AZD6244 for Neurofibromatosis

Not currently recruiting at 7 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests an experimental drug, AZD6244 hydrogen sulfate, to determine its effectiveness against tumors called plexiform neurofibromas. These tumors grow around nerves and are often difficult to remove completely with surgery. The trial aims to discover if the drug can stop, slow, or shrink these tumors. It seeks children and young adults with neurofibromas that cannot be fully removed by surgery. Participants must have these specific tumors and be able to swallow capsules. As a Phase 1, Phase 2 trial, this research focuses on understanding the treatment's effects in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking medical advancements.

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.

Is there any evidence suggesting that AZD6244 hydrogen sulfate is likely to be safe for humans?

Research has shown that AZD6244 hydrogen sulfate, also known as selumetinib, has been tested in both adults and children with certain types of cancer. Studies have found that this treatment can reduce the size of tumors in many patients with plexiform neurofibromas (PNs), which are tumors related to nerves. Reports from earlier trials indicate that this drug is generally well-tolerated. Most participants experience mild to moderate side effects, such as skin rashes or nausea, which are common with many medications. Serious side effects occur less frequently. These findings from trials with both adults and children indicate the drug's safety for treating plexiform neurofibromas. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about AZD6244 for neurofibromatosis because it offers a new approach to treating this condition. Unlike existing treatments that primarily focus on symptom management or surgical removal of tumors, AZD6244 targets the MEK pathway, a key player in cell growth and tumor development. This targeted action could potentially slow or stop tumor growth more effectively than current options. Additionally, AZD6244 is taken orally, providing a non-invasive alternative that could improve patient quality of life.

What evidence suggests that AZD6244 might be an effective treatment for plexiform neurofibromas?

Research has shown that AZD6244 hydrogen sulfate, also known as selumetinib, can help treat plexiform neurofibromas (PNs). Studies have found that it reduces the size of these tumors in most patients and slows their growth. In one study, 72% of patients experienced positive results, with many maintaining these improvements for over six months. For individuals with neurofibromatosis type 1 (NF-1), selumetinib significantly reduced tumor size and pain, making daily activities easier. These findings suggest that AZD6244 could be a promising treatment for tumors that cannot be surgically removed. ^{1 5 6 7 8}

Who Is on the Research Team?

Brigitte Widemann, MD

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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.

Clinical judgement by the investigator

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

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02407405

NCT02407405 | MEK 1/2 Inhibitor Selumetinib (AZD6244 ... Researchers want to test if the drug selumetinib (AZD6244 hydrogen sulfate) causes PNs to shrink or slows down their growth. Objectives: To test if selumetinib ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01362803

Study Details | NCT01362803 | AZD6244 Hydrogen Sulfate ... 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 ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2018.36.15_suppl.10503

SPRINT: Phase II study of the MEK 1/2 inhibitor selumetinib ... Conclusions: The response rate from this study (72%) confirms our previously observed response rate (71%). Most responses were sustained ≥6 ...

4. asco.org asco.org/abstracts-presentations/ABSTRACT301877

Phase II trial of the MEK 1/2 inhibitor selumetinib (AZD6244 ... Selumetinib shrinks the majority of adult PN and results in molecular target suppression and clinical benefit.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11265740/

Selumetinib—A Comprehensive Review of the New FDA ... It has shown good results in the treatment of NF-1-associated PNs, with significant reductions in tumor volume and pain, resulting in better function and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10318822/

Phase 1 dose-escalation study to evaluate the safety ... The response rate of selumetinib in the treatment of pediatric patients with NF1-related PN was approximately 40–70% [21, 22, 30, 31], whilst ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.3612

Phase II trial of the MEK 1/2 inhibitor selumetinib (AZD6244 ... Conclusions: Selumetinib shrinks the majority of adult PN and results in molecular target suppression and clinical benefit. Clinical trial ...

8. asco.org asco.org/abstracts-presentations/ABSTRACT506266

Efficacy and safety of selumetinib in adults with ... Conclusions: In the first international, randomized, placebo-controlled trial in adults with NF1-PN, SELU achieved a significant ORR vs PBO (C16), meeting the ...