Sorafenib for Patients With Extensive Keloids

Dysregulation of several intracellular pathways have been reported by various investigators.

[A] Dysregulated apoptosis pathway: p53 mutations have been found in both hypertrophic scar
and keloids fibroblasts from cultured cells to various extents. p53 plays a central role in
the DNA damage response by inducing cell cycle arrest and/or apoptotic cell death. Time
course experiments making cell cultures at different times to investigate the phenomenon of
apoptosis and its involvement in the process of pathological scarring in both hypertrophic
scars and keloid indicate to dysregulation of apoptotic pathways in Keloid tissue.

[B]Dysregulated TGF- β signaling: Transforming growth factor- β1 (TGF- β1) is well known as
the crucial fibrogenic cytokine promoting ECM production and tissue fibrosis in keloid
forming [9]. TGF- β1 is an essential profibrotic cytokine for collagen synthesis, and it is
well known to increase mRNA expression of procollagen I. Administration of TGF- β1 resulted
in a dramatic increase in intracellular collagen I levels in keloid fibroblasts. Due to the
close relationship between TGF- β signaling and the production of collagen, blocking TGF- β
signaling has the potential of repressing fibroblast proliferation and collagen synthesis,
thereby preventing the formation of keloids.

[C]Dysregulated VEGF signaling pathway: VEGF (Vascular endothelial growth factor), one of
the most widely studied secreted factors involved in angiogenesis, has been implicated as
crucial to normal and pathological wound healing [18]. Gira et al. [19] indicated that VEGF
production is abundant in the underlying dermis of keloids. In vitro studies have indicated
that VEGF is expressed at higher levels in keloid-derived Fibroblasts than in normal skin
Fibroblasts.

Sorafenib is an orally active multikinase inhibitor and has been reported to be an effective
inhibitor of apoptosis, TGF-β signaling and VEGF pathway signaling, making it an ideal drug
to test in the setting of extensive keloid disorder.

Inclusion Criteria:

1. Clinical Diagnosis of a keloid.

2. Presence of extensive keloid disease as defined in section 1.3

3. Age 18 to 50

4. A signed informed consent document (ICD)

5. Able and willing to receive sorafenib

6. Patients must have normal end organ and marrow function

Women of child-bearing potential must have a negative pregnancy test during screening.
The effects of sorafenib on the developing human fetus are unknown. For this reason, women
of child-bearing potential, and men, must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration of
study participation and three months beyond the last dose of sorafenib. Should a woman
become pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately.

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Exclusion Criteria:

1. Diastolic Blood pressure of 90 mm Hg or above

2. History of any degree of hypertension, even medically controlled hypertension

3. History of any form of cardiovascular disease or stroke

4. History of any form of thromboembolic event

5. History of renal dysfunction or proteinuria,

6. History of any form of liver dysfunction

7. History of recent (past 12 month) or planned (next 9 months) major surgery,

8. Men and women who plan to have children within 3 months of their last treatment

9. Psychological Illness that may result in non compliance with treatment

10. Patients receiving any other investigational agents.

11. Patients with a history of serious allergic reactions to eggs (sorafenib is
formulated using egg phospholipids).

12. HIV-positive patients receiving combination anti-retroviral therapy are excluded
because of possible pharmacokinetic interactions with the investigational agent.

13. Patients who cannot swallow pills for whatever reason will be excluded.

14. Patients having any history or current evidence of a bleeding diathesis.

15. Patients who are taking, or have taken anticoagulants in past 12 months for any
reason.

16. Pregnancy and Breast Feeding Pregnant women are excluded from this study because
sorafenib has the potential for teratogenic or abortifacient effects. Because there
is an unknown but potential risk of adverse events in nursing infants secondary to
treatment of the mother with sorafenib, breastfeeding is not allowed during the
course of the study.

Female patients will be advised not to get pregnant during the first 3 months from last
administered dose of sorafenib. Men will be advised to continue using barrier method
contraception and not father a child during the first 3 months from last administered dose
of sorafenib