Four Cycles Versus Six Cycles of Cisplatin-based Chemotherapy in Metastatic Urothelial Carcinoma

Bladder Cancer Clinical Trial

— FOCUS  

Official title:

Four Cycles of Cisplatin-Based Chemotherapy in Metastatic Urothelial Carcinoma Compared to Six Cycles: Randomized Phase III Trial - FOCUS Study -

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03296306
• Other study ID #: KCSG GU16-02
• Status: Recruiting
• Phase: Phase 3
• First received: August 22, 2016
• Last updated: September 23, 2017
• Start date: September 2016
• Est. completion date: February 2022

Study information

• Verified date: September 2017
• Source: Asan Medical Center
• Contact: Jae lyun Lee, MD., PhD.
• Phone: +82-2-3010-5977
• Email: jaelyun[@]amc.seoul.kr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The objective is to show non-inferiority of overall survival between four cycles and six cycles of first-line cisplatin based chemotherapy to determine the optimal duration of chemotherapy in patients with advanced urothelial carcinoma.

Description:

Urothelial carcinoma is the fifth most common cancer in men and seventh among women all around the world. Although a complete surgical resection with or without perioperative treatment is the most effective way to offer a potentially curative therapy to patients with these cancers, 25% of the patients initially present with locally or systemically advanced disease. Systemic chemotherapy is the only current modality that provides the potential for a long-term survival in patients with advanced or metastatic urothelial disease.

Cisplatin based combination chemotherapies such as GP, GP-S, MVAC, and dose dense MVAC with G-CSF supports are regarded as a backbone treatment for patients with advanced bladder cancer on the basis of the results from previous studies.

However, there is no consensus on appropriate number of chemotherapy cycles. In phase III trial comparing MVAC with GP, patients were treated with 6 cycles (every 4 weeks) of chemotherapy. In another phase III trial comparing MVAC with HD-MVAC, there is no pre-determined number of cycles, but the median number of cycles were 4 for MVAC and 6 for HD-MVAC.

However, it is hard to complete six or more cycles of cisplatin based chemotherapy due to cumulative toxicities of cisplatin such as neuropathy and development of resistance. The median age of patients with urothelial cancer is 70 years old and significant proportion of the patients already showed impaired performance status (ECOG PS ≥2).

There has already been reported in several trials of NSCLC, which showed that 4 cycles of chemotherapy containing cisplatin has no significant differences in survival or QoL with lower incidences of toxicities compared with 6 cycles of chemotherapy.

The objective of this trial is to assess whether there is any difference in OS between patients who are treated with four cycles of cisplatin based chemotherapy and patients who are treated with 6 cycles of chemotherapy to determine the optimal duration of chemotherapy in patients with advanced urothelial cancer.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 330
• Est. completion date: February 2022
• Est. primary completion date: August 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

1. Patients with histologically or cytologically confirmed urothelial cancer

2. Unresectable locally advanced (T3b, N2-3), metastatic (M1), or recurrent disease

3. Age 18 years or older

4. Eastern Cooperative Oncology Group performance status 0-1

5. Not progressed disease status after 2 or 4 cycles of platinum-based chemotherapy

6. Adequate organ and bone marrow function for chemotherapy

7. No history of radiation therapy, or radiation field within 25% of whole marrow would be allowed. If patients underwent radiation therapy in entire pelvis, they are excluded to this study. Patients should discontinue radiation therapy at least 4 weeks before enrollment, and the patients should be recovered from radiation therapy associated adverse events.

8. Women should use contraceptive medication for 6 months after the end of the study or she would be post-menopause status. Men should consent with the contraception for 6 months after the end of the study or he would be infertile.

9. Patients should sign a written informed consent before study entry.

Exclusion Criteria:

1. Histologic types other than urothelial cell carcinoma should be excluded. However, urothelial cell types combined with squamous or glandular features are allowed.

2. Patients who showed progressed disease status after 2 or 4 cycles of platinum-based chemotherapy, cannot be treated with additional chemotherapy due to adverse events, or already undertook with reduced dose of more than 50%

3. Presence or history of CNS metastasis

4. Prior systemic chemotherapy (But prior intravesical chemotherapy or immunotherapy was allowed, and recurrent disease after adjuvant or neoadjuvant cisplatin-based systemic chemotherapy is allowed if the last chemotherapy was administered 1 year or more before the patient enrollment)

5. Peripheral sensory neuropathy grade 2 or worse according to NCI CTCAE

6. History of treatment with drugs of another clinical trial within 30 days before enrollment.

7. Concomitant severe medical, surgical, or psychiatric disease or problems which can affect the results of the clinical trial or have possibilities of unexpected medical problems caused be the drug of clinical trial

8. History of another malignancy (but treated malignancy at least two years before enrollment were allowed, and cured non-melanoma skin cancer, any cured in-situ carcinoma, clinically insignificant localized prostate cancer, or papillary thyroid carcinoma are allowed even diagnosed less than 2 years before enrollment).

9. Pregnant or lactating women, women of childbearing potential not employing adequate contraception

Related Conditions & MeSH terms

• Bladder Cancer
• Carcinoma
• Carcinoma, Transitional Cell
• Transitional Cell Carcinoma
• Ureter Cancer
• Ureteral Neoplasms
• Urethral Cancer
• Urethral Neoplasms
• Urinary Bladder Neoplasms

Intervention

Drug:
• Treatment duration of cisplatin based chemotherapy
GP regimen: Gemcitabine (1000 mg/m2 D1, D8), Cisplatin (60 mg/m2 D1), every 3 weeks GP-S regimen: Gemcitabine (1000 mg/m2 D1, D8), Cisplatin (35 mg/m2 D1,D 2 or D8), every 3 weeks MVAC regimen: Methotrexate (30 mg/m2 IV bolus, D1, 15, 22), Vinblastine (3 mg/m2 IV bolus, D2, 15, 22), Doxorubicin (30 mg/m2 IV bolus D2), Cisplatin (70 mg/m2 D2), every 4 weeks HD-MVAC with GCSF regimen: Methotrexate (30 mg/m2 IV bolus, D1), Vinblastine (3 mg/m2 IV bolus, D2), Doxorubicin (30 mg/m2 IV bolus D2), Cisplatin (70 mg/m2 D2), G-CSF (240 ug/m2 SC, D4-10), every 2 weeks

Locations

Country	Name	City	State
Korea, Republic of	Hallym University Medical Center, Hallym University College of Medicine	Anyang
Korea, Republic of	Fatima Hospital	Daegu
Korea, Republic of	Keimyeong University Dongsan Medical Center	Daegu
Korea, Republic of	Chungnam University Hospital	Daejeon
Korea, Republic of	National Health Insurance Service Ilsan Hospital	Goyang
Korea, Republic of	Gil Medical Center	Incheon
Korea, Republic of	Inje University Haeundae Paik Hospital	Pusan
Korea, Republic of	Kosin University Hospital	Pusan
Korea, Republic of	Pusan National University Hospital, Pusan National University School of Medicine	Pusan
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Chung Ang University Hospital	Seoul
Korea, Republic of	Inje University Sanggye Paik Hospital	Seoul
Korea, Republic of	Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine	Seoul
Korea, Republic of	VHS medical center	Seoul
Korea, Republic of	Yonsei Cancer Center	Seoul
Korea, Republic of	St. Vincent's Hospital, The Catholic University of Korea	Suwon
Korea, Republic of	Kwonoh Park	Yangsan	Gyeongsangnam-do

Sponsors (2)

Lead Sponsor	Collaborator
Asan Medical Center	Korean Cancer Study Group

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (6)

Cheng T. Systemic therapy for unresectable and metastatic transitional cell carcinoma of the urothelium: first-line and beyond. Curr Opin Support Palliat Care. 2008 Sep;2(3):153-60. doi: 10.1097/SPC.0b013e328309c72c. Review. — View Citation

Kim YR, Lee JL, You D, Jeong IG, Song C, Hong B, Hong JH, Ahn H. Gemcitabine plus split-dose cisplatin could be a promising alternative to gemcitabine plus carboplatin for cisplatin-unfit patients with advanced urothelial carcinoma. Cancer Chemother Pharm — View Citation

Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with — View Citation

Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Lee JS, Yun YH, Lee JW, Park K. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platin — View Citation

Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; EORTC Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of — View Citation

von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus m — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	Overall survival is defined as the time from enrollment of study until death from any cause (or date of last follow-up for patients still alive)	5 years
Secondary	Progression free survival	PFS is defined as the time from enrollment of study until either first documentation of RECIST-defined disease progression or death due to any cause, whichever come first.	Every 6-8 weeks, from date of enrollment until the date of first documented progression
Secondary	Tumor response rate	Tumor response rate is defined as the proportion of patients with a complete response (CR) or partial response (PR) among patients with evaluable lesions for response of RECIST.	Every 6-8 weeks, assess the tumor response from date of enrollment
Secondary	safety using NCI Common Terminology Criteria for Adverse Events (version 4.03)	Toxicity profiles will be evaluated every cycle with physical examination, vital signs, performance status, CBC, and serum chemistry using NCI Common Terminology Criteria for Adverse Events version 4.03.	Every 2-4 weeks, from date of enrollment until 30th days of last cycles treatment or initation of new regimen
Secondary	Quality of life composite score of EORTC-QoL-C30 and EORTC CIPN20	Investigators measured Quality of life using EORTC-QoL-C30 and EORTC CIPN20 at the time of enrollment, 12-18 weeks, and 30 weeks	0-1 week, 12-18 week, 24-34 week after enrollment