AZD6244 for Neurofibromatosis

Recruiting at 6 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Antiretrovirals, Vitamin E

Disqualifiers: Pregnancy, Severe disease, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

99 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, it advises avoiding medications that affect certain liver enzymes (CYP1A2, CYP2C19, and CYP3A4) as they may interfere with the study drug. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug AZD6244 Hydrogen Sulfate for treating Neurofibromatosis?

There is no direct data on AZD6244 Hydrogen Sulfate for Neurofibromatosis, but similar treatments like AZD8055, which targets related pathways, have shown promise in reducing tumor growth in similar conditions. ^{1 2 3 4 5}

Is AZD6244 safe for humans?

Selumetinib, another name for AZD6244, has been used in children with neurofibromatosis type 1 and showed symptom improvement with an acceptable safety profile, meaning it was generally safe for use. ^{6 7 8 9 10}

How does the drug AZD6244 differ from other treatments for neurofibromatosis?

AZD6244, also known as selumetinib, is unique because it specifically targets the MEK enzyme, which is part of a pathway that promotes tumor growth in neurofibromatosis. This targeted approach is different from other treatments that may not specifically inhibit this pathway. ^{4 8 11 12 13}

What is the purpose of this trial?

Background: - Plexiform neurofibromas are tumors that grow in and around nerves. The only way to treat them is with surgery. Some of these tumors cannot be completely removed. The tumors may be too large, too numerous, or in a bad location for surgery. An experimental drug called AZD6244 hydrogen sulfate may be able to prevent the tumors from growing, slow down their growth, or shrink them. This drug has been tested in adults with cancer and in children with some types of brain cancer. This study will test how well this drug works with these types of tumors. Objectives: - To study the safety and effectiveness of AZD6244 hydrogen sulfate in children and young adults with plexiform neurofibromas that cannot be completely removed by surgery. Eligibility: - Children and young adults between 12 and 18 years of age who have plexiform neurofibromas that cannot be completely removed by surgery. Design: * Patients will be screened with a physical exam, medical history, blood tests, and imaging studies. * They will take the study drug twice a day with 8 ounces of water, every day for 28-day cycles of treatment. During study visits, participants will have blood and urine tests and physical exams. They will also have imaging studies to examine the tumor sizes and locations. They will answer questions about their health. They may have other tests as needed. * Participants will continue to receive the study drug as long as they have no severe side effects and the disease is not getting worse.

Research Team

Brigitte Widemann, MD

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for children and young adults aged 2 to 18 with inoperable plexiform neurofibromas, a type of nerve tumor. Participants must be able to swallow capsules, have no severe allergies to the drug's ingredients, and not require surgery within the first three months. They should also have normal organ function and not be on certain other medications or treatments.

Inclusion Criteria

I am mostly active and can care for myself.

My kidney function is normal or only mildly impaired.

I have been diagnosed with or tested positive for NF1.

Exclusion Criteria

I cannot swallow pills.

I am currently receiving cancer treatment such as radiation, chemotherapy, or immunotherapy.

Clinical judgement by the investigator

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment Phase I

Determine the maximum tolerated dose (MTD) of selumetinib and evaluate acute and chronic toxicities

12 weeks

Regular visits for dose escalation and monitoring

Treatment Phase II

Evaluate the confirmed partial and complete response rate of selumetinib using volumetric MRI analysis

Ongoing, with evaluations prior to cycles 5, 6, 13, 17, 21, 25 and then every 6 cycles

Regular visits for MRI and response evaluations

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• AZD6244 Hydrogen Sulfate

Trial Overview The study tests AZD6244 hydrogen sulfate's ability to stop growth or shrink inoperable plexiform neurofibromas in children. The treatment involves taking the drug twice daily over cycles of 28 days with regular health checks, blood tests, urine tests, and imaging studies.

Participant Groups

Group I: Arm 2 Experimental Treatment 1 Intervention

Phase 2: AZD6244 PO BID x 28 DAYS

Group II: Arm 1 Experimental Treatment 1 Intervention

Phase 1: AZD6244 PO BID x 28 DAYS

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 807 patients with neurofibromatosis type 2 (NF2), the median age of onset was 24 years, and the most common symptoms included bilateral cranial nerve tumors and hearing loss, highlighting the diverse clinical features of NF2.

Significant risk factors for progressive disability in NF2 patients included being diagnosed before age 25, having a family history of NF2, and experiencing specific neurologic deficits like hearing loss and facial paresis, indicating that early intervention may be crucial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Characteristics and Progressive Disability in Neurofibromatosis Type 2. Iwatate, K., Yokoo, T., Iwatate, E., et al.[2017]

In a phase II clinical trial involving 19 patients with Neurofibromatosis type 1 (NF1) and progressive plexiform neurofibromas (PNs), cabozantinib demonstrated efficacy, with 42% of participants achieving a partial response, defined as a ≥20% reduction in tumor volume after 12 cycles of treatment.

Cabozantinib was associated with significant reductions in tumor pain intensity and interference in daily life, although common adverse events included gastrointestinal issues and fatigue, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial. Fisher, MJ., Shih, CS., Rhodes, SD., et al.[2023]

In a national case series of 19 children with neurofibromatosis type 1-associated plexiform neurofibromas, treatment with selumetinib led to symptom improvement or stabilization in all patients, demonstrating its efficacy.

Selumetinib, an oral selective inhibitor of the RAS-MAPK pathway, was well-tolerated with an acceptable toxicity profile, confirming its safety and effectiveness in a real-world setting, even for those previously treated with other medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selumetinib for symptomatic, inoperable plexiform neurofibromas in children with neurofibromatosis type 1: A national real-world case series. Coltin, H., Perreault, S., Larouche, V., et al.[2022]

Cantharidin, a protein phosphatase 2A (PP2A) inhibitor, was found to effectively slow down the growth of malignant peripheral nerve sheath tumor (MPNST) cells in patients with neurofibromatosis type 1 (NF1).

Nifedipine, an L-type calcium channel blocker, significantly reduced local tumor growth in an animal model of MPNST, suggesting that both Cantharidin and Nifedipine could be promising candidates for further preclinical studies in treating NF1-related tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Medium throughput biochemical compound screening identifies novel agents for pharmacotherapy of neurofibromatosis type 1. Semenova, G., Stepanova, DS., Deyev, SM., et al.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Population Characteristics and Progressive Disability in Neurofibromatosis Type 2. [2017]

2. United States pubmed.ncbi.nlm.nih.gov

Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Metalloproteinase 1 downregulation in neurofibromatosis 1: Therapeutic potential of antimalarial hydroxychloroquine and chloroquine. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Sulindac derivatives inhibit cell growth and induce apoptosis in primary cells from malignant peripheral nerve sheath tumors of NF1-patients. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Selumetinib for symptomatic, inoperable plexiform neurofibromas in children with neurofibromatosis type 1: A national real-world case series. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Improving outcomes for neurofibromatosis 1-associated brain tumors. [2015]

8. France pubmed.ncbi.nlm.nih.gov

Medium throughput biochemical compound screening identifies novel agents for pharmacotherapy of neurofibromatosis type 1. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Subsequent Neoplasms After a Primary Tumor in Individuals With Neurofibromatosis Type 1. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Visual spatial learning outcomes for clinical trials in neurofibromatosis type 1. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Nilotinib is more potent than imatinib for treating plexiform neurofibroma in vitro and in vivo. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Silver Nanoparticles Selectively Treat Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors in a Neurofibromin-Dependent Manner. [2022]

13. United States pubmed.ncbi.nlm.nih.gov

Enhanced proliferation and potassium conductance of Schwann cells isolated from NF2 schwannomas can be reduced by quinidine. [2013]