EGFR Inhibition for Skin Disorders

Overseen By Northwestern CTU

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Northwestern University

Must not be taking: CYP3A4 inhibitors/inducers, Oral retinoids

Disqualifiers: Invasive cancer, Pregnancy, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

44 Participants Needed

Trial Summary

What is the purpose of this trial?

Epidermal growth factor receptor (EGFR) signaling plays a key role in regulating epidermal cell proliferation, survival, and differentiation. Keratins form a scaffold with epidermal desmosomes that involves ErbB/ EGFR signaling and keratin deficiency makes keratinocytes more sensitive to EGFR activation. Erlotinib, an EGFR inhibitor, was approved 20 years ago for cancer treatment and is generally used at 150 mg daily in adults \>50 kg. While gastrointestinal and cutaneous side effects commonly occur at doses of 150 mg, adverse events occur less often at lower doses. We first reported erlotinib as effective for Olmsted syndrome, a rare hereditary EDD with painful PPK that results from variants in TRPV3. Erlotinib is now the treatment of choice for children and adults with Olmsted syndrome. Erlotinib is thought to inhibit formation of a complex that includes TRPV3, EGFR, and its primary skin-based ligand, TGF-a, which in turn regulates keratinocyte proliferation and differentiation. High-throughput screening to identify compounds that stabilize keratin filaments have also pointed to the EGFR pathway for targeting. Reviews and recent case reports have suggested the benefit of erlotinib for PC, Given these preliminary data, we hypothesize that EGFR activation is a characteristic feature of keratinopathies. Further, we expect that oral low-dose erlotinib will improve the scaling and skin thickening of the spectrum of keratinopathies and be tolerated by most patients. For those who experience pain, particularly from plantar involvement, we predict that erlotinib therapy will improve mobility and pain. Finally, we aim to find the mechanism by which erlotinib improves the phenotypes of the various keratinopathies to better understand these disorders and predict response. We will look specifically at the impact on differentiation vs. hyperproliferation and barrier function, as well as the immune modulatory effects of the erlotinib using a multi-omics approach.

Will I have to stop taking my current medications?

The trial requires that you stop taking oral retinoids or oral steroids at least 4 weeks before starting the study drug. You must also avoid any investigational drugs or biologics within 4 weeks or 5 half-lives before starting the trial. Otherwise, stable medications that you've been on for at least a month before the observation period can be continued.

What data supports the effectiveness of the drug Erlotinib (Tarceva) for skin disorders?

Erlotinib has shown effectiveness in treating a skin condition called keratoacanthoma, which is known to have high levels of EGFRs, by demonstrating an excellent response in a reported case. ^{1 2 3 4 5}

Is Erlotinib (Tarceva) generally safe for humans?

Erlotinib (Tarceva) is generally well tolerated, but it can cause skin rashes and diarrhea. Some people may experience more severe skin reactions or rare lung issues, so it's important to monitor and manage these side effects with medical help. ^{1 2 3 6 7}

How is the drug Erlotinib unique for treating skin disorders?

Erlotinib is unique for treating skin disorders because it targets the epidermal growth factor receptor (EGFR), which is abundant in certain skin conditions, and it is typically used for cancer treatment, making its application in skin disorders novel. Unlike traditional treatments, it works by inhibiting specific cellular pathways, potentially offering a new approach for conditions with strong EGFR expression. ^{1 2 3 4 8}

Research Team

Amy Paller

Principal Investigator

Northwestern University

Eligibility Criteria

This trial is for individuals with certain skin conditions like Epidermolytic Hyperkeratosis and Palmoplantar Keratoderma. Participants should have symptoms such as thickened skin or malformed nails. The study is open to those who can tolerate oral medication and are not currently using other treatments that might interfere with the study.

Inclusion Criteria

Participant must have an investigator scored IGA of at least 2 at affected sites

Participant is willing to have blood collected for safety and biopsies for investigation

Participant must be in good general health

Exclusion Criteria

I have infected sores in the area being examined.

Participant is pregnant, breastfeeding, or planning pregnancy

Participant has hypersensitivity to study medication ingredients

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Observation

Natural history of keratinopathies and baseline scores determined

8 weeks

Regular assessments

Dose Escalation

Participants receive escalating doses of erlotinib (50 mg, 75 mg, 100 mg) to assess safety and efficacy

24 weeks

Regular assessments every 8 weeks

Open-label Extension

Participants continue dosing for an additional 6 months based on tolerance and effect

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Erlotinib

Trial Overview The trial tests Erlotinib, an EGFR inhibitor typically used in cancer treatment, at a low dose to see if it improves skin scaling and thickness in keratinopathies. It also aims to understand how Erlotinib affects cell growth, differentiation, pain relief, mobility, and immune system changes in these conditions.

Participant Groups

Group I: Erlotinib Treatment Arm Experimental Treatment 1 Intervention

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

Approved in European Union as Tarceva for:

• Non-small cell lung cancer
• Pancreatic cancer

Approved in United States as Tarceva for:

• Non-small cell lung cancer
• Pancreatic cancer

Approved in Canada as Tarceva for:

• Non-small cell lung cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

Yale University

Collaborator

Trials

1,963

Recruited

3,046,000+

References

1. England pubmed.ncbi.nlm.nih.gov

Erlotinib-induced florid acneiform rash complicated by extensive impetiginization. [2015]

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

Erlotinib (Tarceva) for advanced non-small cell lung cancer. [2015]

3. France pubmed.ncbi.nlm.nih.gov

[Hand-foot syndrome: A new side effect of erlotinib]. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Refractory aggressive keratoacanthoma centrifugum marginatum of the scalp controlled with the epidermal growth factor receptor inhibitor erlotinib. [2018]

5. Germany pubmed.ncbi.nlm.nih.gov

Phase II trial of epidermal growth factor ointment for patients with Erlotinib-related skin effects. [2022]

6. France pubmed.ncbi.nlm.nih.gov

[Description of erlotinib-related skin effects management in France. Results of the PRECEDE study]. [2015]

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

Nondermatologic adverse events associated with anti-EGFR therapy. [2018]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Perifollicular Xanthoma Occurring in Patients after Erlotinib Treatment. [2023]