Effect of Sorafenib or Regorafenib on P63 Expression and Keratinocyte Differentiation in Human Skin

A Study of the Effect of Sorafenib or Regorafenib on p63 Expression and Keratinocyte Differentiation in Human Skin

Skin toxicity is a frequently observed side effect in the era of "molecularly targeted therapies". Skin toxicity following administration of protein kinase inhibitors such as sorafenib, regorafenib, lapatinib, sunitinib, and others can be debilitating to the patient, resulting in dose reduction and discontinuation of treatment. The mechanisms of skin toxicity induced by targeted chemotherapy, such as sorafenib or regorafenib, are poorly understood. Further research is warranted to better understand the pathophysiology of drug-related skin toxicity in this setting and develop correction strategies. This study tests the hypothesis that sorafenib and regorafenib interfere with p63 expression and keratinocyte differentiation and skin remodeling.

Eligible study participants will be evaluated clinically for evidence of skin toxicity during their visits to the outpatient Oncology clinics. Study participants will undergo skin biopsies before sorafenib or regorafenib treatment is initiated and once rash develops or 12 weeks into treatment with sorafenib or regorafenib. Skin biopsies will be performed in Oncology clinics by the study investigators and clinic support staff.

Study participants will undergo both skin biopsies regardless of whether they develop a rash. In patients who develop a rash the most representative lesion will be biopsied. A normal appearing area of skin will be biopsied in participants who do not develop a rash.

Study Overview

• Status: Terminated
• Conditions: Renal Cell Carcinoma; Hepatocellular Carcinoma; Colorectal Carcinoma
• Intervention / Treatment: Procedure: skin punch biopsy

• Study Type: Observational
• Enrollment (Actual): 4

Contacts and Locations

Study Locations

• United States
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center
  • Vermont
    • White River Junction, Vermont, United States, 05009
      • White River Junction VA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Cancer diagnosis of Renal Cell Carcinoma (RCC) or Hepatocellular Carcinoma (HCC) or Colorectal Carcinoma

Description

Inclusion Criteria:

1. Male or female, 18 years old or older.
2. Histologically or cytologically confirmed diagnosis of a solid tumor (RCC, HCC, or colorectal cancer).
3. Participants are planning to initiate treatment with either sorafenib or regorafenib as a single chemotherapeutic agent
4. Able to swallow and retain oral medication and does not have any clinically relevant, active gastrointestinal disease or other condition that may significantly alter absorption, distribution, metabolism, or excretion of drugs.
5. Be able to provide written informed consent.

Exclusion Criteria

1. Patients who are or will be receiving other chemotherapeutic or molecularly targeted agents in addition to sorafenib or regorafenib
2. Concurrent moderate or severe chronic inflammatory skin condition (eczema, psoriasis)
3. Concurrent blistering skin disorder of any severity (such as pemphigus, bullous pemphigoid)
4. Connective tissue disorders with skin involvement (systemic lupus erythematosus, scleroderma, dermatomyositis, etc.)
5. Patients manifesting an allergic skin reaction (such as urticaria) or skin reaction as a complication of prior chemotherapy
6. Patients with skin lesions of infectious or non-infectious cause, precluding skin biopsy
7. Patients not willing to undergo skin biopsy
8. Patients who are pregnant or planning to become pregnant during their participation in the study.
9. Chemotherapy, targeted therapy, or biological therapy within two weeks of start of treatment.
10. Ability to give informed consent is compromised by cognitive and/or decisional impairment.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
p63 expression levels	Tissue collection is done within 7 days prior to treatment and when rash develops. If no rash develops, normal skin will be biopsied at week twelve of treatment.	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor response	Sorafenib and regorafenib potentially interfere with p63 expression and keratinocyte differentiation and skin remodeling. The extent of interference may indicate extent of tumor response.	Week 12

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Investigators: Principal Investigator: Alexey V Danilov, MD, Dartmouth-Hitchcock Medical Center

Publications and helpful links

Helpful Links

• Norris Cotton Cancer Center

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: October 31, 2011
• First Submitted That Met QC Criteria: November 7, 2011
• First Posted (Estimate): November 8, 2011

Study Record Updates

• Last Update Posted (Estimate): April 15, 2013
• Last Update Submitted That Met QC Criteria: April 11, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: Sorafenib; HCC; Regorafenib; RCC; P63; rash; skin toxicity; colorectal carcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Kidney Neoplasms; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Carcinoma, Renal Cell; Carcinoma; Colorectal Neoplasms
• Other Study ID Numbers: D11004