MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas
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|ClinicalTrials.gov Identifier: NCT02407405|
Recruitment Status : Recruiting
First Posted : April 3, 2015
Last Update Posted : October 8, 2020
Neurofibromatosis type 1 (NF1) is a disorder that can cause plexiform neurofibromas (PNs). These are tumors that grow along nerves. Some PNs cause serious health problems. PNs often can t be operated on because of their large size, location, or number. There are no effective treatments known for people with NF1 and PNs. Researchers want to test if the drug selumetinib (AZD6244 hydrogen sulfate) causes PNs to shrink or slows down their growth.
To test if selumetinib helps treat PNs. To test how the body handles selumetinib and how it affects peoples symptoms.
People ages 18 and older with NF1, with an inoperable PN that causes morbidity or is growing
Participants will be screened with:
Medical history and physical exam
Blood, urine, and heart tests
MRI: They lie in a machine that takes pictures of the body.
PN biopsy: A small piece of the tumor is removed by a large needle.
Participants will swallow selumetinib capsules every 12 hours for several 28-day cycles. The capsules are taken with a full glass of water on an empty stomach. Participants may have only water for 2 hours before and 1 hour after each dose.
Participants will keep a drug diary. They will continue taking the drug as long as they tolerate it and their disease doesn t progress.
Participants will have several visits throughout the study. These will include repeats of the screening tests.
Participants will have a final visit after they stop taking selumetinib.
|Condition or disease||Intervention/treatment||Phase|
|Neurofibromatosis 1 (NF1) Plexiform Neurofibromas (PN)||Drug: Selumetinib||Phase 2|
- Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with an incidence of 1:3500 in the US. One of the cardinal features of NF1 is the development of histologically benign peripheral nervesheath tumors called plexiform neurofibromas (PN) in 25-40% of individuals with NF1. Unlike discrete neurofibromas, PN grow along the length of nerves and involve multiple branches of a nerve. They are a major source of morbidity, causing disfigurement, impairment of nerve function, pain, and in some cases development of malignant peripheral nerve sheath tumors.
- Selumetinib (AZD6244) is a novel orally bioavailable mitogen activated protein kinase inhibitor, is a specific inhibitor of MEK 1/2, which may mediate anti-tumor effects in PN by inhibition of downstream signaling of Ras. Selumetinib is currently undergoing evaluation in adult cancers and children with brain tumors and NF1-related plexiform neurofibromas.
- In an NCI phase I trial of selumetinib for children and young adults with NF1 and inoperable PN we have observed preliminary activity with PN volume decrease in >50% of patients enrolled. This degree of activity has not been observed in prior trials directed at PN. While preliminary activity has been seen in most patients enrolled to date, in several patients who required (Bullet) 1 dose reduction for toxicity, after an initial volume decrease, the PN volumes appear to be increasing slowly, and in one patient a nodular appearing lesion is not responding to selumetinib. These findings suggest that not all PN types may be responsive to selumetinib and that a certain selumetinib tissue concentration may be required for target inhibition and anti-tumor activity.
-Determine the objective response rate (PN volume decrease greater than or equal to 20% compared to baseline) to selumetinib in adult patients with inoperable PN.
- Patients must be at least 18 years of age with a diagnosis of NF1, with an inoperable, measureable PN that causes morbidity or is growing, which is amenable to percutaneous biopsy, and must be willing to undergo two biopsies.
- Up to 10 patients who meet all criteria, but have PN, which cannot be biopsied safely, will be eligible for the treatment portion of the study.
- Patients must have adequate organ function, be able to undergo serial MRI scans and have recovered from acute toxicity of all prior treatment.
- This is a single site open label phase II study in which all subjects will receive selumetinib orally approximately every 12 hours until patient develops progression of disease, unacceptable toxicity or, in patients with non-progressive, symptomatic PN at enrollment, a maximum of 2 years (unless they experience a partial response, or an improvement in symptoms or function in which case they may continue until progression of disease).
- Selumetinib will be administered at a dose of 50 mg BID on a continuous dosing schedule (1 cycle=28 days), which is the recommended adult dose. A maximum accrual of 35 evaluable patients to meet the primary objective; while a maximum of 60 patients in total may be enrolled to allow for a small number of screen failures, inevaluable patients and up to 10 patients who cannot safely undergo two biopsies of PNs. Enrollment will proceed over approximately 24 months.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||60 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase II Trial of the MEK1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas|
|Actual Study Start Date :||January 7, 2016|
|Estimated Primary Completion Date :||January 1, 2025|
|Estimated Study Completion Date :||January 1, 2025|
selumetinib 50 mg BID daily
orally 50 mg/dose, every 12 hours every day continuously (1 cycle = 28 days)
- Determine objective response rate [ Time Frame: at each response evaluation visit ]Efficacy
- Correlate 3D MRI responses with % target inhibition of pERK in PN biopsies [ Time Frame: Prior to cycle 5, 9, 13, 17, 21, 25 Then after every 6 cycles ]Correlate 3D MRI responses with % target inhibition of pERK in PN biopsies
- Analyze paired biopsies with mechanisms of response andresistance [ Time Frame: Prior to cycle 2 or 3, at time of progression and/or prior to cycle 2 or 3 after dose reduction ]Analyze paired biopsies with mechanisms of response andresistance
- Compare pERK inhibition in dermal neurofibromas and PN [ Time Frame: Prior to cycle 2 or 3, at time of progression and/or prior to cycle 2 or 3 after dose reduction ]Compare pERK inhibition in dermal neurofibromas and PN
- Evaluate immune infiltrate of PN and Peripheral blood for circulating tumor cells [ Time Frame: Prior to cycle 2 or 3, at time of progression and/or prior to cycle 2 or 3 after dose reduction ]Evaluate immune infiltrate of PN and Peripheral blood for circulating tumor cells
- Analyze bone marrow derived precursor cells and cytokines before and after treatment [ Time Frame: Prior to cycle 3, 5, 9, 13 ]Analyze bone marrow derived precursor cells and cytokines before and after treatment
- Characterize effects on pain, quality of life, physical functioning [ Time Frame: Prior to cycle 3, 5, 9, 13, Then after every 12 cycles ]Characterize effects on pain, quality of life, physical functioning
- Determine time to progression and progression free survival [ Time Frame: at time of progression ]Time to progression and progression free survival
- Evaluate change in dermal neurofibroma by photography. [ Time Frame: Prior to cycle 5, 9, 13, 17, 21, 25 Then after every 12 cycles ]Evaluate change in dermal neurofibroma by photography.
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): NCT02407405
|Contact: Amanda M Carbonell||(240) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office 888-624-1937|
|Principal Investigator:||Brigitte C Widemann, M.D.||National Cancer Institute (NCI)|