Study to Investigate the Efficacy, Safety, and Tolerability of Topical HT-001 for the Treatment of Skin Toxicities Associated With Epidermal Growth Factor Receptor Inhibitors

Study Overview
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Brief Summary
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The goal of this clinical trial is to learn about HT-001 Topical Gel for treatment of EGFR inhibitor-induced skin toxicities. The main questions it aims to answer are: Determine the therapeutic effect of HT-001 for treatment of patients who develop acneiform rash undergoing Epidermal Growth Factor inhibitor (EGFRI) therapy using the acneiform rash investigator's global assessment scale [ARIGA] Evaluate the safety of HT-001 during treatment Participants will apply HT-001 Gel once per day for 6 weeks, during which the effect on treating acneiform rash or other skin disorders induced by EGFRI therapy will be evaluated using different assessment tools to measure severity of rash, pain, and itching (pruritus), as well as the change in quality of life. The study will be completed in 2 periods: the first period is open-label (unblinded) and all patients will receive HT-001 topical gel with the active ingredient; the second period is blinded and patients will be randomized to receive one of three concentrations of HT-001 or placebo. Researchers will compare HT-001 to the placebo in the second period to see if HT-001 provides a significant treatment effect.

Detailed Description
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This is a randomized, double-blind, placebo-controlled, multi-center Phase 2a dose-ranging study to evaluate the efficacy, safety, and tolerability of HT-001 for treatment of EGFRI-induced skin toxicity. The study will include adult patients (≥ 18 years of age) scheduled to receive initial or repeat EGFRI therapy. The study will be conducted in 2 periods: Part 1, an open-label cohort consisting of 12 patients to measure pharmacokinetics of HT 001 gel followed by Part 2, a randomized, parallel arm study comparing 3 dose strengths of HT-001 gel to placebo (HT 001 vehicle). Patients in the randomized cohorts will be randomly assigned to 1 of the 4 treatment arms in a 2:2:2:1 ratio (active groups = 2: placebo = 1). All patients in both open-label and blinded cohorts will apply the study drug once a day to each area affected with cutaneous toxicity up to 30% body surface area (BSA) involvement, inclusive of skin, scalp, and nails. The goal of the study is to determine the minimum efficacious dose strength(s) for further investigation. The dose effect, together with the application site safety assessments, and therapeutic effects based on the primary and secondary endpoints will be evaluated.

Official Title
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A Randomized, Placebo-controlled, Parallel Phase 2a Dose-ranging Study to Investigate the Efficacy, Safety, and Tolerability of Topical HT-001 for the Treatment of Skin Toxicities Associated With Epidermal Growth Factor Receptor Inhibitors

Conditions
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Acneiform Eruption Due to Chemical, Xerosis Cutis, Paronychia

Intervention / Treatment
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* Drug: HT-001 2% Topical Gel
* Drug: HT-001 1% Topical Gel
* Drug: HT-001 0.5% Topical Gel
* Drug: HT-001 Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patient (ie, ≥ 18 years of age at Screening [V1]) prescribed an approved EGFRI to treat cancer (indication within the approved labeling for the EGFRI) and is expected to begin EGFRI treatment within < 4 weeks of Screening (V1). Patient has developed a rash or symptoms of a rash (papular and/or pustular eruptions) or symptoms of a rash (cutaneous burning), at Baseline (V2), as assessed by both the Common Terminology Criteria for Adverse Events (CTCAE) grading and Acneiform rash IGA scales (ARIGA) (severity ≤ 3) with overall involvement ≤ 30% BSA. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Predicted life expectancy ≥ 3 months. Patient is able and willing to comply with contraceptive requirements. Patient must have the ability and willingness to attend the necessary visits (telehealth and in person). Patient must be willing and able to provide written informed consent after the nature of the study has been explained and prior to the commencement of any study procedures. Exclusion Criteria: Patient has severe cutaneous toxicity (severity = 4 on the CTCAE grading and Acneiform rash IGA scales) or cutaneous toxicity involvement that is > 30% BSA, or other severe systemic toxicity (severity > 3 on the CTCAE v5.0 scale ) as a result of EGFRI therapy. Subject has a presence of any underlying physical or psychological medical condition that, in the opinion of the Investigator, would make it unlikely that the patient will comply with the protocol or complete the study per protocol. Patient has a history of other skin disorders (eg, atopic dermatitis, psoriasis, recurrent skin infections) and presence of active dermatological symptoms at the time of screening (prior to initiation of EGFRI therapy), or history of illness that, in the opinion of the Investigator, would confound results of the study or pose unwarranted risk in administering study drug to the patient. Patient has abnormal laboratory values at Screening (V1): Absolute neutrophil count < 1000/mm3 and white blood cell (WBC) count < 3000/mm3 Platelet count < 50,000/mm3 Aspartate transaminase (AST) > 2.5 × upper limit of normal (ULN) Alanine transaminase (ALT) > 2.5 × ULN Bilirubin > 1.5 × ULN Creatinine > 1.5 × ULN Patient has a prescribed EGFRI therapy treatment plan that is less than 8 weeks total duration. Patient has a prescribed cancer treatment plan that requires radiation treatment to the head, neck, or upper trunk concurrent with EGFRI therapy or has previously received radiation therapy within 4 weeks prior to Screening (V1). Patient has received neurokinin-1 receptor antagonist within 4 weeks prior to Screening (V1). Patient has had prior treatment with an investigational drug within 4 weeks prior to Screening (V1), or at least 8 half-lives of the drug, whichever is longer. Subject has an active infection (eg, pneumonia) or any uncontrolled disease except for the malignancy that, in the opinion of the Investigator, might confound the result or the study or pose unwarranted risk in administering the study drug to the patient. Patient has received topical antibiotics, topical steroids, or other topical treatments (non-medicated emollients are allowed up until 1 day prior to V2) within 14 days to Baseline (V2). Patient has used systemic steroids within 14 days prior to Screening (V1) except for low dose systemic corticosteroids as part of standard of care for prevention or treatment of chemotherapy-induced nausea and vomiting; acceptability of the steroid and dose is determined by the study Investigator. Use of steroid inhalers and nasal corticosteroids is allowed. Patient has received treatment with a systemic antibiotic within 7 days prior to Screening (V1) (unless minocycline/doxycycline administered for CTCAE grade 3 acneiform rash). Patient has received concomitant treatment with pimozide, moderate to strong CYP3A4 inhibitors (diltiazem, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir), or strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin) with 30 days of Day 1 of treatment (V2). Patient has a history of hypersensitivity to any component of HT-001 (to be confirmed at Screening [V1] with patch testing). Patient is pregnant or lactating at Screening (V1) or planning to become pregnant (self or partner) at any time during the study, including the follow-up period.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-Label PK Cohort<br>Topical treatment with HT-001 2% Gel unblinded. | Drug: HT-001 2% Topical Gel<br>* Topical gel, 2% active<br>|
| Placebo Comparator: Randomized, Double Blind Cohort<br>Topical treatment with HT-001 (2%, 1%, or 0.5%) or placebo (HT-001 vehicle), blinded | Drug: HT-001 2% Topical Gel<br>* Topical gel, 2% active<br>Drug: HT-001 1% Topical Gel<br>* Topical gel, 1% active<br>Drug: HT-001 0.5% Topical Gel<br>* Topical gel, 0.5% active<br>Drug: HT-001 Placebo<br>* Topical gel, vehicle gel<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acneiform Rash Investigator's Global Assessment Scale [ARIGA ] | Proportion of patients with a grade ≤ 1 based on the Acneiform Rash Investigator's Global Assessment [ARIGA] Scale; novel 5-point scale 0-4 with score of 0 is clear and grade 4 being most severe | 6 weeks | 
| Pharmacokinetics of HT-001 applied topically [Cohort 1] - Area Under the Curve (AUC) | Characterize pharmacokinetics of HT-001 parameters including: measured drug concentrations above the lower limit of quantitation, number of patients with measurable systemic exposure; if data allow - area under the curve (AUC) | Day 1 and Day 42 | 
| Pharmacokinetics of HT-001 applied topically [Cohort 1] - Peak Plasma Concentration (Cmax) | Characterize pharmacokinetics of HT-001 parameters including: maximum (or peak) serum concentration (Cmax) | Day 1 and Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pruritus Numeric Rating Scale (NRS) | Change from Baseline in Pruritus Numeric Rating Scale (average itch and worst itch); The numerical scale is ranked from 0 (no itch) to 10 (worst imaginable itch). | 3 weeks and 6 weeks | 
| Pain Numeric Rating Scale | Change from Baseline in pain based on a 11-point NRS (where 0 indicates no pain, 5 indicates moderate pain and 10 indicates worst pain imaginable) | 3 weeks and 6 weeks | 
| Change in acneiform rash severity | Change from Baseline in acneiform rash grade based on the Acneiform Rash Investigator's Global Assessment Scale [ARIGA]; novel 5-point scale 0-4 with score of 0 is clear and grade 4 being most severe | 3 weeks and 6 weeks | 
| Time to improvement | Time to improvement in at least one grade using the Acneiform Rash Investigator's Global Assessment Scale [ARIGA ] for acneiform rash; novel 5-point scale 0-4 with score of 0 is clear and grade 4 being most severe | 6 weeks Day 1- Day 42 | 
| Time to rescue therapy | Time to topical rescue therapy treatment after initiation of HT-001 | Treatment Day 1- Day 42 | 
| EGFR Inhibitor dose reduction or discontinuation | Proportion of patients with EGFRI dose reduction or discontinuation during the 6-week treatment period | Treatment Day 1- Day 42 | 
| Safety and tolerability of HT-001 | Incidence of treatment-emergent adverse events and treatment-emergent serious adverse events | screening, Day 1 - 42, follow-up (Day 56) | 
| Modified Draize Scale | Assessment of skin irritation through measurement of cutaneous signs of erythema (score 0-3; 3 is most severe) and edema (add 0.5 if present) | Day 1, 7, 21, 35, 42, 56 | 
| Physical Examination | full physical examination will include examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, and nervous system. An AE form must be completed for all changes identified as clinically noteworthy. | Day 1, 7, 21, 35, 42, 56 | 
| Height | Height recorded in inches | Screening | 
| Body weight | Body weight in pounds. | Day 1, 21, 42, 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acneiform rash, EGFR inhibitor, Cutaneous toxicities