A Double-blind, Placebo-controlled Study of the Safety and Efficacy of Vitamin K1 Ointment for the Treatment of Patients with Cetuximab-induced Acneiform Eruption

Article (PDF Available)inJapanese Journal of Clinical Oncology 43(1) · November 2012with10 Reads
DOI: 10.1093/jjco/hys183 · Source: PubMed
Abstract
A double-blind, placebo-controlled study evaluating the efficacy and safety of vitamin K1 ointment for the treatment of patients with cetuximab-induced acneiform eruption has started. Vitamin K1 ointment and placebo are applied twice daily for 8 consecutive weeks after the development of acneiform eruptions. Vitamin K1 ointment is applied in the middle of one side (face, neck or chest) and placebo is applied to the other side. The primary endpoint is the regression rate of acneiform eruptions on right- and left-side lesions in the same patient, compared with baseline at the final evaluation in the 10-week trial. The secondary endpoints include adverse events of acneiform eruption and other adverse events.
A Double-blind, Placebo-controlled Study of the Safety and Efficacy
of Vitamin K1 Ointment for the Treatment of Patients with
Cetuximab-induced Acneiform Eruption
Hironobu Hashimoto
1,*
, Satoru Iwasa
2
, Takako Yanai
1
, Yoshitaka Honma
2
, Ken Kato
2
, Tetsuya Hamaguchi
2
,
Yasuhide Yamada
2
, Yasuhiro Shimada
2
, Kenjiro Namikawa
3
, Arata Tsutsumida
3
, Naoya Yamazaki
3
and
Hiroshi Yamamoto
1
1
Division of Pharmacy, National Cancer Center Hospital, Tokyo,
2
Gastrointestinal Oncology Division, National
Cancer Center Hospital, Tokyo and
3
Dermatologic Oncology Division, National Cancer Center Hospital, Tokyo,
Japan
*For reprints and all correspondence: Hironobu Hashimoto, Division of Pharmacy, National Cancer Center Hospital,
Tokyo, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: hhashimo@ncc.go.jp
Received July 3, 2012; accepted October 11, 2012
A double-blind, placebo-controlled study evaluating the efficacy and safety of vitamin K1 oint-
ment for the treatment of patients with cetuximab-induced acneiform eruption has started.
Vitamin K1 ointment and placebo are applied twice daily for 8 consecutive weeks after the de-
velopment of acneiform e ruptions. Vitamin K1 ointment is applied in the middle of one side
(face, neck or chest) and placebo is applied to the other side. The primary endpoint is the re-
gression rate of acneiform eruptions on right- and left-side lesions in the same patient, com-
pared with baseline at the final evaluation in the 10-week trial. The secondary endpoints
include adverse events of acneiform eruption and other adverse events.
Key words: colorectal cancer cetuximab acneiform eruption vitamin K1
INTRODUCTION
The epidermal growth factor receptor (EG FR) in hibitors
such as cetuximab and panitumumab are used to treat
advanced stages of solid tumors, especially colorectal
cancer. Acneiform eruptions, the most common side-effects
of cetuximab and panitumumab, stigmatize the p atients’
daily life and may lower compliance.
A controlled study called Skin Toxicity Evaluation
Protocol with Panitumumab (STEPP) is the first prospective
trial designed specifically to compare primary preemption
with reactive treatment for EGFR inhibitor-mediated skin
toxicity. Patients receiving second-line irinoteca n-based
chemotherapy plus panitumumab were randomized to
primary preemptive or reactive skin treatment. Patients ran-
domized to the preemptive treatment arm received daily skin
treatment f rom 24 h before their first dose of panitumumab
through Week 6. Patients in the reactive treatment arm
received treatment after development of skin toxicity. The
treatment for skin toxicity in the preemptive arm included
skin moisturizer, sunscreen, 1% hydrocortisone cream and
doxycycline 100 mg twice daily. This study demonstrated
that, w hen compared with reactive treatment, preemptive
treatment reduced the incidence of grade 2 s kin toxicity
by .50% without additional side-effects (1).
While topical steroids have tremendous benefit in reducing
inflammation, they also have significant side-effects. Most of
these side-effects are seen with long-term use, but some may
be noticed within days of starting therapy. The most
common side-effects of topical steroid use are rosacea, skin
atrophy, striae (stretch marks) and alteration of infection. As
topical steroids have these side-effects, an effective topical
non-steroid agent is needed.
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Recently, topical vitamin K ointment showed effectiveness
in promoting down-staging of EGFR-inhibitor-induced
acneiform eruptions (2 4). In view of these promising data,
we are performing a double-blind, placebo-controlled study
evaluating the use of 0.1% vitamin K1 ointment as a topical
treatment for cetuximab-induced acneiform eruption.
PROTOCOL DIGEST OF THE STUDY
PURPOSE
The aim of this study was to evaluate the efficacy and safety
of vitamin K1 ointment in the treatment of patients with
cetuximab-induced acneiform eruption.
S
TUDY SETTING
This is a single-institutional, phase II, double-blind, placebo-
controlled study.
E
NDPOINTS
The primary endpoint is comparative regression rates of
acneiform eruptions of right- and left-side lesions (face,
neck or chest) in the same patient, compared with baseline at
the final evaluation in the 10-week trial. The secondary end-
points include adverse events of acneiform eruption
(CECAE v4.0 and MASSC scale), and other adverse events.
E
LIGIBILITY CRITERIA
INCLUSION CRITERIA
Prior to enrollment in the study, patients must fulfill all of the
following criteria: experienced a cetuximab-induced acnei-
form eruption; age 20 or older; written informed consent.
E
XCLUSION C RITERIA
Patients are excluded for any of the following reasons:
undergoing treatment with vitamin K analog or anta gonist;
pregnancy or breastfeeding; serious como rbidities that would
affect the patient’s decision to participate.
T
REATMENT METHODS
Vitamin K1 ointment and placebo are applied twice daily for
8 consecutive weeks after the development of acneiform
eruptions. The composition of the vitamin K1 ointment
0.1% is as follows: white petrolatum 100 g with the addition
of vitamin K1 100 mg (Wako Pure Chemical Industries
Ltd.); placebo ointment: white petrolatum 100 g with the
addition of colored solution 100 mg (purified water 2.5 ml
with yellow food color additive). Each ointment was
assigned at random to ointment A or B. Topical ointment is
applied at bedtime or after facial wash. Topical vitamin K1
ointment is applied to one side (right or left lesion on the
face, neck, or chest), and placebo is applied to the other
side. The first administration of the drug is made under the
supervision of a pharmacist. L ater applications are self-
administered on an outpatient b asis. The preemptive treat-
ment is allowed to use skin moisturizers and tetracycline
before and during cetuximab-containing treatment as con-
comitant medications, but topical steroid is not allowed.
S
TUDY DESIGN AND STATISTICAL METHODS
The present study was designed to explore the effects of
vitamin K 1 ointment, compared with those of placebo oint-
ment, on the regression rate of cetux imab-induced acneiform
eruptions, which was determined on the basis of change in
the overall surface area of the treated lesions compared with
baseline at the final evaluation after the first 10 weeks of
treatment.
In this study, the ratio of the number of acneiform erup-
tions at placebo-applied site after drug treatment relative to
those at the placebo-applied site after treatment will be cal-
culated based on the following formula: [(the number of
acneiform eruptions at placebo-applied site at the end of
treatment) (the number of acneiform eruptions at study
drug-applied site at the end of treatment)]/[the number of
acneiform eruptions at placebo-applied site at the end of
treatment]. The differences in the occurrence of acneiform
eruptions between the beginning and the end of the treatment
will be compared (paired t-test).
If the diffe rence in the rate of ch ange between the begin-
ning and the end of treatment for acneiform eruption was
assumed as 0.25, standard error as 0.4 and an alpha-error of
0.05 (two-sided) and a beta-error of 0.1 were set, the
required sample size is estimated as 27 patients. Therefore,
the target sample size was set at 30 patients.
F
OLLOW-UP
The treatment and observation periods were planned for a
durationof10weeks,dependingonlesionresponse.
Advers e events are monitored at least every 2 weeks during
the protocol treatment using CTCAE ver. 4.0. Cetuximab-
induced eruption is evaluated at least every 2 weeks during
t he protocol treatment using CTCAE ver. 4.0 and MASCC
scale.
R
EGISTRATION OF THE PROTOCOL
The study was registered at the University Hospi tal Medical
Information N etwork (UMIN) Clinical Trials Registry
(protocol ID: UMIN000008099) on 11 June 2012.
Funding
This study was supported by National Cancer Center
Research and Development Fund 23-C-2.
Jpn J Clin Oncol 2013;43(1) 93
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Conflict of interest statement
None declared.
References
1. Lacouture ME, Mitchell EP, Piperi di B, et al. Skin to xicity evaluation
protocol with panitumumab (STEPP), a phase II, open-label, randomized
trial evaluating the impact of a pre-Emptive Skin treat men t regimen on
skin toxicities and quality of life in patients with metastatic colorectal
cancer. J Clin Oncol 2010;28:13517.
2. Perez-Soler R, Zou Y, Li T, Tornos C, Ling Y. Topical vitamin K3 (Vit
K3, Menadione) prevents erlotinib and cetuximab-induced EGFR
inhibition the skin. J Clin Oncol 2006;24:2036. ASCO Annual Meeting
Proceedings Part I.
3. Ocvirk J, Rebersek M. Management of cutaneous side effects of
cetuximab therapy with vitamin K1 creme. Radiol Oncol 2008;42:
215 24.
4. Li T, Perez-Soler R. Skin toxicities associated with epidermal growth
factor receptor inhibitors. Target Oncol 2009;4:10719.
94 Topical VitK1 for Cmab-induced acneiform eruption
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