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Also known as Mirdametinib (PD-0325901) oral capsule or dispersible tablet, Mirdametinib or dispersible, Mirdametinib (MEK Inhibitor), PD-0325901
Mirdametinib · 6 trials · 37 indications
Vascular malformations present with a range of different symptoms. Therefore, there is no single outcome measure that can capture the effectiveness of a systemic treatment across different patients. Thus for this study, an individualised primary outcome for each patient informed by their symptoms will be used, termed the Vascular Malformation Patient Specific Outcome Measure (VM-PSOM). The study "Outcome Committee" will define an individualised primary outcome for each patient informed by their symptoms and vascular malformation features prior to starting trial treatments. The VM-PSOM endpoint will therefore define a binary outcome for each patients (achieved or failed to reach the threshold improvement in the chosen measure).
Response will be determined by a blinded centralized review of volumetric MRI. The confirmed objective response rate (complete or partial response) by the end of Treatment Phase (i.e., Cycle 24) is defined as the proportion of participants who have a confirmed ≥ 20% reduction in target tumor volume as compared to baseline as assessed by a BICR, and the response needs to be confirmed by BICR in a consecutive tumor assessment within 2 - 6 months. Partial response is defined as a ≥ 20% reduction in target tumor volume from baseline. Complete response is defined as the complete resolution of the target tumor.
To determine the best overall neurologic response rate
To determine the recommended phase 2 dose (RP2D) of mirdametinib plus palbociclib in patients with DDLPS
Phase II: To determine the progression-free survival rate at 18 weeks by RECIST 1.1
Phase 1 will test the safety and tolerability of multiple dose regimens of mirdametinib, in order to identify the recommended phase 2 dose(s) for phase 2a. The study will continue until one of the stopping conditions is met. * The RP2D(s) have been identified with sufficient accuracy (The dose regimen(s) selected as the RP2D have been fully enrolled with at least 3 cycles of treatment completed for all participants) * All dose regimens are deemed to have unacceptable safety The study will continue until one of the following stopping conditions is met. * The RP2D(s) have been identified with sufficient accuracy (The dose regimen(s) selected as the RP2D have been fully enrolled with at least 3 cycles of treatment completed for all participants) * All dose regimens are deemed to have unacceptable safety
Phase 2a of the study will test the efficacy and safety of a maximum of two RP2Ds in adults with NF1 and cNF.
Evaluate the efficacy of mirdametinib monotherapy at the RP2D in adults with NF1 and cNF. We will determine efficacy of Anti-tumor activity with 3D photography (Sum of the surface area, sum of the tumor volume, sum of the longest diameter) and Digital Caliper (Sum of the longest diameter).
The maximum tolerated dose (MTD) is empirically defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level determined to be too toxic. The MTD estimate will not be available if the lowest dose level studied is too toxic or the highest dose level studied is considered safe. In the latter case, the highest studied safe dose may be considered as the recommended phase 2 dose (RP2D). The MTD estimation will be limited to evaluable patients and toxicity assessments from course 1 (28 days). We will require that at least 12 DLT evaluable subjects are assessed before the MTD/RP2D is declared.
Incidence of adverse event data at least possibly related to treatment will be summarized in cohort specific tables by grade and attribution throughout treatment.
Mirdametinib plasma concentration will be provided and area under the curve (AUC0-8h) estimated based on course 1, days 1 and 15 PK samples
The response rate, defined as the rate of minor response, partial response (PR), major response, or complete response (CR) will be calculated as the percentage of confirmed responders among all response assessable patients. These rates as well as their exact confidence intervals will be provided and will be summarized by each response category (i.e., PR, major response, and CR). Subjects without an assessment will be considered non-responders.
The response rate, defined as the rate of minor response, partial response (PR), major response, or complete response (CR) will be calculated as the percentage of confirmed responders among all response assessable patients. These rates as well as their exact confidence intervals will be provided and will be summarized by each response category (i.e., PR, major response, and CR). Subjects without an assessment will be considered non-responders.
Rate of stable disease from start of treatment until the time of progression or time of last follow-up.
Rate of stable disease from start of treatment until the time of progression or time of last follow-up.
Incidence of adverse event data at least possibly related to treatment will be summarized in cohort specific tables by grade and attribution throughout treatment.
| Arm | Type | Description |
|---|---|---|
| Module 1: Slow-flow vascular malformations | EXPERIMENTAL | Slow-flow vascular malformations with identified causative variants in the phosphoinositide 3-kinase (PI3K) signalling pathway will receive alpelisib (provided by Novartis Pharmaceuticals), an oral alpha-specific PI3-kinase inhibitor for a total duration of 48 weeks as monotherapy, followed by 24 weeks of follow-up. |
| Module 2: Fast-flow vascular malformations | EXPERIMENTAL | Fast-flow vascular malformations with identified causative variants in the RAS-MEK-ERK signalling pathway will receive mirdametinib (provided by SpringWorks Therapeutics, Inc.), an investigational oral MEK inhibitor for a total duration of 48 weeks as monotherapy, followed by 24 weeks of follow-up. |
| Mirdametinib (PD-0325901) | EXPERIMENTAL | Mirdametinib (PD-0325901) capsule or dispersible tablet 2 mg/m\^2 (maximum dose of 4 mg) by mouth twice daily |
| Cohort A: Mirdametinib | EXPERIMENTAL | 11 participants with refractory neurohistiocytosis will be treated with mirdametinib in continuous treatment cycles |
| Cohort B: Perioperative mirdametinib | EXPERIMENTAL | 15 participants with recurrent NF1-mutant glioma will be randomized in a 2:1 ratio to receive either perioperative mirdametinib (for 5 days) or no drug before standard of care surgery. All 15 participants will be treated with mirdametinib twice daily after surgery, continuously until clinical or radiographic progression of disease |
| Cohort B: No perioperative mirdametinib | NO_INTERVENTION | 15 participants with recurrent NF1-mutant glioma will be randomized in a 2:1 ratio to receive either perioperative mirdametinib (for 5 days) or no drug before standard of care surgery. All 15 participants will be treated with mirdametinib twice daily after surgery, continuously until clinical or radiographic progression of disease |
| Phase I | EXPERIMENTAL | Dose escalation phase |
| Phase II | EXPERIMENTAL | During the phase II portion, 30 patients with advanced DDLPS will be enrolled. All patients in the phase II study will receive the RP2D of mirdametinib plus palbociclib. |
| Phase 1 | EXPERIMENTAL | For the Phase 1 portion, treatment will be administered continuously (Dose regimens 1, 2, 4) or intermittently (Dose regimen 3; 3 weeks on/1 week off) in 28-day cycles). All participants will receive study drug until: 1. cessation of study treatment due to death, intolerance, or withdrawal of consent from the study; 2. completion of 24 cycles of treatment (unless the investigator's benefit-risk assessment supports continued treatment); 3. participants enroll in the phase 2a portion of the study; 4. disease progression; or 5. Investigator's decision. Treatment period ends with the administration of the last dose. The study ends 30 days after the last dose |
| Phase 2 | EXPERIMENTAL | For the Phase 2 portion, treatment will be administered based on recommended RP2D from Phase 1. All participants will receive study drug until: 1. cessation of study treatment due to death, intolerance, or withdrawal of consent from the study; 2. completion of 24 cycles of treatment (unless the investigator's benefit-risk assessment supports continued treatment; 3. disease progression; or 4. Investigator's decision. Treatment period ends with the administration of the last dose. The study ends 30 days after the last dose. |
| Phase I: Recurrent and/or progressive low-grade glioma without prior exposure to MEK inhibitors | EXPERIMENTAL | Participants will receive mirdametinib at one of the dose levels twice daily days 1-28. For the first cycle of treatment, participants will take mirdametinib tablets dissolved in water. After the first cycle of treatment, participants may receive the medicine the same way (dissolved in water) or may receive capsules. Treatment repeats every 28 days for up to 26 cycles of treatment (24 months) in the absence of disease progression or unacceptable toxicity. |
| Phase 2, Cohort 1: Newly diagnosed and/or previously untreated (except surgery) | EXPERIMENTAL | Participants will receive the RP2D of mirdametinib. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity. |
| Phase 2, Cohort 2: Recurrent and/or Progressive without prior exposure to MEK inhibitors | EXPERIMENTAL | Participants will receive the RP2D of mirdametinib. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity. |
| Phase 2, Cohort 3a: | EXPERIMENTAL | Participants with recurrent and/or progressive low-grade glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy. Participants will receive the RP2D of mirdametinib. Participants with previous exposure to mirdametinib may receive a starting dose lower than the RP2D, depending on the dose they tolerated during their previous exposure. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity. |
| Phase 2, Cohort 3b: | EXPERIMENTAL | Participants with recurrent and/or progressive low-grade glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy. Participants will receive the RP2D of mirdametinib. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity. |
| Name | Type | Description |
|---|---|---|
| Alpelisib | DRUG | Oral alpha-specific PI3-kinase inhibitor |
| Mirdametinib | DRUG | An investigational oral MEK inhibitor |
| Mirdametinib (PD-0325901) oral capsule or dispersible tablet | DRUG | Mirdametinib (PD-0325901) capsule or dispersible tablet |
| Palbociclib | DRUG | Palbociclib (IBRANCE®) is a kinase inhibitor FDA approved for the following indications: treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men or fulvestrant in patients with disease progression following endocrine therapy. |
MODULE 1 Inclusion Criteria: 1. Adult or paediatric patient, 2 years of age or over 2. Patient has a clinical diagnosis of a slow-flow vascular malformation 3. Patient has received standard therapy for the vascular malformation or in which, in the opinion of the investigator, standard therapy is n...
Mirdametinib is an oral small molecule MEK inhibitor being developed by SpringWorks Therapeutics, Inc. (ticker SWTX). It is an investigational agent in clinical development, studied in oncology and related settings including central nervous system tumors, low-grade glioma, NF1, plexiform neurofibroma, slow-flow vascular malformation, and well differentiated liposarcoma.
Mirdametinib targets MAP2K1 and MAP2K2, also known as MEK1 and MEK2. It acts as an inhibitor of these kinases, which sit in the MAP kinase signaling pathway. The drug is a small molecule and is being studied with biomarker selection in its clinical programs.
Mirdametinib is developed by SpringWorks Therapeutics, Inc., which trades under the ticker SWTX. The company is the sponsor of the clinical studies evaluating the drug across central nervous system tumors, liposarcoma, neurofibromatosis type 1, and vascular malformation indications.
Mirdametinib is in Phase 1 development overall and is investigational. It has not been established as approved, and the clinical program includes Phase 1 studies plus a Phase 2 trial in vascular malformations. The studies are currently recruiting participants.
Mirdametinib is being studied in NCT07539441 in central nervous system tumors and glioma, NCT06843967 in combination with palbociclib in liposarcoma, NCT06159166 as monotherapy in NF1 with cutaneous neurofibromas, and NCT05983159 in slow-flow and fast-flow vascular malformations. All four trials are recruiting.
Yes, Mirdametinib is also known as PD-0325901. It is supplied as an oral capsule or dispersible tablet and is described as a MEK inhibitor. These names refer to the same investigational small molecule developed by SpringWorks Therapeutics.