MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas

• Register: ClinicalTrials.gov
• Last refreshed on: 27 February 2024
• Main ID: NCT02407405
• Date of registration: 02/04/2015
• Prospective Registration: Yes
• Primary sponsor: National Cancer Institute (NCI)
• Public title: MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas
• Scientific title: Phase II Trial of the MEK1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas
• Date of first enrolment: January 7, 2016
• Target sample size: 36
• Recruitment status: Active, not recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT02407405
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2

Countries of recruitment

United States

Contacts

• Name: Brigitte C Widemann, M.D.
• Affiliation: National Cancer Institute (NCI)

Key inclusion & exclusion criteria

- INCLUSION CRITERIA:

- Patients must have positive genetic testing for NF1in a CLIA certified laboratory or a
diagnosis of NF1 based on clinical NIH consensus criteria51 of at least one other
diagnostic criterion in addition to the presence of a PN. NF1 mutation analysis will
be performed on germline DNA as described by Messiaen & Wimmer 52. Histologic
confirmation of tumor is not necessary in the presence of consistent clinical and
imaging findings, but should be considered if malignant transformation of a PN is
clinically suspected. Additional criteria are as follows:

- Six or more cafe-au-lait macules (greater than or equal to 0.5cm in prepubertal
subjects or greater than or equal to1.5 cm in post pubertal subjects)

- Freckling in axilla or groin

- Optic glioma

- Two or more Lisch nodules

- A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or
thinning of long bone cortex)

- A first-degree relative with NF1

- Measurable disease: Patients must have at least one measurable PN, defined as a lesion
of at least 3 cm measured in one dimension. Patients who underwent surgery for
resection of a PN are eligible provided the PN was incompletely resected and is
measurable as per criteria above. Measurability and suitability for volumetric MRI
analysis of the target PN must be confirmed with the NCI POB prior to enrolling a
patient. The target PN will be defined as the clinically most relevant PN, which has
to be amenable to volumetric MRI analysis. PN will be classified as typical PN versus
nodular PN versus solitary nodular PN prior to enrollment

- The PN must be inoperable, defined as a PN that cannot be surgically completely
removed without risk for substantial morbidity due to: encasement of or close
proximity to vital structures, invasiveness, or high vascularity of the PN. The PN
either causes morbidity or it is growing and has the potential to cause morbidity such
as (but not limited to): Head and neck lesions that could compromise the airway or
great vessels, paraspinal lesions that can cause myelopathy, brachial or lumbar plexus
lesions that could cause nerve compression and loss of function, lesions that could
result in major deformity (e.g., orbital lesions) or are significantly disfiguring,
and lesions of the extremity that cause limb hypertrophy or loss of function or pain.
PN growth will be defined as a greater than or equal to 20% increase in PN volume
within approximately 3 years prior to enrollment on this trial.

- Patients must have a PN amenable to a percutaneous biopsy to participate in the biopsy
portion of this study, and must be willing to undergo pre-, and on treatment tumor
biopsies. There should be no contraindication for serial biopsies. NOTE: 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.

- Must be able to undergo serial MRI scans for response evaluation

- Age greater than or equal to 18 years

- ECOG performance status less than or equal to 2 (Patients who are wheelchair bound
because of paralysis secondary to a plexiform neurofibroma should be considered
ambulatory when they are up in their wheelchair. Similarly, patients with limited
mobility secondary to need for mechanical support (such as an airway PN requiring
tracheostomy or CPAP) will also be considered ambulatory for the purpose of the
study.)

--ECOG Performance Status:*

- Grade/ECOG

- 0 Fully active, able to carry on all pre-disease performance without restriction

- 1 Restricted in physically strenuous activity but ambulatory and able to carry
out work of a light or sedentary nature, e.g., light house work, office work

- 2 Ambulatory and capable of all self-care but unable to carry out any work
activities. Up and about more than 50% of waking hours

- 3 Capable of only limited self-care, confined to bed or chair more than 50% of
waking hours

- 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or
chair

- 5 Dead

- As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C.,
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol
5:649-655, 1982.

- Patients must have normal organ and marrow function as defined below:

- hemoglobin greater than or equal to 10 g/dL (not requiring RBC transfusions)

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL (not requiring platelet
transfusions)

- total bilirubin less than or equal to 1.5 upper limit of normal (ULN), with the
exception of patients with Gilbert Syndrome

- ALT(SGPT) & AST(SGOT) less than or equal to 3.0 X ULN

- upper limit of normal institutional limits

- OR

- creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients
with creatinine levels above institutional normal.

- Hematologic parameters for patients undergoing biopsy only: Patients should have INR
less than or equal to 1.4 and PT less than or equal to 40 seconds (unless due to lupus
anticoagulant). In patients not meeting these parameters, clearance by hematology will
be required prior to undergoing a biopsy.

- Cardiac Function: Normal ejection fraction (ECHO) greater than or equal to 53% (if a
range is given then the upper value of the range will be used) or cardiac MRI; QTcF
less than or equal to 450 msec.

- Ability of subject or Legally Authorized Representative (LAR)) to understand and the
willingness to sign a written informed consent document.

- Willingness to avoid excessive sun exposure and use adequate sunscreen protection if
sun exposure is anticipated.

- Willingness to avoid the ingestion of grapefruit and Seville oranges (as well as other
products containing these fruits, e.g. grapefruit juice or marmalade) during the
study.

- Prior therapy: Patients with NF1 will only be eligible if complete tumor resection is
not considered to be feasible without substantial risk or morbidity, or if a patient
with a surgical option refuses surgery.

- Since there is no standar


Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Neurofibromatosis 1 (NF1)

Plexiform Neurofibromas (PN)

Intervention(s)

Drug: Selumetinib

Primary Outcome(s)

Determine objective response rate [Time Frame: at each response evaluation visit]

Secondary Outcome(s)

Analyze paired biopsies with mechanisms of response and resistance [Time Frame: Prior to cycle 2 or 3, at time of progression and/or prior to cycle 2 or 3 after dose reduction]

correlate 3D MRI responses with % target inhibition of pERK in PN biopsies [Time Frame: rior to cycle 5, 9, 13, 17, 21, 25 Then after every 6 cycles]

determine time to progression and progression free survival [Time Frame: at time of progression]

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]

Analyze bone marrow derived precursor cells and cytokines before and after treatment [Time Frame: Prior to cycle 3, 5, 9, 13]

characterize effects on pain, quality of life, physical functioning [Time Frame: Prior to cycle 3, 5, 9, 13, Then after every 12 cycles]

evalaute change in dermal neurofibroma by photography. [Time Frame: Prior to cycle 5, 9, 13, 17, 21, 25 Then after every 12 cycles]

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]

Secondary ID(s)

160043

16-C-0043

Source(s) of Monetary Support

Please refer to primary and secondary sponsors