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: 13 June 2016
• Main ID: NCT02644512
• Date of registration: 31/12/2015
• Prospective Registration: No
• 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: December 2015
• Target sample size: 50
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/show/NCT02644512
• Study type: Interventional
• Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
• Phase: Phase 2

Countries of recruitment

United States

Contacts

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

• Name: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

• Name: Patricia Whitcomb, R.N.

Key inclusion & exclusion criteria

- Inclusion Criteria:

- Patients must have a documented germline NF1 mutation in 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 caf(SqrRoot)(Copyright)-au-lait macules ( (Bullet)0.5cm in prepubertal
subjects or (Bullet)1.5 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 (See

section 3.1 and Appendix I).

-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, 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 (Bullet)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 > 18 years

- ECOG performance status < 2

--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 > 10 g/dL (not requiring RBC transfusions)

- absolute neutrophil count > 1,500/mcL

- platelets > 100,000/mcL (not requiring platelet transfusions)

- total bilirubin < 1.5 upper limit of normal (ULN), with the exception of
patients with Gilbert Syndrome

- ALT(SGPT) & AST(SGOT) < 3.0 X ULN

- creatinine within normal institutional limits

OR

--creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above
institutional normal.

- Hematologic parameters for patients undergoing biopsy only: Patients should have INR
< 1.4 and PT 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) (Bullet) 53% (if a range is given
then the upper value of the range will be used) or cardiac MRI; QTcF 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 standard effective chemotherapy for patients with NF1 and PN, patients
may be treated on this trial without having received prior medical therapy directed at
their PN.

Since selumetinib is not expected to cause substantial myelosuppression, there will be no
limit to number of prior myelosuppressive regimen for PN or other tumor manifestations
associated with NF1 such as optic glioma.

Patients who have received previous investigational agents or biologic therapy, such as
tipifarnib, pirfenidone, Peg-Intron, sorafenib, or other VEGFR inhibitors are eligible for
enrollment.

Growth factors that support platelet or white cell number or function must not have been
administered within the past 7 days and are not permitted while on the study.

At least 6 weeks must have elapsed prior to enrol


Age minimum: 18 Years
Age maximum: 99 Years
Gender: Both

Health Condition(s) or Problem(s) studied

Plexiform Neurofibromas

Neurofibromatosis 1

Intervention(s)

Drug: Selumetinib

Primary Outcome(s)

Objective response rate [Time Frame: at each response evaluation visit]

Secondary Outcome(s)

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 dosereduction]

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]

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

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]

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]

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

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]

Secondary ID(s)

160043

16-C-0043

Source(s) of Monetary Support

Please refer to primary and secondary sponsors