Selumetinib + Cabozantinib for Plexiform Neurofibroma

(NF113 Trial)

Overseen By Juliette Southworth, BS

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Girish Dhall, MD

Must not be taking: Anticoagulants, CYP3A4 inducers

Disqualifiers: Cancer, Surgery, Cardiovascular, 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

Compensation: Varies

Number of Visits: 6

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of two drugs, selumetinib and cabozantinib, to determine if they work better together than alone for individuals with Neurofibromatosis Type 1 (NF1). NF1 can cause painful or disfiguring tumors called plexiform neurofibromas (PN). The trial will test different doses to find the optimal balance between effectiveness and manageable side effects. Suitable candidates for this trial are those aged 16 and up with NF1 who have tumors that are growing or causing significant issues, such as pain or nerve problems. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

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

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that selumetinib is generally safe for adults with neurofibromatosis type 1 and can help manage plexiform neurofibromas, a type of tumor, with few side effects. The most common side effects include mild skin rash and stomach upset.

Cabozantinib is also used safely in humans for various types of cancer. People taking cabozantinib often experience fatigue, diarrhea, and appetite loss, but these side effects are usually manageable.

When combined, selumetinib and cabozantinib are tested in lower doses to ensure safety. The goal is to harness the benefits of both drugs while minimizing side effects. As the trial is in an early stage, researchers closely monitor participants' responses to the treatment. This phase focuses on identifying a safe dose that participants can tolerate well before progressing to larger studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Selumetinib and Cabozantinib for Plexiform Neurofibroma because it introduces a new approach by targeting specific molecular pathways involved in tumor growth. Unlike traditional treatments which might focus on surgical removal or symptomatic management, Selumetinib is a MEK inhibitor and Cabozantinib is a tyrosine kinase inhibitor. This combination aims to directly interfere with the signals that tumors use to grow and spread. The hope is that by targeting these pathways, the treatment could be more effective in shrinking tumors or slowing their growth compared to existing options.

What evidence suggests that the combination of selumetinib and cabozantinib could be effective for plexiform neurofibroma?

This trial tests the combination of selumetinib and cabozantinib for treating plexiform neurofibromas. Studies have shown that selumetinib effectively shrinks these tumors in adult patients with Neurofibromatosis type 1 (NF1). Similarly, cabozantinib has reduced tumor size in these conditions. The trial explores this combination because selumetinib and cabozantinib work differently in the body, potentially leading to better outcomes. Early findings suggest this combination could be effective with manageable side effects. ^{1 2 3 4 5}

Who Is on the Research Team?

Girish Dhall, MD

Principal Investigator

University of Alabama at Birmingham

Are You a Good Fit for This Trial?

This trial is for individuals aged 16 or older with a condition called Neurofibromatosis type 1 (NF1) who have progressive and/or symptomatic Plexiform Neurofibromas (PN). Specific eligibility criteria are not provided, but typically participants must meet certain health standards to be included.

Inclusion Criteria

Written informed consent must be obtained from all participants or their legal guardians

Sexually active fertile participants and their partners must agree to use effective contraception

I have been diagnosed with NF1 according to the latest criteria.

Exclusion Criteria

I have not had serious bleeding in the last 3 months.

I have a brain or nerve tumor that needs treatment.

I am experiencing side effects from previous radiation therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Open label, dose escalation phase to determine dose limiting toxicity (DLT) with cabozantinib and selumetinib

16 weeks

Rolling enrollment with up to 6 participants per dose level

Phase 1b Treatment

Expanded cohort to further assess the recommended phase 2 dose

12 months

Phase 2 Treatment

Open label, single-arm phase using the recommended phase 2 dose

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Selumetinib

Trial Overview The study tests the combination of two oral drugs, Selumetinib and Cabozantinib, for treating PN in NF1 patients. It's conducted in three phases: dose escalation to find safe levels (Phase 1), expanded testing at these doses (Phase 1b), and then using the established safe dose on more people (Phase 2).

How Is the Trial Designed?

Group I: Phase 1 cabozantinib and selumetinib combination Experimental Treatment 2 Interventions

The first enrolled participants will start at dose level one with a starting dose of cabozantinib of 20 mg once daily and a starting dose of selumetinib of 15 mg/m2 twice daily. The doses of drug a participant receives will depend on when the participant enrolls on the study. The first group of participants (3 - 6) will receive selumetinib and cabozantinib at half of the typical dose when given separately. If the side effects are tolerable, the second group of 3 to 6 participants will receive a higher dose of selumetinib and cabozantinib. If the drug combination is well-tolerated, there could be up to 5 groups (maximum 6 participants in each group) with each group taking an increased dose from the previous group's dose. If this is tolerated, then this will be the recommended dose of this combination for the Phase 1b of this study. If the side effects are too severe, the participants will receive a lower dose of both drugs.

Cabozantinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in United States as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Canada as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Japan as Cabometyx for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

Girish Dhall, MD

Lead Sponsor

Trials

1

Recruited

30+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Indiana University

Collaborator

Trials

1,063

Recruited

1,182,000+

Published Research Related to This Trial

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]

Cabozantinib is an effective treatment for advanced hepatocellular carcinoma (HCC) after failure of sorafenib, showing significant improvement in overall survival and progression-free survival compared to placebo in the phase 3 CELESTIAL trial.

Common side effects of cabozantinib include palmar-plantar erythrodysesthesia, hypertension, fatigue, and diarrhea, which are important to manage in patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib for the Treatment of Advanced Hepatocellular Carcinoma: Current Data and Future Perspectives. Trojan, J.[2021]

Cabozantinib (CAB) has shown significant improvements in overall survival and progression-free survival in phase-III studies for patients with advanced renal cell carcinoma and hepatocellular carcinoma, leading to its approval in Japan for these conditions.

CAB may enhance antitumor immunity and, when combined with PD-1 checkpoint inhibitors like nivolumab, has demonstrated increased progression-free survival compared to standard treatments, indicating a potential synergistic effect in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological properties and clinical outcomes of the anti-cancer drug, cabozantinib (CABOMETYX®)]. Osaka, T., Yamaguchi, N., Hara, T.[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]

Cabozantinib is an effective receptor tyrosine kinase inhibitor that targets multiple pathways involved in tumor growth and metastasis, showing significant activity in various cancer types, including medullary thyroid cancer (MTC) and prostate cancer.

It gained FDA approval for first-line treatment of advanced MTC after demonstrating clinical benefit in trials, and ongoing phase III studies are investigating its efficacy in metastatic prostate cancer, where it has shown promising response rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor. Grüllich, C.[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]

In a phase Ib/II study involving 64 patients with progressive non-small cell lung cancer (NSCLC) who had previously received erlotinib, cabozantinib alone showed a modest objective response rate (ORR) of 8.2%, indicating some efficacy as a treatment option.

However, in the phase II portion, the combination of cabozantinib and erlotinib did not yield any responses in patients with acquired resistance to erlotinib, suggesting that cabozantinib did not effectively re-sensitize these patients to erlotinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. Wakelee, HA., Gettinger, S., Engelman, J., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06502171

NCT06502171 | Study of Cabozantinib With Selumetinib ... This will be an open label, single arm, prospective, multicenter study to assess the tolerability and efficacy of selumetinib and cabozantinib in combination in ...

2. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(25)00986-9/fulltext?rss=yes

Efficacy and safety of selumetinib in adults with ... The ongoing international KOMET study evaluates the efficacy and safety of selumetinib versus placebo in adults with NF1-plexiform neurofibromas ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12298819/

Selumetinib in Adult Neurofibromatosis 1 with Plexiform ... Conclusion: Our case adds to the growing body of evidence suggesting that selumetinib is effective and well tolerated in adult patients with NF1 ...

4. withpower.com withpower.com/trial/phase-1-neurofibromatoses-9-2024-ff5a1

Selumetinib + Cabozantinib for Plexiform Neurofibroma ... What data supports the effectiveness of the drug Selumetinib + Cabozantinib for Plexiform Neurofibroma? Research shows that Cabozantinib reduced tumor size ...

5. hopkinsmedicine.org hopkinsmedicine.org/neurology-neurosurgery/specialty-areas/neurofibromatosis/clinical-trials

Neurofibromatosis Clinical Trials Overview: This study will explore the use of two medications, cabozantinib and selumetinib, for the treatment of plexiform neurofibromas in adults and ...