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

30 Participants Needed

Trial Summary

What is the purpose of this trial?

Based on the clinical activity of both selumetinib and cabozantinib as monotherapies in clinical trials, the demonstrated activity of these agents in reduced doses in preclinical studies, and the non-overlapping toxicity profiles, the study will assess the tolerability and efficacy of selumetinib and cabozantinib in combination in participants with NF1 ≥16 years old with progressive and/or symptomatic PN in a phase 1/1b/2 clinical trial. Trial Design Phase 1 This will be an open label, dose escalation phase. Dose level escalation will be determined by a rolling six design. In this design, up to 6 participants can be enrolled at a given dose level and then evaluated for dose limiting toxicity (DLT) within the DLT window. The DLT window is defined as 16 weeks in this study based on the long half-life of cabozantinib and the desire to have maximum confidence about long-term tolerability of the combination prior to proceeding to the next dose level. Phase 1b Once the recommended phase 2 dose has been determined in phase 1, an expanded cohort of 12 participants will be enrolled in phase 1b portion of the study. Phase 2 This will be an open label, single-arm phase using the recommended phase 2 dose.

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.

What data supports the effectiveness of the drug Selumetinib + Cabozantinib for Plexiform Neurofibroma?

Research shows that Cabozantinib reduced tumor size in patients with neurofibromatosis type 1-related plexiform neurofibromas, with 42% of participants experiencing a significant reduction. Selumetinib has been approved for children with similar conditions, showing a 66% response rate in reducing tumor symptoms and improving function. ^{1 2 3 4 5}

Is the combination of Selumetinib and Cabozantinib safe for humans?

Cabozantinib has been used safely in humans for various cancers, with common side effects including fatigue, diarrhea, decreased appetite, and skin reactions. A safe dose for children has been identified, though some side effects may require dose adjustments. ^{6 7 8 9 10}

What makes the drug combination of Selumetinib and Cabozantinib unique for treating Plexiform Neurofibroma?

The combination of Selumetinib and Cabozantinib is unique because it targets multiple pathways involved in tumor growth and spread, with Cabozantinib inhibiting MET, VEGFR2, and RET, and Selumetinib targeting the MEK pathway. This multi-targeted approach may offer a novel way to manage Plexiform Neurofibroma, a condition with limited standard treatment options. ^{6 7 11 12 13}

Research Team

Girish Dhall, MD

Principal Investigator

University of Alabama at Birmingham

Eligibility Criteria

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 a brain or nerve tumor that needs treatment.

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

Dental braces or prosthesis that interfere with volumetric analysis of the neurofibroma(s)

Timeline

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

Treatment Details

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).

Participant Groups

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+

Findings from Research

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]

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 (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]

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]

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]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

Selumetinib in Japanese pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas: An open-label, phase I study. [2023]

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

Selumetinib for plexiform neurofibromas in neurofibromatosis type 1: a single-institution experience. [2021]

4. 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]

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

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

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

Cabozantinib for relapsed neuroblastoma: Single institution case series. [2020]

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

Cabozantinib (XL184) for the treatment of locally advanced or metastatic progressive medullary thyroid cancer. [2019]

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

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

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

Incidence and risk of hand-foot skin reaction with cabozantinib, a novel multikinase inhibitor: a meta-analysis. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Cabozantinib for the treatment of progressive metastatic medullary thyroid cancer. [2015]

11. Japan pubmed.ncbi.nlm.nih.gov

[Pharmacological properties and clinical outcomes of the anti-cancer drug, cabozantinib (CABOMETYX®)]. [2022]

12. Germany pubmed.ncbi.nlm.nih.gov

Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor. [2022]

13. Germany 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. [2023]