A Trial of Tamoxifen and Letrozole in Recurrent and Persistent Squamous Cell Carcinoma of the Cervix

Uterine Cervical Neoplasms Clinical Trial

— TGOG1005  

Official title:

An Open, Randomized, Multi-center, Phase 2 Trial of Tamoxifen and Letrozole in Recurrent and Persistent Squamous Cell Carcinoma of the Cervix: the Efficacy and New Biomarkers

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02482740
• Other study ID #: TGOG1005
• Status: Recruiting
• Phase: Phase 2
• First received: May 12, 2015
• Last updated: June 23, 2015
• Start date: May 2015
• Est. completion date: June 2017

Study information

• Verified date: June 2015
• Source: Buddhist Tzu Chi General Hospital
• Contact: Mun Kun Hong, MD
• Phone: +886-3-8561825
• Email: jeff06038[@]gmail.com
• Is FDA regulated: No
• Health authority: Taiwan: Institutional Review BoardTaiwan: Ministry of Health and WelfareTaiwan: Research Ethics Committee
• Study type: Interventional

Clinical Trial Summary

The investigators design a phase 2, open labeled, randomized trial of Tamoxifen (20 mg/day) and Letrozole (2.5 mg) in treatment of squamous carcinoma of the cervix. Forty four patients with recurrent or persistent disease will be recruited, randomized, treated and followed three-monthly for 12 months. The primary end point is the treatment response rates. Secondary end points include survivals, ECOG performance status, quality of life and efficacy of biomarkers in predicting the responses. Candidate biomarkers including ER, PR, GPER and HPV genotype in paraffin cancer tissues as well as methylated genes in the blood will be studied in relation to the therapeutic outcomes.

Description:

Although human papillomavirus (HPV) is a necessary cause of cervical cancer, HPV infection itself is inefficient and insufficient to cause cancer. New evidences have suggested endogenous and exogenous sex hormones confer risk of developing cervical cancer. In unscreened populations, incidence of cervical cancer starts after menarche and constantly increases before menopause, after then the incidence is flattening and declines [21]. Indeed, after menopause, newly incident CIN3 is seldom detected[22]. Large-scale epidemiological studies also showed high number of full-term pregnancy[23] (rather than abortion) and long-term use of hormonal contraceptives[24] to be independent risk factors of cervical cancer. These evidences pointed to female sex hormones to be another culprit of cervical cancer.

The role of estrogen and ERα on HPV-induced cervical carcinogenesis is best demonstrated by the pK14-HPV E6/E7transgenic mice which, without estrogen exposure, develop benign skin tumors only. However, when these mice are treated with exogenous estradiol at physiological level, they develop cervical cancers in nearly 100% efficiency[25-28]. These cervical neoplasia recapitulate characteristics of human cervical cancer in all aspects: originated from the squamous-columnar junction, with early lesions of atypical squamous metaplasia, CIN and to invasive squamous cell carcinoma [29]. Most importantly, removal of exogenous estrogen or castration of these mice led to diminish of progression and partial regression of pre-existing neoplasia[30].

The investigators design an open, randomized, multi-center trial of tamoxifen and letrozole in treatment of recurrent or persistent squamous cell carcinoma of the cervix. Patients with recurrent or persistent SCC of cervix who are not amenable for further cytotoxic treatment will be randomized by block and by participating center to one of the two arms. The block size will be two . Medication will be given orally in daily dose of tamoxifen (Nolvadex) 20 mg, letrozole (Femara) 2.5 mg until disease progression or until the end of the study.

Primary end point of the study is the response rate (complete response and partial response rates) for tamoxifen and letrozole arms. Secondary end points include progression-free survival (PFS) and overall survival (OS) compared to the historical results, ECOG Performance Status, quality of life and outcome predictors (biomarkers and clinical characteristics) of responsiveness and survival. The experienced survival data of the participating center will be compared.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 44
• Est. completion date: June 2017
• Est. primary completion date: January 2017
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 30 Years to 85 Years

Eligibility

Inclusion Criteria:

1. With a histology proven primary squamous cell carcinoma of the cervix prior to the treatment failure

2. Must sign and date informed consent.

3. With age between 30 and 85

4. With tissue blocks of the recurrent cancer lesion or primary cancer lesion available for the study.

5. With a treatment-free interval of at least 4 weeks.

6. With currently (within 1 month) measurable (by CT) tumor of at least 2 cm in one diameter (at least twice the scan slice thickness), AND elevated SCC level over 2 folds of the institutional upper limit of normal (ULN),

7. With a ECOG performance status score of 0 to 2,

8. With adequate hematologic function (ANC?500/uL and platelets?50,000/uL),

9. With adequate renal function (serum creatinine?2.0 mg/dL; if higher, then creatinine clearance?40 mL/min was required),

10. With adequate hepatic function (ALT/AST ?3.0 folds of ULN

Exclusion Criteria:

1. With histology type other than SCC

2. Had liver, brain metastasis or malignant ascites

3. Those having multiple metastasis (more than one metastasis lesion)

4. Whose cancer had been treated for more than three therapeutic courses [including 1 primary therapy (Operation+ CCRT is considered 1 primary therapy) and 2 secondary therapies] courses.

5. Who have received any investigational drugs within 30 days prior to enrollment

6. Who were pregnant or lactating

7. Who are taking selective serotonin receptor inhibitors (SSRI) (eg. Prozac, Celexa, Lexapro, Lubox, Paxi, Zoloft, etc.)

8. With pulmonary embolism or other veneous embolism

9. With uncontrolled medical conditions such as cardiac disease, cirrhosis of liver, active on chronic hepatitis, diabetes mellitus, autoimmune disease.

10. With current or prior therapy (less than 3 months ) of selective estrogen receptor modulators (SERMs) (tamoxifen, raloxifen, fulvestrant, etc.), or aromatase inhibitors (eg. Letrozole, Anastrozole, Exemestane, Vorozole, Formestane, Fadrozole, etc.)

11. Currently taking Warfarin or Rivaroxaben .

12. With history of malignant disease, except those had been disease-free for at least 5 years.

13. Patient who had allergy history to Tamoxifen or Letrozole

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Squamous Cell
• Uterine Cervical Neoplasms

Intervention

Drug:
• Letrozole
letrozole 2.5 mg qd was given for 12 months or till disease progress
• tamoxifen
tamoxifen was given 20 mg qd for 12 months or till disease progress

Locations

Country	Name	City	State
Taiwan	Dept. of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital	Kaohsiung	No 123, Dapi Rd, Niaosong Dist
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung	No.100, Ziyou 1st Rd., Sanmin Dist.
Taiwan	Kaohsiung Veterans General Hospital	Kaohsiung	No.386, Dazhong 1st Rd., Zuoying Dist.
Taiwan	China Medical University Hospital	Taichung	No.2, Yude Rd., North Dist.,
Taiwan	Chung Shan Medical University Hospital	Taichung	No.110,sec. 1,Jianguo NRd.,South Dist.
Taiwan	National Cheng Kung University Hospital	Tainan	No.138, Shengli Rd., North Dist.
Taiwan	Department of OB/GYN, Linkou Chang Geng Memorial Hospital	Taoyuan

Sponsors (8)

Lead Sponsor	Collaborator
Buddhist Tzu Chi General Hospital	Chang Gung Memorial Hospital, China Medical University Hospital, Chung Shan Medical University, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung Veterans General Hospital., National Cheng-Kung University Hospital, Taiwan Ministry of Science and Technology

Country where clinical trial is conducted

Taiwan, 

References & Publications (10)

Arbeit JM, Howley PM, Hanahan D. Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2930-5. — View Citation

Brake T, Connor JP, Petereit DG, Lambert PF. Comparative analysis of cervical cancer in women and in a human papillomavirus-transgenic mouse model: identification of minichromosome maintenance protein 7 as an informative biomarker for human cervical cancer. Cancer Res. 2003 Dec 1;63(23):8173-80. — View Citation

Brake T, Lambert PF. Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model. Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2490-5. Epub 2005 Feb 7. — View Citation

Elson DA, Riley RR, Lacey A, Thordarson G, Talamantes FJ, Arbeit JM. Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis. Cancer Res. 2000 Mar 1;60(5):1267-75. — View Citation

International Collaboration of Epidemiological Studies of Cervical Cancer, Appleby P, Beral V, Berrington de González A, Colin D, Franceschi S, Goodhill A, Green J, Peto J, Plummer M, Sweetland S. Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet. 2007 Nov 10;370(9599):1609-21. Review. — View Citation

International Collaboration of Epidemiological Studies of Cervical Cancer. Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies. Int J Cancer. 2006 Sep 1;119(5):1108-24. — View Citation

Plummer M, Peto J, Franceschi S; International Collaboration of Epidemiological Studies of Cervical Cancer. Time since first sexual intercourse and the risk of cervical cancer. Int J Cancer. 2012 Jun 1;130(11):2638-44. doi: 10.1002/ijc.26250. Epub 2011 Aug 12. — View Citation

Riley RR, Duensing S, Brake T, Münger K, Lambert PF, Arbeit JM. Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis. Cancer Res. 2003 Aug 15;63(16):4862-71. — View Citation

Rodríguez AC, Schiffman M, Herrero R, Hildesheim A, Bratti C, Sherman ME, Solomon D, Guillén D, Alfaro M, Morales J, Hutchinson M, Katki H, Cheung L, Wacholder S, Burk RD. Longitudinal study of human papillomavirus persistence and cervical intraepithelial neoplasia grade 2/3: critical role of duration of infection. J Natl Cancer Inst. 2010 Mar 3;102(5):315-24. doi: 10.1093/jnci/djq001. Epub 2010 Feb 15. — View Citation

Shai A, Brake T, Somoza C, Lambert PF. The human papillomavirus E6 oncogene dysregulates the cell cycle and contributes to cervical carcinogenesis through two independent activities. Cancer Res. 2007 Feb 15;67(4):1626-35. Erratum in: Cancer Res. 2007 Apr 1;67(7):3492. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The response rate	The guideline for the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) will be followed. Target tumor will be identified and followed by CT scan. Other efficacy parameters are tumor markers (SCC), and pelvic examination and physical examination findings.	one year	Yes
Secondary	Progression-free survival	Progression-free survival (PFS) comparing to the historical results	one year	Yes
Secondary	Quality of life	The European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life questionnaire cervical cancer module: EORTC QLQ-CX24 and C30 will be evaluated for every patient at every visit during study period.	one year	No
Secondary	ECOG Performance Status	ECOG Performance status will be evaluated every visit during study period	one year	No
Secondary	Overall survival	overall survival (OS) comparing to the historical results	one year	No