial Overview The study is testing the combination of two oral drugs: mirdametinib (capsules) taken twice daily for three weeks in a four-week cycle and sirolimus (tablets) taken once daily throughout the cycle. The first part determines a safe dosage; the second part assesses effectiveness against RRMM.

Participant Groups

Group I: Arm 2 Experimental Treatment 2 Interventions

Sirolimus and RP2D of mirdametinib

Group II: Arm 1 Experimental Treatment 2 Interventions

Sirolimus and escalating doses of mirdametinib

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Recent advancements in anti-myeloma treatments, including thalidomide, lenalidomide, and bortezomib, have shown significant clinical responses, especially in patients who do not respond to traditional chemotherapy.

The review highlights the ongoing development of various novel therapeutic classes, such as second-generation proteasome inhibitors and HDAC inhibitors, which are currently in clinical trials or advanced preclinical stages, indicating a promising expansion of treatment options for myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From the bench to the bedside: emerging new treatments in multiple myeloma. Mitsiades, CS., Hayden, PJ., Anderson, KC., et al.[2023]

References

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

Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Molecular targets for the treatment of multiple myeloma. [2019]

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

Pegylated liposomal doxorubicin and immunomodulatory drug combinations in multiple myeloma: rationale and clinical experience. [2019]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Upfront treatment for newly diagnosed transplant-ineligible multiple myeloma patients: A systematic review and network meta-analysis of 14,533 patients over 29 randomized clinical trials. [2020]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Combination Treatment Targeting mTOR and MAPK Pathways Has Synergistic Activity in Multiple Myeloma. [2023]

6. Netherlands pubmed.ncbi.nlm.nih.gov

From the bench to the bedside: emerging new treatments in multiple myeloma. [2023]

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

Outcomes in patients with relapsed or refractory multiple myeloma in a phase I study of everolimus in combination with lenalidomide. [2021]

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

Everolimus shows synergistic antimyeloma effects with bortezomib via the AKT/mTOR pathway. [2021]

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

Novel treatment approaches for patients with multiple myeloma. [2018]