MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas (RENEU)
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|ClinicalTrials.gov Identifier: NCT03962543|
Recruitment Status : Recruiting
First Posted : May 24, 2019
Last Update Posted : September 11, 2019
|Condition or disease||Intervention/treatment||Phase|
|Plexiform Neurofibroma Neurofibromatosis Type 1 (NF1)||Drug: PD-0325901 oral capsule||Phase 2|
Neurofibromas are benign peripheral nerve sheath tumors, which are classified as plexiform neurofibromas (PNs) if they extend longitudinally along a nerve and involve multiple fascicles. PNs are a major cause of morbidity and disfigurement in individuals with NF1, and as the tumor growth progresses, can cause a multitude of clinical deficits including pain and impaired physical function. PNs have the potential to undergo malignant transformation to Malignant Peripheral Nerve Sheet Tumors (MPNST).
PD-0325901 is an orally delivered, highly selective small-molecule inhibitor of the dual specificity kinases, MEK1 and MEK2 (MAPK/ERK Kinase) which prevents the phosphorylation and subsequent activation of mitogen-activated protein kinase (MAPK).
Previous studies of PD-0325901 demonstrated PN shrinkage and sustained inhibition of pERK. Reduced tumor volume indicated that cell proliferation or cell death may be altered in PNs with administration of PD-0325901.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||100 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||All participants will receive PD-0325901 at a dose of 2 mg/m^2 twice daily (maximum dose of 4 mg twice daily), calculated based on body surface area. Dose will be administered in a 3-week on, 1-week off schedule.|
|Masking:||None (Open Label)|
|Official Title:||A Phase 2b Trial of the MEK 1/2 Inhibitor (MEKi) PD-0325901 in Adult and Pediatric Patients With Neurofibromatosis Type 1 (NF1)-Associated Inoperable Plexiform Neurofibromas (PNs) That Are Causing Significant Morbidity|
|Actual Study Start Date :||September 6, 2019|
|Estimated Primary Completion Date :||July 31, 2022|
|Estimated Study Completion Date :||July 31, 2022|
PD-0325901 capsule 2 mg/m^2 (maximum dose of 4 mg) by mouth twice daily
Drug: PD-0325901 oral capsule
Other Name: PD-0325901
- Complete or partial response rate compared to baseline. Partial response is defined as a ≥ 20% reduction in target tumor volume. [ Time Frame: Up to 24 months ]Response will be determined by a blinded centralized review of volumetric MRI.
- Incidence of treatment-emergent adverse events [ Time Frame: Up to 24 months ]Adverse events will be assessed according to toxicities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
- Duration of response (DOR) for participants who meet criteria for objective response rate. [ Time Frame: Up to 24 months ]Response will be determined by a blinded centralized review of volumetric MRI.
- Change from Baseline on quality of life as measured by the Pediatric Quality of Life Inventory (PedsQL), Acute version. [ Time Frame: Up to 24 months ]The PedsQL consists of a 23-item core measure of global QOL that can be completed in approximately 5 minutes. There are four subscales: physical functioning, emotional functioning, social functioning and school/work functioning. Participants ≥ 5 years of age complete an age-appropriate self-report; and parents/guardians of children ages 2-17 complete a parent proxy report of the age-specific QOL. The recall period is 7 days.
- Change from Baseline in pain as measured by the Numeric Rating Scale-11 (NRS-11). [ Time Frame: Up to 24 months ]The NRS-11 is a self-reported 11-point numerical scale that assesses pain severity. Participants ≥ 8 years of age are asked to select a number from 0 (no pain) to 10 (worst pain you can imagine) that best describes their worst pain. The recall period is 24 hours.
- Change from Baseline in pain as measured by the Pain Interference Index (PII). [ Time Frame: Up to 24 months ]The PII assesses relevant aspects of one's life, including pain interference with activities, spending time with family/friends, mood, sleep and attention. Participants ≥ 6 years of age complete a self-report, and parents/guardians of children age 6-17 complete a parent proxy report. The recall period is 24 hours.
- Change from Baseline in physical function status as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS): physical function/mobility/upper extremity short forms (8a and 8b). [ Time Frame: Up to 24 months ]PROMIS measures capability of physical functioning, with questions related to daily activities. Participants ≥ 18 years of age complete a self-report of physical function. Participants 8-17 years of age complete a self-report of physical function in the upper extremity or lower extremity (mobility), depending on location of the PN. Parents/guardians of children ages 2-17 complete a parent proxy report corresponding to the pediatric version. The recall period is 7 days.
- Change from Baseline in localized strength. [ Time Frame: Up to 24 months ]
- Change from Baseline in range of motion of PN-associated functional impairment. [ Time Frame: Up to 24 months ]
- Change from Baseline in endurance. [ Time Frame: Up to 24 months ]
- Time to Response defined as the time between first dose and the first date of objective response. [ Time Frame: Up to 24 months ]Response will be determined by a blinded centralized review of volumetric MRI.
- Time to progression, from the first dose to the date of a ≥ 20% increase in tumor volume. [ Time Frame: Up to 24 months ]Evidence of progression or tumor growth will be determined by a blinded centralized review of volumetric MRI.
- Progression Free Survival, defined as the time in months from the first dose to the date of a ≥ 20% increase in tumor volume or death. [ Time Frame: Up to 24 months ]Evidence of progression or tumor growth will be determined by a blinded centralized review of volumetric MRI.
- Change from Baseline in PN-associated disfigurement using standardized photography, centrally reviewed. [ Time Frame: Up to 24 months ]For participants with a PN that is visible and amenable to photography, changes in visible tumor aspects will be evaluated by a centralized reviewer.
- Comparison of tumor response to levels of pERK and biomarkers indicative of inhibition of downstream targets of MEK (eg, ERK phosphorylation). [ Time Frame: Up to 24 months ]Measured in tumor biopsies in participants ≥ 18 years of age.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03962543
|Contact: Nicole H Leedomfirstname.lastname@example.org|
|United States, Arkansas|
|Arkansas Children's Hospital||Recruiting|
|Little Rock, Arkansas, United States, 72202|
|Contact: Susan Hall, SC email@example.com|
|Principal Investigator: Kevin Bielamowicz, MD|
|United States, North Carolina|
|UNC Medical Center||Recruiting|
|Chapel Hill, North Carolina, United States, 27514|
|Contact: Shelia Joshi, SC firstname.lastname@example.org|
|Principal Investigator: Timothy R. Gershon, MD, PhD|