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A Randomized Controlled Phase II Study of the Prophylactic Effect of Urea-Based Cream on the Hand-Foot Skin Reaction Associated with Sorafenib in Advanced Hepatocellular Carcinoma Zhenggang Ren1ďźŒKangshun Zhu2, Haiyan Kang3, Minqiang Lu2, Zengqiang Qu4, Ligong Lu5, Tianqiang Song6, Weiping Zhou4, Hui Wang7, Weizhu Yang8, Xuan Wang9, Yongping Yang10, Lehua Shi4, Yuxian Bai11, Sheng-Long Ye1* 1 Zhongshan Hospital, Fudan University, Shanghai, China; 2 The Third Affiliated Hospital of Sun Yat-sen University, Guangdong, China; 3 301 Military Hospital, Beijing, China; 4 Eastern Hepatobiliary Surgery Hospital of the Second Military Medical University, Shanghai, China; 5 Guangdong Provincial People's Hospital, Guangdong, China; 6 Tianjin Cancer Hospital , Tianjin, China; 7 Jilin Provincial Tumor Hospital, Jilin, China; 8 Union Hospital of Fujian Medical University, Fujian, China; 9 The 81 Hospital of the Chinese People's Liberation Army, Nanjing, China; 10 302 Military Hospital, Beijing, China; 11 Heilongjiang Provincial Cancer Hospital, Heilongjiang, China


Disclosure Information Relationships Relevant to this Session

Ye, Sheng-Long, MD No relevant relationships to disclose.

Please note, all disclosures are reported as submitted to ASCO, and are always available at chicago2012.asco.org


Background •  Hand-foot skin reaction (HFSR) is one of the most common adverse events associated with Sorafenib (SOR), with the incidence ranging from 21% to 93%.1 •  HFSR can significantly impact the physical, psychological, and social well-being of patients and can lead to dose reductions and discontinuations that may potentially diminish the beneficial effects of anticancer therapy.2-3 •  Randomized, controlled trials (RCTs) targeting prevention/palliation of HFSR have not been reported.4-5 •  We sought to investigate the prophylactic effect of urea-based creams on the incidence of HFSR associated with SOR treatment of patients with advanced HCC. L. Zhang, et al. Clin and Exp Dermatology 2011, 36, 344–350 Porta C, et aI. Clin Exp Med 2007; 7: 127-134. 3 Robert C, et al. Lancet Oncol 2005; 6: 491-500. 1 2

4Anderson

R, et al. The Oncologist 2009; 14: 291-302. ME, et al. The Oncologist 2008;13:1001-1011.

5 Lacouture


Study Rationale and Objective •  Rationale –  Mild hyperkeratosis is an early sign of HFSR, and sometimes the only manifestation of sorafenib-related HFSR; –  Urea is useful for the treatment of hyperkeratotic conditions and has been recommended for treatment of multitargeted kinase inhibitor-related HFSR1

•  Objective –  To investigate the prophylactic effect of an urea-based cream on HFSR associated with SOR; -  Primary endpoint: §  Incidence of all grade HSFR within 12 weeks of starting SOR treatment. -  Secondary endpoint: §  Incidence of grade ≥ 2 HFSR within 12 weeks of starting SOR treatment; §  Time to first HFSR occurrence; §  Duration of HFSR §  Percentage of patients undergoing dose reduction/interruption §  Percentage of patients undergoing dose termination §  HFSR associated health-related quality of life using the HF-QoL questionnaire. 1

Lacouture et al., The Oncologist 2008; 13:1001-1011


Study Design •  Design -  An investigator-initiated*, phase II, open-label, prospective, randomized study, conducted at 64 centers in China; -  Patient Population: patients with advanced HCC untreated for SOR -  Statistics: Primary endpoint compared between the treatment groups using a Fisher’s exact test; the severity in HFSR analyzed by appropriate Mantel-Haenszel statistics. -  Time to first HFSR and duration of HFSR described between the two groups by Kaplan-Meier estimates and log-rank tests. -  One-sided α of 0.025 and a power of 90%; -  26 pre-selected/pre-coded AEs were recorded from week 0-14 and included AEs commonly associated with SOR (eg: 1. diarrhea, 2. rash, etc.) * This study was sponsored by the Chinese Anti-Cancer Association (CACA) with financial support from Bayer Healthcare.


Study Schema Inclusion Criteria: • Patients being started on SOR for HCC Exclusion Criteria: • Previous SOR • Concomitant anticancer therapy • SOR > 800mg/d

Arm A: Urea-based cream plus best supportive care with concomitant SOR on Day 1

R A N D O N=871 M I Arm B: Z Best supportive care (BSC) E until development of HFSR with concomitant SOR on Day 1

n=439

n=432

Primary Endpoint: - Incidence all grade HFSR within 12wks Secondary Endpoint: - Incidence of grade ≥2 HFSR - Time to first HFSR - Duration of HFSR - % of patient with dose reduction/ interruption - % of patient with dose termination - HF-QoL

•  • 

SOR dosage and dose modification/interruption was to follow the local label. Arm A: Urea (10%) based cream (Eucerin) TID.

• 

Arm B: BSC allowed use of moisturizing creams (non-urea-based) as needed. Once HFSR occurred, patients were able to use any cream as guided by investigator, including urea-based creams. Type of cream and frequency of use in Arm B were not recorded. Patients were followed every 2 weeks for 12 weeks with one follow up visit at week 14.

• 


Patient Disposition Total Enrolled (N=901) Randomized (N=871) BSC Arm B (N=432)

Prophylactic Urea-based Cream + BSC Arm A (N=439)

N=11 (2.5%)

IC* withdrawal

N=9 (2.1%)

N=18 (4.1%)

Death

N=24 (5.6%)

N=37 (8.4%)

PD**

N=38 (8.8%)

N=25 (5.7%)

Lost to F/U***

N=20 (4.6%)

91 patients censored in Arm A * IC: informed consent ** PD: Progression Disease *** F/U: follow-up

ArmA N=439

AcmB N=432

Final Analysis for HFSR

91 patients censored in Arm B


Baseline Patient Characteristics - 1 Prophylactic Urea-based Cream + BSC (Arm A) N=439, %

BSC (Arm B) N=432, %

Total N=871, %

51.8 yr

52.0 yr

51.9 yr

Male

85.9

85.2

85.5

Median Weight (kg)

67.0

66.5

67.0

Median Height (cm)

171.0

171.0

171.0

Hepatitis B

90.2

87.1

88.6

Hepatitis C

7.3

5.3

6.3

0

47.7

46.5

47.1

1

48.2

49.8

49.0

2

3.9

3.7

3.8

68.7

67.8

68.3

35.5

34.0

34.8

Median age at enrollment

Etiology

ECOG score

Previous anti-cancer therapy Yes Hepatectomy


Baseline Patient Characteristics - 2 Prophylactic Urea-based Cream + BSC (Arm A) N=439, % (n)

BSC (Arm B) N=432, % (n)

Total N=871, % (n)

0.7 (3)

0.9 (4)

0.8 (7)

Allergy

0.9 (4)

0.5 (2)

0.7 (6)

Emphysema / COPD

1.2 (5)

0.2 (1)

0.7 (6)

Asthma

0.9 (4)

0.9 (4)

0.9 (8)

Hypertension

5.3 (23)

4.4 (19)

4.9 (42)

Diabetes

2.5 (11)

3.3 (14)

2.9 (25)

Thyroid gland disease

0.2 (1)

0.2 (1)

0.2 (2)

Dermatosis*

0.2 (1)

0.5 (2)

0.4 (3)

Disease History Alcohol / drug addiction

* Including 1 patient of skin eruption in Arm A; 1 patient of psoriasis and 1 patient of unidentified dermatosis in Arm B


Incidence of Worst-grade HFSR Prophylactic Ureabased Cream + BSC Grade of HFSR* (Arm A) N=439 (%)

BSC (Arm B) N=432 (%)

Total N=871 (%)

193(44.0)

114(26.4)

307(35.3)

246(56.0%)

318(73.6%)

564(64.8%)

1

155(35.3)

192(44.4)

347(39.8)

2

72(16.4)

98(22.7)

170(19.5)

3

19(4.3)

28(6.5)

47(5.4)

2/3

91 (20.7)

126(29.2)

217(24.9)

0 All Grade (%)

P Value

<.0001

0.004

• 

Primary Endpoint: The incidence of all-grade HFSR was significantly lower in Arm A (p<0.0001)

• 

Secondary Endpoint: The incidence of grade ≥ 2 HFSR was significantly lower in Arm A (p=0.004)

• 

The incidence of HFSR by grade was lower in Arm A

• 

More patients in Arm A did not develop HFSR


Prevalence of All-grade HFSR at Each Visit 60 50

Arm A Arm B

%

40 30 20 10 0

Week 0

Week 2

Week 4

Week 6

Arm A

1.16

31.4

40.8

36.2

28.9

23.2

18.5

13

Arm B

1.18

36.1

49.8

52.1

47.2

33.8

28.2

17.8

*EOS: 2 weeks after end of study

Week 8 Week 10 Week 12

EOS*

%


Time to the first HFSR event Secondary Endpoint â&#x20AC;˘â&#x20AC;Ż The median time to the first HFSR event was 2.5 fold longer in Arm A compared to Arm B (84 days vs. 34 days, p<0.0001)


HF-QoL* Secondary Endpoint HFSR Symptoms (20 items)

Module P value

HFSR Daily Activity (18 items)

Week 2

Week 4

Week 6

Week 8

Week 10

Week 12

EOS**

HFSR Symptoms

0.2681

0.0171

<0.001

0.0001

0.0036

0.0041

0.0255

HFSR Daily Activity

0.8630

0.2406

0.0015

0.0365

0.3876

0.4937

0.7796

* Based on a scoring algorithm that creates a total score value range of 0 to 100, where a higher score is indicative of worse symptom burden or greater impact of the HFS/R on daily activities. ** EOS: two weeks after end of study


Dose Modification (interruption, reduction, termination) Prophylactic Urea-based Best Supportive Care Cream + BSC Dose Modification Due (Arm B) (Arm A) to HFSR N=432 (%) N=439 (%)

Total N=871 (%)

Dose Reduction/ Interruption

40 (9.1)

51 (11.8)

91 (10.5)

Dose Termination

5 (1.1)

3 (0.7)

8 (0.9)


Efficacy Results at Week 12 Prophylactic UreaTumor Response based Cream + BSC (Arm A) at Week 12 N=333 (%)

Best Supportive Care (Arm B) N=337 (%)

Total N=670

P Value

CR

0 (0)

1 (0.3)

1(0.15)

PR

37 (11.1)

33 (9.8)

70(10.45)

SD

292 (87.7)

297(88.1)

589(87.9)

PD

4 (1.2)

6 (1.8)

10 (1.5)

RR (CR+PR)

37 (11.1)

34 (10.1)

71 (10.6)

.6674

DCR (CR+PR +SD)

329 (98.8)

331 (98.2)

660 (98.5)

.5350

•  At Week 12, there was no significant difference in response rate (RR) or disease control rate (DCR) between the two arms (RR: p=0.6674, DCR: p=0.5350).


Sorafenib-related AEs* (all Grade) Prophylactic Urea-based Cream + BSC (Arm A) N=333 (%)

Best Supportive Care (Arm B) N=337 (%)

Diarrhea

46 (10.5)

44 (10.2)

Fatigue

13 (3.0)

19 (4.4)

Anorexia

8 (1.8)

10 (2.3)

Hypertension

7 (1.6)

Rash

7 (1.6) 6 (1.4) 5 (1.1) 4 (0.9)

13 (3.0) 6 (1.4)

Nausea

2 (0.5)

3 (0.7)

Weakness

1 (0.2)

2 (0.5)

1 (0.2) 268 (61.0)

3 (0.7) 327 (75.7)

Adverse Event

Headache Dry skin

Vomiting Total

* Duration of AE observation period was 14 weeks

12 (2.8)


Limitations •  Non-blinded study •  Observation period of 14 weeks possibly too short •  Extent of use of a moisturizing cream in Arm B prior to development of HFSR was not documented •  Lack of a true control arm (no cream)


Summary •  This is the first large prospective, randomized control trial examining the prophylactic use of an urea-based cream for treatment of HFSR associated with a multikinase inhibitor. •  This study met its primary endpoint of significantly reducing incidence of all grade HFSR within 12 weeks of starting Sorafenib treatment (p<0.001). •  Use of an urea-based cream significantly reduced the incidence of grade ≥ 2 HFSR (p=0.004). •  The time to the first HFSR event was 2.5 fold longer in the arm receiving prophylactic urea cream (p<0.0001) •  The prophylactic use of urea-base cream improved health-related quality of life as measured by the HF-QoL, reducing the HFSR symptom burden and impact of HF symptoms on daily activities.


Conclusions •  These results suggest that prophylactic use of an urea-based cream in advanced HCC patients treated with sorafenib: –  Reduces the incidence and severity of HFSR –  Delays the time to first occurrence of HFSR –  Improves hand-foot associated health related quality of life


Acknowledgement Beijing: Haiyan Kang, Yongping Yang, Hui Chen, Chunyi Hao, Jiasheng Zheng, Baocai Xing, Jianqiang Cai, Zhe Liu, Huai Li, Guangming Li, Jianming Xu, Zhenwen Liu, Fengyong Liu, Tianjun Jiang, Wuwei Yang, Hong Chen

Chongqing: Xiaowu Li, Wei Mou

Heilongjiang: Yuxian Bai Henan: Sheng Guan, Hailiang Li, Yun Zhou

Hubei: Tao Yin, Lei Nie, Bixiang Zhang

Hunan: Jinshu Wu, Xiongying

Shanghai: Sheng-Long Ye, Zhenggang Ren, Zengqiang Qu, Weiping Zhou, Lehua Shi, Guoliang Lou, Wentao Li, Aiying Ma, Jialin Shen, Xinyu Huang, Guangwen Zhou, Sheng Dong

Shandong: Dianyuan Cui, Lijun Sheng, Jun Liang

FuJian: Weizhu yang, Hailan Lin,

Miao

Jingfeng Liu, Bin Li, Yanling Chen, Cheng Shi, Yaodong Wang, Jiaji Jiang

Jiangsu: Xuan Wang, Tongshan

Zhengyin Liao

Wang, Yudong Qiu, Wen Fang, Jun Chen, Aibing Xu

Tianjin: Tianqiang Song, Zhi Guo,

Guangzhou: Kangshun Zhu, Minqiang Lu, Ligong Lu, Yongchong Dou, Hua Ye, Lijian Liang, Linfeng Xu, Feng Huo, Zhixiang Jian, Huanwei Chen

Guangxi: Yilong Ma, Guosheng Feng

Jiangxi: Wuhua Guo, Xinwen Zhou Jilin: Hui Wang Liaoning: Zhaoyu Liu, Xiangdong

Sichuan: Bo Li, Guohui Xu,

Hongli Song, Liying Sun

Zhejiang: Li Zhuang, Zhenhua Tu, Yiping Zhang, Bin Li, Liping Cao, Qijin Shu, Yutang Chen, Peifeng Chen, Yuqing Du

Hua, Rui Ma, Tao Sun, Yujia Gao

Guizhou: Shi Zhou

We thank the patients for their contribution to this study! This study was operated and conducted by Chinese Anti-Cancer Association, and financially supported by Bayer Health Care Pharmaceuticals


BACKUP SLIDES


Best Supportive Care (BSC) Treatment type

Patient-led practical prevention

Patient-led practical management

Recommendations 1. Reduce exposure of hands and feet to hot water 2. Avoid constrictive clothing 3. Avoid excessive rubbing 4. Avoid vigorous exercise or activities that place undue stress on hands and feet 5. Sparingly apply an alcohol-free moisturizer after bathing if the skin gets dry 6. Moisturizing cream can be applied sparingly on the hands and feet 7. Moisturizing cream can be worn at night under cotton gloves and socks 8. Wear open shoes with padded soles during treatment 9. A pedicure prior to treatment may be effective for patients with plantar hyperkeratosis 1. Soak hands in very cool water for 10 to 15 minutes three times a day if this is found to provide relief and dry well 2. Apply petroleum jelly to the hands and feet while the skin is still moist 3. Apply moisturizers sparingly 4. Use a foot bath and pumice stone to exfoliate feet (or regular pedicures) in case of hyperkeratotic lesion and apply moisturizing cream immediately afterwards 5. Use shock-absorbing soles to relieve painful pressure points


HF-QoL •  The HF-QoL is a 38 item questionnaire, containing 20 items related to hand-foot syndrome/hand-foot skin reaction (HFS/R) symptoms (HFS/R Symptom Cluster), and 18 items related to the impact of HFS/R symptoms on daily activities (HFS/R Activities Cluster). •  It was developed to measure HFS/R symptoms and QoL impacts from a broad spectrum of anticancer agents •  Response options for the HF-QoL items range from 0 “Not at all” to 4 “always”, or “extremely”. •  For items in each cluster, the scoring algorithm creates a total score value range of 0 to 100, where a higher score is indicative of worse symptom burden or greater impact of the HFS/R on daily activities •  The HF-QoL was developed following FDA Guidelines1-2. It was validated in a Phase IIb randomized double-blind multinational breast cancer study3. 1 Guidance

for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims DRAFT GUIDANCE released February 2006. http://www.fda.gov/OHRMS/DOCKETS/98fr/06d-0044-gdl0001.pdf 3 M. Aklilu, et al. Journal of Clinical Oncology. Vol 26, No 15S (May 20 Supplement), 2008: 20713 3 Data not published


A Randomized Controlled Phase II