Official Title: “A Pilot Pediatric/Adult Study of Gene Expression Profiling and Clinical Characterization of Phototoxicity”

RATIONALE: Certain drugs, such as doxycycline and voriconazole, may cause phototoxicity when a patient is exposed to ultraviolet (UV) radiation (sunlight). Studying the pattern of gene expression after exposure to UV light may help doctors prevent phototoxicity and plan the best treatment.

PURPOSE: This clinical trial is studying gene expression profiling and phototoxicity in adults and children who are taking doxycycline or voriconazole and who are exposed to UV radiation.

Study Type: Observational

Study Design: N/A

Study Primary Completion Date: June 2008

OBJECTIVES:

Primary - Determine the global gene expression profiles of phototoxic skin reactions in healthy volunteers treated with doxycycline and compare these expression profiles with the expression profiles of skin exposed to ultraviolet radiation in the absence of doxycycline. - Characterize voriconazole-related phototoxicity in participants utilizing phototesting. - Determine if participants with phototoxicity related to voriconazole receive reasonable phototoxic protection from the use of sunblock.

Secondary - Determine the relationship between voriconazole phototoxicity and pharmacogenomics (cytochrome P450 isoenzyme CYP2C19). - Determine the role of UVA (320-400 nm) and visible light in phototoxicity reactions associated with doxycycline and voriconazole.

OUTLINE: This is a pilot study. - Healthy volunteers: On day 1, participants undergo baseline phototesting comprising solar-simulated ultraviolet radiation (ssUVR), UVA, and visible light exposures on sun-protected skin and pre- and post-exposure photographic documentation. On day 2, participants undergo additional photographic documentation, colorimeter measurements of non-exposed laterally adjacent skin and post-exposure sites with minimal visible erythema, and biopsies (using a modified shave biopsy technique) of exposed and unexposed skin. Participants receive oral doxycycline twice daily on days 3-5. On day 6, participants receive the final dose (7th dose of oral doxycycline) followed 2 hours later by blood draws (for liver function testing and pharmacologic analyses).

Participants also undergo phototesting comprising ssUVR, UVA, and visible light exposure and pre- and post-exposure photographic documentation. On day 7, participants undergo additional photographic documentation, colorimeter measurements, and biopsies of exposed and unexposed skin.

Skin biopsies are examined by gene expression microarray studies. - Participants currently receiving, previously received, or scheduled to receive voriconazole: On days 1 and 2, participants undergo baseline phototesting, pre- and post-exposure photographic documentation, and colorimeter measurements as in healthy volunteers. Biopsies are optional. On or about day 10 (after ≥ 7 days of receiving oral voriconazole), participants receive a dose of oral voriconazole followed 1 hour later by blood draws (for liver function testing and pharmacologic analyses). Participants also undergo sunscreen phototesting comprising ssUVR, UVA, and visible light exposure on skin protected with an over-the-counter sunscreen and sunblock, and pre- and post-exposure photographic documentation. On day 11, participants undergo additional photographic documentation, colorimeter measurements, and optional biopsies.

Blood is examined for cytochrome P450 genotyping (CYP2C19 gene variations) via restriction fragment-length polymorphism-based techniques or nucleotide sequencing.

PROJECTED ACCRUAL: A total of 195 participants will be accrued for this study.

Intervention(s) in this Clinical Trial

• Drug: doxycycline
• Drug: voriconazole
• Procedure: biopsy
• Procedure: dermatologic complications management
• Procedure: gene expression analysis
• Procedure: laboratory biomarker analysis
• Procedure: management of therapy complications
• Procedure: molecular genetic technique
• Procedure: pharmacological study
• Procedure: polymorphism analysis

Primary Measures

• Global gene expression profiles of phototoxic skin reactions in healthy volunteers treated with doxycycline
• Comparison of gene expression profiles of phototoxic skin reactions in healthy volunteers treated with doxycycline with gene expression profiles of skin exposed to ultraviolet radiation in the absence of doxycycline
• Voriconazole-related phototoxicity utilizing phototesting
• Phototoxic protection from the use of sunblock in participants with phototoxicity related to voriconazole

Secondary Measures

• Relationship between voriconazole phototoxicity and pharmacogenomics
• Role of UVA (320-400 nm) and visible light in phototoxicity reactions associated with doxycycline and voriconazole

DISEASE CHARACTERISTICS:

• Meets 1 of the following criteria:
• Scheduled to begin voriconazole therapy OR previously received OR currently receiving chronic voriconazole therapy
• 8 years of age and over
• Any skin phototype
• Unexposed skin available for testing (no extensive skin disease) (for participants who are scheduled to begin voriconazole therapy)
• Test sites for solar-stimulated ultraviolet radiation (ssUVR), UVA, and visible light exposures must be devoid of sunburn, suntan, scars, active dermal lesions, prior radiotherapy exposure, or uneven skin tone
• Presence of nevi allowed provided they will not interfere with study results
• Excess hair allowed if clipped or shaved
• No history of idiopathic abnormal response to sunlight, such as polymorphic light eruption or solar urticaria (for participants who are scheduled to begin voriconazole therapy)
• Prior remote history of phototoxicity reaction allowed
• No history of keloid formation (for adult participants who are scheduled to begin voriconazole therapy and are undergoing modified shave biopsy)
• Healthy volunteer
• Age 18 to 45 years
• Skin phototype II
• Antinuclear antibodies/extractable nuclear antigen < 3
• No history of idiopathic abnormal response to sunlight, such as polymorphic light eruption or solar urticaria
• Prior remote history of phototoxicity reaction allowed
• Unexposed skin available for testing (no extensive skin disease)
• Test sites for ssUVR, UVA, and visible light exposures must be devoid of sunburn, suntan, scars, active dermal lesions, prior radiotherapy exposure, or uneven skin tone
• Presence of nevi allowed provided they will not interfere with study results
• Excess hair allowed if clipped or shaved
• No history of keloid formation

PATIENT CHARACTERISTICS:

• Not pregnant or nursing
• Fertile participants must use effective contraception
• No confounding past or present medical illness that, in the opinion of the investigator, would increase risk for study participation, including any of the following:
• History of graft-vs-host disease
• Receiving concurrent chemotherapy or completed chemotherapy within the past 2 weeks with known photoexacerbating agents (e.g., alkylating agents, doxorubicin hydrochloride, methotrexate, or cisplatin)
• Received prior radiotherapy to the intended sites for phototesting
• No history of allergic reaction to lidocaine (for healthy volunteers OR for adult participants who are scheduled to begin voriconazole therapy and are undergoing modified shave biopsy)
• No allergy to tetracycline (for healthy volunteers)
• Liver function profile normal (for healthy volunteers)
• No history of liver disease or hepatitis
• Willing to avoid excessive sun exposure and tanning equipment for 6 weeks prior to, during, and for 1 week after study participation

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 7 days or 7 half-lives of phototesting (whichever is longer) since prior and no concurrent systemic medication, herbal supplements, or vitamins that are known to be associated with abnormal light response or effect cytochrome P450 enzymes (for healthy volunteers)
• No concurrent medications, herbal supplements, vitamins, or compounds containing bismuth subsalicylate (e.g., Pepto-Bismol) (for healthy volunteers)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 8 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: National Cancer Institute (NCI)

Overall Clinical Trial Officials and Contacts

Maria L. Turner, MD Principal Investigator NCI - Dermatology Branch  

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00411008

Study ID Number: CDR0000498292

ClinicalTrials.gov Identifier: NCT00411008

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database