Clinical trial NCT04864717: Doxycycline vs Isotretinoin for Acneiform Eruptions of TKI
Official title: A Randomized Control Trial to Compare Doxycycline to Isotretinoin for the Treatment of Acneiform Eruptions in Cancer Patients on Tyrosine Kinase Inhibitors
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Acneiform Eruptions
Cancer, Treatment-Related
Keywords: Isotretinoin
Doxycyline
Tyrosine Kinase Inhibitors
EGFR Gene Mutation
Lead sponsor: Lady Davis Institute
Sponsor class: OTHER
First posted: 2021-04-29
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two arm study: one arm isotretinoin, one arm doxycycline.
Primary purpose: TREATMENT

Brief summary: Tyrosine Kinase inhibitors (TKIs) have become standard of care in patients with EGFR mutations in non-small cell lung cancer and other EGFR-mutated cancers. However, TKIs are well-known to cause cutaneous adverse events, including acneiform eruptions. Moderate to severe acneiform eruptions are often associated with severe pruritus and pain. Current treatment recommendations rely on expert consensus. Moderate and severe reactions requiring systemic therapy, usually tetracycline antibiotics or isotretinoin. No randomized trial has compared the relative effectiveness of tetracyclines versus isotretinoin.

The objective of this unblinded, randomized trial is to compare tetracyclines to isotretinoin for treatment of moderate to severe acneiform eruptions in cancer patients on tyrosine kinase inhibitors. The primary aim of this clinical trial is to elucidate which systemic treatment is more effective in clearing acneiform eruptions caused by TKIs. The results of this study will add to the literature in this field and will aid in developing evidence based clinical guidelines.

Detailed description: Background and Study Aims:

Tyrosine Kinase inhibitors (TKIs) have become standard of care in patients with EGFR mutations in non-small cell lung cancer and other EGFR-mutated cancers. However, TKIs are well-known to cause cutaneous adverse events, including acneiform eruptions. Moderate to severe acneiform eruptions are often associated with severe pruritus and pain. Current treatment recommendations rely on expert consensus. Moderate and severe reactions requiring systemic therapy, usually tetracycline antibiotics or isotretinoin. No randomized trial has compared the relative effectiveness of tetracyclines versus isotretinoin.

The objective of this unblinded, randomized trial is to compare tetracyclines to isotretinoin for treatment of moderate to severe acneiform eruptions in cancer patients on tyrosine kinase inhibitors. The primary aim of this clinical trial is to elucidate which systemic treatment is more effective in clearing acneiform eruptions caused by TKIs. The results of this study will add to the literature in this field and will aid in developing evidence based clinical guidelines. The study will be held at Jewish General Hospital, Division of Dermatology, G026, 3755 Cote Ste Catherine, Montreal (Quebec) H3T 1E2.

Who can participate? This study is open to adult patients (\>18 years old) at the Jewish General Hospital who have a histologically- or pathologically-confirmed cancer with a known sensitizing EGFR mutation. Participants must have started EGFR-TKI treatment, and subsequently had an acneiform eruption rated moderate or severe per the Leeds scale. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2, a life expectancy of at least 3 months. Premenopausal participants must use highly effective method of contraception. Female participants are neither pregnant nor breastfeeding

What does the study involve?

Participants who meet the inclusion criteria will be referred to dermatology by their treating oncologist. Participants will meet with dermatology to confirm their diagnosis, review the study protocol and ensure no exclusion criteria are met. If the participant agrees to participate in the trial, signed consent will be obtained and the participant will be randomly assigned to either the doxycycline or isotretinoin group. Participants will receive a prescription for their prescribed medication and will get the medication from their preferred pharmacy. Participants will continue regular follow up with their oncologists as per standard of care. Dermatologic study visits coincide with the follow up visit by the treating Oncologist. During these dermatology visits the following will take place:

1. Global assessment of response to skin therapy: The study dermatologist will grade the skin rash using a standardized grading system.
2. DLQI, a dermatology quality of life questionnaire
3. Participant reported new or worsening of symptoms and compliance to both the cancer medicine (TKI) and the study drug.
4. If participant consented to be photographed, follow up photographs will be obtained.
5. Routine blood tests to ensure no adverse events related to the study therapy will be reviewed.

No extra blood tests will be ordered for the study, but the blood tests already ordered by oncology will be reviewed to ensure that there are no adverse effects from the study medication. The total study duration is six months. At the end of six months, participants can choose to continue to be followed by dermatology and may continue treatment. If a participant withdraws from the study prior to six months, they will still have access to a dermatologist for treatment of the acneiform eruption.

What are the possible benefits and risks of participating? The investigators cannot guarantee that participants will receive any benefits from this study. However, this study will make an important contribution to the field of cancer care and clinical research by providing essential information on the effective treatment of common skin side effects of TKI treatment of cancer patients in the clinical setting.

Participants may have side effects from the drugs used in this study. Side effects can vary from mild to serious and may vary from person to person. Everyone taking part in the study will be watched carefully for any side effects.

All patients will be counselled on the usual adverse effects of the study medicines. In addition, specific counselling, and special emphasis, will be made for the following:

1. Pregnancy \& breastfeeding. Both study medications are contra-indicated in pregnancy and breastfeeding. Pre-menopausal women will be required to use highly-effect birth control, and b-HCG will be checked with other blood tests.
2. Photosensitivity. Both study medications have a risk of photosensitivity. All patients will be counselled, and advised to use a CDA (Canadian Dermatology Association) approved sunscreen of ≥ SPF 50 at least twice daily
3. Esthetic procedures. Patients on isotretinoin will be counselled to avoid any full-depth esthetic procedures for the duration of taking the medication, plus 12 months.
4. Extreme physical exercise. Patients on isotretinoin will be counselled to avoid extreme physical exercise.
5. Mental health problems and suicide. Some patients, while taking, or soon after stopping, isotretinoin, have become depressed or developed other serious mental health problems. Signs of these problems include feelings of sadness, irritability, unusual tiredness, trouble concentrating, and loss of appetite, or even had thoughts about ending their own lives (suicidal thoughts), tried to end their own lives, and some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotretinoin becoming aggressive or violent. Patients will be counselled on the importance of bringing any of the symptoms above to the attention of the study dermatologist should they arrive.
6. Neurologic (brain) problems. Patients will be asked to report symptoms of headaches, nausea, vomiting and visual disturbances given the association between isotretinoin use and benign intracranial hypertension, especially if also taking certain antibiotics (doxycycline or other tetracyclines).

Doxycycline may cause diarrhea, nausea, vomiting, exaggerated sunburn reactions, skin rash, low blood counts, liver problems, elevated intracranial pressure (which may cause changes in vision, nausea/vomiting or headaches). Some patients may develop an allergic reaction to the medication.

Isotretinoin may lead to an increase in cholesterol and triglyceride levels, liver problems, muscle pains elevated intracranial pressure (which may cause changes in vision, nausea/vomiting or headaches), abnormal development of a fetus for women who become pregnant on the medication, eye changes (dryness, decreased night vision), joint pains, pancreatitis (in patients with high blood triglyceride levels). Rarely, patients can develop a severe allergic reaction to the medication. Isotretinoin may also cause depression.

Participants will be closely monitored, including with regular bloodwork to ensure that they do not have any serious side effects to the study medications. At each visit, the study dermatologist will ask about any new symptoms that may suggest an adverse reaction to the medication. If a severe side effect develops, the study medication will be stopped and participants will be closely monitored.

Where is the study run from? The study will take place at the Jewish General Hospital in Montreal QC, Canada.

When is the study starting and how long is it expected to run for? The aim is to start the study as soon as ethics approval is obtained. The estimated start and stop dates of the trial are 01/06/2021 to 01/06/2022. The total study duration for each participant is 6 months.

Who is funding the study? There is no funding for the study.

Who is the main contact? The main contact of the study is the principal investigator. Dr. Kevin Pehr. Jewish General Hospital Senior Investigator/Chercheur Clinicien, Lady Davis Institute Associate Professor Dermatology McGill University Chief Multidisciplinary Cutaneous Lymphoma Clinic 2727B rue St Patrick Montréal (Québec) H3K 0A8 Canada (o) 514-935-1051; (c) 514-880-5122; (fax) 514-932-3793 email: kevin.pehr@mcgill.ca

Eligibility criteria: Inclusion Criteria:

1. Participant must be ≥18 years of age, able to understand the study procedures, and agrees to participate in the study by providing written informed consent
2. Participant has histologically- or pathologically-confirmed cancer with a known sensitizing EGFR mutation.
3. Participants must have started EGFR-TKI treatment, and subsequently had an acneiform eruption rated moderate or severe per the Leeds scale.
4. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2.
5. Participant has a life expectancy of at least 3 months.
6. Premenopausal participants must use highly effective method of contraception. Female participants are neither pregnant nor breastfeeding

Exclusion Criteria:

1. Absolute contraindications: pregnancy, breastfeeding, drug allergy
2. Relative contraindications:

   1. moderate to severe hypercholesterolemia (total cholesterol \>7.8 mmol/L)
   2. hypertriglyceridemia (TG \>2.55 mmol/L)
   3. significant hepatic dysfunction (AST \> 55IU/L, ALT \> 94 IU/L)
   4. suicidal ideation, pseudotumor cerebri
   5. refractory nausea or vomiting
   6. GI pathology that would prevent absorption of oral therapy.

Primary outcomes:
measure: Quantitative improvement in acneiform eruptions in cancer patients on tyrosine kinase inhibitors as defined by a change in Leeds Revised Acne Grading Scale.
timeFrame: 6 months
Secondary outcomes:
measure: Quantitative change on patient's quality of life with treatment of the acneiform eruption as measured by the dermatology life quality index scale.
timeFrame: 6 months
measure: Response of malignancy to cancer therapy using RECIST v1.1 guidelines
timeFrame: 6 months
measure: Adverse events from the study medications as defined using the CTCAE version 5.0 guidelines
timeFrame: 6 months
Other outcomes:
Locations:
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
Study officials:
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