Mitogen Activated Protein Kinase Kinase (MEK1/2) Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in People With Neurofibromatosis Type 1 (NF1) Mutated Gastrointestinal Stromal Tumors (GIST)

Neurofibromatosis 1 Clinical Trial

Official title: A Phase II Trial of the Mitogen Activated Protein Kinase Kinase (MEK1/2) Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Patients With Neurofibromatosis Type 1 (NF1) Mutated Gastrointestinal Stromal Tumors (GIST)

Status Withdrawn

Clinical Trial Summary

Background:

Gastrointestinal stromal tumors (GIST) can cause serious medical problems. The only known treatment is surgery. But completely removing a GIST tumor with surgery is often not possible. Researchers want to see if a new drug, selumetinib, can help treat these tumors.

Objective:

To find out if selumetinib shrinks or slows the growth of GIST tumors and to see its side effects.

Eligibility:

People ages 3 and over who have one or more GIST tumors and may have neurofibromatosis type I (also called NF1). Their NF1 GIST has shown some growth or cannot be completely removed with surgery.

Design:

Participants will be screened with heart and eye tests and scans.

Participants will be told what foods and medicines they cannot take during the study. Participants will keep a diary of the medicine they take during the study.

Participants will take selumetinib capsules twice daily on an empty stomach for 28 days in a row. This is 1 cycle.

During the cycles, participants will have study visits. These may include:

Medical history

Physical exam

Blood and urine tests

Heart tests

Scans of their tumors

Eye exam

Positron emission tomography scan. They will be get radioactive glucose an IV line. They will lie quietly in a darkened room for 50-60 minutes then have the scan.

Participants will answer questions about how they are feeling.

Participants can stay in the study until they have bad side effects or their tumor grows.

After finishing treatment, participants will be watched for side effects for 30 days.

Clinical Trial Description

BACKGROUND:

• Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract, and traditional cytotoxic chemotherapy is not effective. Patients with Neurofibromatosis 1 (NF1) have an increased risk of developing GIST, and surgery remains the only standard treatment option for NF1-related GIST. While the tyrosine kinase inhibitors (TKIs) imatinib and sunitinib prolong survival in patients with KIT/PDGFRA mutated GIST, they have no documented efficacy in patients with NF1 related GISTs, which lack KIT/PDGFRA mutations. Radiation therapy also seems to be ineffective. Therefore, new therapies are needed.

• Selumetinib (AZD6244 hyd sulfate), a novel orally bioavailable mitogen activated protein kinase inhibitor, is a specific inhibitor of MEK 1/2, which is currently undergoing evaluation in adults with refractory cancers, in adults and children with NF1 and plexiform neurofibromas (PN) and children with brain tumors. Evaluation of selumetinib in children and young adults with NF1 related plexiform neurofibromas (PN) has demonstrated activity with most patients demonstrating some PN shrinkage, and a partial response rate of 71%. Selumetinib has also demonstrated activity in children with NF1 and low-grade gliomas. It is thus possible that selumetinib may mediate anti-tumor effects in NF1 GIST by inhibition of downstream signaling of Ras.

OBJECTIVES:

• To estimate the response rate (radiologic response as defined by RECIST v1.1) of selumetinib in children and adults with measurable NF1-mutated GIST which is unresectable, progressive or metastatic.

ELIGIBILITY:

• Patients who are greater than or equal to 3 years of age and able to swallow capsules, with a histologically or cytologically confirmed measurable GIST without Kit or PDGFRA mutation, who have a clinical diagnosis of NF1 or a mutation of NF1 in the GIST.

• Patients tumors must demonstrate progression within the past 12 months or be metastatic; patients who do not meet this criterion will be followed, on the NF1 Natural History Study if appropriate; in the event that they demonstrate subsequent progression they may be enrolled.

• Patients must have adequate major organ function, adequate performance status, and normal LVEF by ECHO.

• No prior medical therapy is required; patients should have surgical resection if this is deemed feasible without unacceptable morbidity. Patients must meet the time requirements since prior therapy and have recovered from prior therapy toxicities.

• No prior treatment with selumetinib or another specific MEK1/2 inhibitor is permitted.

DESIGN:

• Selumetinib will be administered at a starting dose of 50 mg/dose orally in patients 18 years or older and 25 mg/m^2/dose in children < 18 years of age; drug will be given twice daily continuously in the absence of toxicity or disease progression, using 28-day cycles. The pediatric dose is the recommended phase II dose of selumetinib determined in a CTEP sponsored phase I trial of selumetinib for children and young adults with NF1 and inoperable plexiform neurofibromas, and the adult dose is equal to that used in our phase II study of adults with NF1 and inoperable PN. Adults will be allowed a one-time intrapatient dose escalation to 75mg BID provided the drug is well tolerated during the first cycle. Patients will be asked to co-enroll on POB protocol 10-C-0086: "Comprehensive Omics Analysis of Pediatric Solid Tumors and Establishment of a Repository for Related Biological Studies and 08-C-0079: Natural History Study and Longitudinal Assessment of Children, Adolescents, and Adults with Neurofibromatosis Type 1".

• Patients will be monitored for toxicity and response.

• Response will be assessed on a regular schedule. FDG-PET will be obtained at baseline prior to therapy, on day 11 (+/- 3 days) to assess for early FDG-PET response (optional), after 3 cycles and as clinically indicated.

• This study will use a Simon optimal two-stage phase II design with a target response rate of 25%, enrolling a minimum of 7 and a maximum of 16 evaluable patients. A maximum accrual of 20 patients may be accrued allowing for a small number (4) of inevaluable patients. ;

Related Conditions & MeSH terms

• Gastrointestinal Stromal Tumors
• Heredodegenerative Disorders, Nervous System
• Neoplasms, Nerve Tissue
• Nervous System Diseases
• Neurofibroma
• Neurofibromatoses
• Neurofibromatosis 1
• Peripheral Nervous System Diseases

• NCT number: NCT03109301
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Withdrawn
• Phase: Phase 2
• Start date: April 7, 2017
• Completion date: March 27, 2019