Combination Therapy (Mirdametinib and Sirolimus) for RAS Mutated Relapsed Refractory Multiple Myeloma
- Conditions
- Multiple MyelomaRelapsed and/or Refractory Multiple Myeloma (RRMM)
- Interventions
- Registration Number
- NCT06876142
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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.
- Detailed Description
Background:
* Multiple myeloma (MM) is the second most prevalent hematologic malignancy. Despite advances in therapy, almost all patients who survive their original presentation eventually relapse. There remains an unmet need in patients who are primary refractory or who have exhausted available therapies.
* To date, the successful therapies in MM have targeted vulnerabilities in myeloma biology such as high protein turnover or overexpressed cell markers. Less success has been had in targeting the molecular pathogenesis or signaling pathways involved in MM oncogenesis.
* RAS mutations can be found in 40-60% of MM tumors and the incidence of RAS mutations goes up with more advanced and heavily pretreated disease.
* The RAS pathway leads to downstream MEK activation which in turn enhances survival, proliferation, and migration of MM cells.
* Preclinical studies suggest that inhibition of both MEK and mTOR is required to impede RAS-dependent pathogenic signaling in MM cells.
* This study will use a MEK inhibitor (mirdametinib) in combination with an mTOR inhibitor (sirolimus) to attempt to block the pathogenic RAS pathway in MM.
Objectives:
* Phase 1b: To determine the recommended phase 2 dose (RP2D) of mirdametinib in combination with sirolimus in participants with RAS mutated relapsed refractory multiple myeloma (RRMM)
* Phase 2: To determine the preliminary efficacy of mirdametinib at RP2D in combination with sirolimus in participants with RAS mutated RRMM as assessed by the overall response rate (ORR) per International Myeloma Working Group (IMWG) criteria
Eligibility:
* Age \>= 18 years old.
* Eastern Cooperative Oncology Group (ECOG) performance score \<= 2.
* Participants must have a documented diagnosis of MM defined by the International Myeloma Working Group (IMWG) Criteria.
* Participants must have relapsed and/or refractory multiple myeloma (RRMM) with "pentaclass exposed" disease including previous therapy with an anti-CD38 monoclonal antibody, 2 immunomodulatory drugs (IMiDs), and 2 proteasome inhibitors (PIs).
* Participants must have a somatic NRAS or KRAS mutation.
Design:
* This is an open-label, non-randomized, prospective, single-center Phase 1b/2 study evaluating the combination of mirdametinib and sirolimus in participants with RASmutated RRMM.
* During Phase 1b we will find RP2D of mirdametinib in combination with sirolimus using a standard 3 + 3 design.
* During Phase 2 we will use RP2D of mirdametinib in combination with sirolimus to evaluate the efficacy of this combination.
* All participants will receive study drugs for 12 cycles (1 year) or until off-treatment criteria are met. Both drugs will be taken orally daily at home. There will be a one-week break from mirdametinib every cycle (3 weeks on and 1 week off). Sirolimus will be taken continuously.
* Participants will have regular evaluations for safety and response.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 54
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Arm 1 Mirdametinib Sirolimus and escalating doses of mirdametinib Arm 1 Sirolimus Sirolimus and escalating doses of mirdametinib Arm 2 Mirdametinib Sirolimus and RP2D of mirdametinib Arm 2 Sirolimus Sirolimus and RP2D of mirdametinib
- Primary Outcome Measures
Name Time Method Phase 1: determine the RP2D of the mirdametinib in combination with sirolimus in participants with RAS-mutated RRMM 28 days The RP2D will be determined by the dose found in the 3+3 design to cause \< 33% toxicity as defined by the DLT criteria.
Phase 2: determine the preliminary efficacy of mirdametinib at RP2D in combination with sirolimus in participants with RAS-mutated RRMM as assessed by the ORR per IMWG Day 1 of every cycle, at suspected CR, End of cycles 6 and 12, Safety Follow Up visit, every 3 months after that until progression, initiation of another line of therapy, or 5 years since treatment initiation. The fraction of participants with a RAS mutation who experience a response (PR, VGPR, CR, or sCR) while on the study treatment will be determined by dividing the number of responders by the total number of evaluable participants. The fraction will be reported along 95% two-sided confidence intervals.
- Secondary Outcome Measures
Name Time Method Duration of Response (DOR) Day 1 of every cycle, at suspected CR, End of cycles 6 and 12, Safety Follow Up visit, every 3 months after that until progression, initiation of another line of therapy, or 5 years since treatment initiation. DOR will be assess with blood tests and radiographic findings and reported using the Kaplan-Meier method.
Progression Free Survival (PFS) Day 1 of every cycle, at suspected CR, End of cycles 6 and 12, Safety Follow Up visit, every 3 months after that until progression, initiation of another line of therapy, or 5 years since treatment initiation. PFS will be assessed with blood tests and radiographic findings and reported using the Kaplan-Meier method.
Overall Survival (OS) Day 1 of every cycle, EOT, Safety Follow-up visit, then every 3 months(+/-2 weeks) until disease progression or the initiation of another line of therapy for up to 5 years after the treatment initiation. After progression or initiation of a new treatment OS will be assessed and reported using the Kaplan-Meier method and include any cause of death.
Safety Until 30 days after the last dose of study agents The number and frequency of adverse events for participants as assessed per CTCAE version 5. Safety will be analyzed by reporting the number of patients experiencing toxicity, classified by type and grade to the experimental regimen.
Related Research Topics
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Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States