Selumetinib Granules for Neurofibromatosis

(SPRINKLE Trial)

Recruiting at 40 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: AstraZeneca

Must not be taking: MEKi, Herbal supplements

Disqualifiers: Malignant glioma, Cardiovascular disease, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 25 cycles (each cycle is 28 days)

36 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests selumetinib granules in children aged 1 to 7 years with inoperable NF1-related tumors. The medication works by blocking signals that make the tumors grow. The study aims to find the right dose and check if it's safe and effective.

Will I have to stop taking my current medications?

The trial requires that participants stop taking herbal supplements or medications that strongly affect certain liver enzymes (CYP3A4 and CYP2C19) at least 14 days before starting the study medication. If you are taking such medications, you may need to stop them.

What data supports the effectiveness of the drug Selumetinib for treating neurofibromatosis?

Selumetinib has been shown to be effective in treating children with neurofibromatosis type 1 who have inoperable plexiform neurofibromas, with a 66% response rate in a clinical trial. Most patients who responded to the treatment experienced benefits lasting at least 12 months. ^{1 2 3 4 5}

Is Selumetinib safe for humans?

Selumetinib has been evaluated for safety in both children and adults, showing some risks like eye, heart, muscle, stomach, and skin issues, but it was generally well-tolerated with mostly mild side effects reported. ^{1 2 3 4 5}

What makes the drug Selumetinib unique for treating Neurofibromatosis?

Selumetinib is unique because it specifically targets a pathway involved in the growth of tumors in Neurofibromatosis, offering a novel approach compared to other treatments that may not directly address this pathway. It is also administered as granules, which can be easier for some patients to take compared to traditional pills or injections. ^{6 7 8 9 10}

Research Team

Study physician Study physician, MD

Principal Investigator

AstraZeneca

Eligibility Criteria

This trial is for children aged 1 to less than 7 with Neurofibromatosis Type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). They must have a body surface area within specified limits and at least one measurable PN. Children who've had incomplete surgery for PN are eligible if the remaining PN can be measured. Those with certain renal, liver, or hematological issues, previous MEKi treatment complications, or inability to undergo MRI are excluded.

Inclusion Criteria

I am a parent or guardian of a child aged 1 to less than 7 years.

My body surface area is between 0.4 and 1.09 square meters.

I can do most activities, but may need help, or I use a wheelchair/breathing support but can still do some activities.

Exclusion Criteria

Liver function tests: Bilirubin > 1.5 × the ULN for age with the exception of those with Gilbert syndrome (≥ 3 × ULN) or AST/ALT > 2 × ULN

I have a serious heart condition as defined in the study.

I have eye conditions listed in the study protocol.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment

Participants receive selumetinib for 25 cycles to evaluate pharmacokinetics, safety, and tolerability

25 cycles (each cycle is 28 days)

Safety Follow-up

Participants are monitored for safety and effectiveness after treatment, continuing until they reach the age of 5 years or commence an alternative treatment

Treatment Details

Interventions

• Selumetinib

Trial Overview The study tests Selumetinib granule formulation versus capsule formulation in young children with NF1-related PNs. It aims to determine appropriate dosing and assess how the drug moves through and affects the body (pharmacokinetics), its safety profile, as well as preliminary effectiveness of reducing symptoms related to these tumors.

Participant Groups

Group I: Selumetinib single arm Experimental Treatment 2 Interventions

This study consists of a screening period (up to 28 days), a treatment period (25 cycles) and a long term safety follow-up for participants until they are 5 years old or commence an alternative systemic NF1-PN treatment, whichever is the earlier. Participants may continue treatment with selumetinib throughout the long term safety follow-up as long as they are considered to be receiving clinical benefit in the opinion of their Investigator. A safety follow up assessment will be performed 30 days after the last dose of study intervention for all study participants.

Selumetinib is already approved in United States, European Union for the following indications:

Approved in United States as Koselugo for:

• Neurofibromatosis type 1 (NF1) in pediatric patients 2 years of age and older with symptomatic, inoperable plexiform neurofibromas (PN)

Approved in European Union as Koselugo for:

• Neurofibromatosis type 1 (NF1) in pediatric patients 2 years of age and older with symptomatic, inoperable plexiform neurofibromas (PN)

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

Selumetinib (KOSELUGO) was approved by the FDA for treating pediatric patients aged 2 and older with inoperable plexiform neurofibromas, showing a 66% overall response rate in a trial of 50 patients, with many experiencing significant symptom relief for at least 12 months.

While selumetinib is effective, it carries risks typical of MEK inhibitors, including potential ocular, cardiac, and gastrointestinal side effects, but the overall benefit-risk assessment is considered favorable for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma. Casey, D., Demko, S., Sinha, A., et al.[2022]

A Phase I study involving 24 healthy male volunteers evaluated a new granule formulation of selumetinib, showing that its absorption is comparable to the existing capsule form, making it a potential alternative for younger patients or those who have difficulty swallowing capsules.

The study found that the granule formulation was well-tolerated with low incidence of mild adverse events, and participants rated its palatability positively, indicating they would be willing to take it again.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I, Open-label, Randomized, Crossover Study of the Relative Bioavailability of Capsule and Granule Formulations of Selumetinib. Cohen-Rabbie, S., Mattinson, A., So, K., et al.[2022]

Selumetinib, a MEK inhibitor, has shown significant efficacy in treating plexiform neurofibromas in patients with neurofibromatosis type 1, with 68% of 50 symptomatic patients experiencing a partial response and a median tumor volume reduction of 27.9%.

The treatment demonstrated a favorable safety profile, with manageable adverse effects, and resulted in an 84% estimated progression-free survival at 3 years, marking it as the first FDA-approved therapy for inoperable plexiform neurofibromas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Review of Selumetinib in the Treatment of Neurofibromatosis Type 1-Related Plexiform Neurofibromas. Anderson, MK., Johnson, M., Thornburg, L., et al.[2022]

Afatinib, an irreversible pan-ErbB inhibitor, has been approved for treating advanced non-small cell lung cancer (NSCLC) with specific EGFR mutations, showing promise in overcoming resistance to first-generation EGFR inhibitors like gefitinib and erlotinib.

Clinical studies indicate that afatinib is well tolerated, with side effects similar to those of first-generation EGFR TKIs, including diarrhea and rash, while providing effective treatment options for patients with sensitizing mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Afatinib for the treatment of metastatic non-small cell lung cancer. Joshi, M., Rizvi, SM., Belani, CP.[2022]

Capmatinib (Tabrecta) is FDA-approved for treating metastatic non-small cell lung cancer in adults with specific mutations, but patients must be monitored for serious side effects like interstitial lung disease and hepatotoxicity.

Fam-trastuzumab deruxtecan-nxki (Enhertu) has also received accelerated FDA approval for a different type of metastatic non-small cell lung cancer, with warnings about risks such as interstitial lung disease and embryo-fetal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two New Drugs Approved for Non-Small Cell Lung Cancer. Aschenbrenner, DS.[2023]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Selumetinib: First Approval. [2021]

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

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma. [2022]

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

A Phase I, Open-label, Randomized, Crossover Study of the Relative Bioavailability of Capsule and Granule Formulations of Selumetinib. [2022]

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

A Review of Selumetinib in the Treatment of Neurofibromatosis Type 1-Related Plexiform Neurofibromas. [2022]

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

Effect of food on capsule and granule formulations of selumetinib. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Afatinib for the treatment of metastatic non-small cell lung cancer. [2022]

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

Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Afatinib (BIBW 2992) development in non-small-cell lung cancer. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Plain language summary of publication: new information for the potential role of afatinib in treating people with NRG1 gene fusion-positive cancer. [2022]

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

Two New Drugs Approved for Non-Small Cell Lung Cancer. [2023]