Mirdametinib for Neurofibromatosis (Mirda Trial)
Recruiting in Palo Alto (17 mi)
Overseen ByCarlos Romo, MD
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Johns Hopkins University
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a Phase 1/2a, open-label, non-randomized, multi-dose study of mirdametinib monotherapy in adults with NF1 and cNF.
In both Phases of the study, participation in the study will comprise three periods: screening, treatment and post-study safety follow-up to be performed at the NF1 and cNF specialty center: Johns Hopkins University.
Is the drug Mirdametinib a promising treatment for Neurofibromatosis?Yes, Mirdametinib is a promising drug for treating Neurofibromatosis type 1-related plexiform neurofibromas. It has shown positive results in trials, reducing tumor size in patients where surgery is not an option.12478
What safety data is available for Mirdametinib in treating Neurofibromatosis?The safety data for Mirdametinib, also known as PD-0325901, in treating Neurofibromatosis type 1-related plexiform neurofibromas is primarily derived from a Phase II trial (NF106) involving adolescents and adults. While the primary focus was on response rates, the trial contributes to understanding the safety profile of Mirdametinib. Additionally, other MEK inhibitors like Selumetinib have been studied extensively, showing risks consistent with the MEK inhibitor class, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. These findings provide a context for understanding potential safety concerns with Mirdametinib, as it shares a similar mechanism of action.34578
What data supports the idea that Mirdametinib for Neurofibromatosis is an effective drug?The available research shows that Mirdametinib has proven its effectiveness in treating neurofibromatosis type 1-related plexiform neurofibromas, especially in adults. Although specific data points for Mirdametinib are not detailed, it is mentioned alongside other effective treatments like Selumetinib, which has shown a 68% response rate in children. This suggests that Mirdametinib is considered effective based on its inclusion in successful trials and its comparison to other approved treatments.14678
Do I have to stop taking my current medications for the trial?The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are currently receiving systemic glucocorticoid therapy or systemic treatment with CYP inducers like rifampin or ritonavir within 14 days before the first dose. It's best to discuss your specific medications with the trial team.
Eligibility Criteria
Adults over 18 with Neurofibromatosis type 1 (NF1) and at least 12 measurable cutaneous neurofibromas (cNF). They must have a certain level of overall health, including specific blood cell counts and performance status. Participants need to be able to undergo tumor biopsies.Inclusion Criteria
I have at least 24 measurable skin growths, with 2 areas having at least 6 each.
I am 18 years old or older.
My eligible neurofibromas are in the study's specified areas or can be biopsied if outside those areas.
I can carry out normal activities with minimal symptoms.
I agree to follow the specified contraception guidelines.
My organ and bone marrow functions are within normal ranges.
Exclusion Criteria
I have a history of eye problems related to the retina.
I have a condition that affects how my body absorbs medication.
I have been treated with MEK inhibitors before.
I have had high calcium levels due to cancer.
I do not have any significant liver diseases or abnormalities.
Participant Groups
The trial is testing Mirdametinib as a single-agent therapy for adults with NF1 and cNF. It's an open-label study, meaning both doctors and patients know what treatment is being given, conducted in multiple doses across three phases: screening, treatment, and follow-up.
2Treatment groups
Experimental Treatment
Group I: Phase 2Experimental Treatment1 Intervention
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.
Group II: Phase 1Experimental Treatment1 Intervention
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
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Johns Hopkins HospitalBaltimore, MD
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Who is running the clinical trial?
Johns Hopkins UniversityLead Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsLead Sponsor
Neurofibromatosis Therapeutic Acceleration ProgramCollaborator
References
Comprehensive pharmacological profiling of neurofibromatosis cell lines. [2020]Patients with Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are predisposed to tumors of the nervous system. NF1 patients predominantly develop neurofibromas, and Malignant Peripheral Nerve Sheath Tumors (MPNST) while NF2 patients develop schwannomas and meningiomas. Here we quantified the drug sensitivities of NF1 and NF2 tumor cell lines in a high throughput platform. The platform contained a comprehensive collection of inhibitors of MEK, RAF, RAS, farnesyl transferase, PAK and ERK, representative drugs against many other cancer pathways including Wnt, Hedgehog, p53, EGF, HDAC, as well as classical cytotoxic agents recommended for treating MPNST, such as doxorubicin and etoposide. We profiled seven NF1-associated MPNST cell lines (ST88-14, ST88-3, 90-8, sNF02.2, T265, S462TY, SNF96.2), one sporadic MPNST cell line (STS26), one schwannoma from a NF2 patient (HEI193), one NF2-deficient malignant meningioma (KT21-MG-Luc5D), one mouse NF2 schwannoma (SC4) and one sporadic rat schwannoma (RT4-67 or RT4). NF1 cells were primarily distinguished from NF2 cells and the sporadic MPNST cell line by their sensitivity to MEK and ERK inhibitors, and to a smaller extent their sensitivity to BH3 mimetics and farnesyl transferase inhibitors. The platform was highly successful in predicting the effects of clinical trials for Neurofibromas.
Selumetinib Shrinks Tumors in Neurofibromatosis. [2021]A new clinical trial suggests that the MEK inhibitor selumetinib induces partial responses in children with neurofibromatosis type 1 who have inoperable plexiform neurofibromas. The drug led to confirmed partial responses in 70% of patients; progression-free survival was 84% after 3 years.
Durable Complete Response of a Recurrent Mesencephalic Glioblastoma Treated with Trametinib and Low-Dose Dabrafenib in a Patient with Neurofibromatosis Type 1. [2020]Patients with neurofibromatosis type 1 (NF1) have an increased lifetime risk for the development of nervous system tumors, including high-grade gliomas (glioblastoma). NF1 is associated with the loss of expression of neurofibromin 1 (NF1 gene product). This hyperactivates the mitogen-activated protein kinase pathway, leading to cellular proliferation and survival. MEK-inhibitor monotherapy is a promising treatment strategy in this setting, but is associated with distinct adverse events, most prominently cutaneous toxicity. We report the case of a young NF1 patient with a recurrent, heavily pretreated mesencephalic glioblastoma who was treated with the MEK-inhibitor trametinib (2 mg once daily). A partial response was documented, but unfortunately, he developed dose-limiting cutaneous toxicity (rash, paronychia). Based on interim results of a phase 2 trial in advanced BRAF V600 wild-type melanoma indicating that a low dose of the BRAF-inhibitor dabrafenib is able to counter trametinib-related cutaneous toxicity, dabrafenib 50 mg twice daily was added. The cutaneous adverse events gradually recovered after addition of dabrafenib to trametinib. The patient eventually achieved a durable complete response, has excellent tolerance of his treatment and remains fully active.
NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas. [2022]Patients with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), which can cause significant morbidity. We performed a phase II trial of the MAPK/ERK kinase inhibitor, mirdametinib (PD-0325901), in patients with NF1 and inoperable PNs. The primary objective was response rate based on volumetric magnetic resonance imaging analysis.
FDA Approval Summary: Selumetinib for Plexiform Neurofibroma. [2022]On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. Approval was based on demonstration of a durable overall response rate per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and supported by observed clinical improvements in plexiform neurofibroma-related symptoms and functional impairments in 50 pediatric patients with inoperable plexiform neurofibromas in a single-arm, multicenter trial. The overall reponse rate per NCI investigator assessment was 66% (95% confidence interval, 51-79) with at least 12 months of follow-up. The median duration of response was not reached, and 82% of responding patients experienced duration of response ≥12 months. Clinical outcome assessment endpoints provided supportive efficacy data. Risks of selumetinib are consistent with MAPK (MEK) inhibitor class effects, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. Safety was assessed across a pooled database of 74 pediatric patients with plexiform neurofibromas and supported by adult and pediatric selumetinib clinical trial data in cancer indications. The benefit-risk assessment for selumetinib in patients with inoperable plexiform neurofibromas was considered favorable.
Neurofibromatosis in the Era of Precision Medicine: Development of MEK Inhibitors and Recent Successes with Selumetinib. [2022]Patients with neurofibromatosis type 1 (NF1) are at increased risk for benign and malignant neoplasms. Recently, targeted therapy with the MEK inhibitor class has helped address these needs. We highlight recent successes with selumetinib while acknowledging ongoing challenges for NF1 patients and future directions.
Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review. [2021]Neurofibromatosis type 1 (NF1) is a genetic disorder that carries a higher risk of tumor development. Plexiform neurofibromas (PNs) are present in 50% of NF1 and cause significant morbidity when surgery is not feasible. Systemic therapies had not succeeded to reduce PN tumor volume until 2016 when the first trial with an MAPK/extracellular-signal-regulated kinase (MEK) inhibitor was published. We performed a systematic research on novel targeted therapies for patients with NF1 and PNs in PubMed, EMBASE, and conference abstracts with the last update in February 2021. Since 2016, seven trials have reported positive results with MEK inhibitors and other molecular targeted therapies (cabozantinib). Selumetinib has shown an overall response rate of 68% in children with NF1 and symptomatic inoperable PNs, and was associated with pain improvement and a manageable adverse events profile. This led to Food and Drug Administration (FDA) approval of selumetinib in May 2020. Recently, cabozantinib and mirdametinib have also proven their efficacy in adult population. Other MEK inhibitors such as trametinib and binimetinib have also communicated promising preliminary results. Ongoing trials in different populations and with intermittent dosing strategies are underway.
A Review of Selumetinib in the Treatment of Neurofibromatosis Type 1-Related Plexiform Neurofibromas. [2022]To evaluate the safety and efficacy of selumetinib, a novel MEK inhibitor, for the treatment of plexiform neurofibromas (PN) in patients with neurofibromatosis type 1 (NF1).