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

Primary Purpose

Bladder Cancer, Ureter Cancer, Urethral Cancer

Status
Unknown status
Phase
Phase 3
Locations
Korea, Republic of
Study Type
Interventional
Intervention
Treatment duration of cisplatin based chemotherapy
Sponsored by
Asan Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bladder Cancer focused on measuring urothelial carcinoma, cisplatin, first-line chemotherapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Kwonoh ParkRecruiting
  • Hallym University Medical Center, Hallym University College of MedicineRecruiting
  • Fatima HospitalRecruiting
  • Keimyeong University Dongsan Medical CenterRecruiting
  • Chungnam University HospitalRecruiting
  • National Health Insurance Service Ilsan HospitalRecruiting
  • Gil Medical CenterRecruiting
  • Inje University Haeundae Paik HospitalRecruiting
  • Kosin University HospitalRecruiting
  • Pusan National University Hospital, Pusan National University School of MedicineRecruiting
  • Asan Medical CenterRecruiting
  • Chung Ang University HospitalRecruiting
  • Inje University Sanggye Paik HospitalRecruiting
  • Kangbuk Samsung Hospital, Sungkyunkwan University School of MedicineRecruiting
  • Korea University Anam HospitalRecruiting
  • Seoul National University Hospital, Cancer Research Institute, Seoul National University College of MedicineRecruiting
  • VHS medical centerRecruiting
  • Yonsei Cancer CenterRecruiting
  • St. Vincent's Hospital, The Catholic University of KoreaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

6 cycles arm

4 cycles arm

Arm Description

Patients without evidence of disease progression or unacceptable toxicities after completion of two or four treatment cycles of cisplatin based chemotherapy (GP, GP-S, MVAC, HD-MVAC with GCSF) were randomly assigned to receive additional two to four cycles of chemotherapy (totally six cycles)

Patients without evidence of disease progression or unacceptable toxicities after completion of two or four treatment cycles of cisplatin based chemotherapy (GP, GP-S, MVAC, HD-MVAC with GCSF) were randomly assigned to receive additional zero to two cycles of chemotherapy (totally four cycles)

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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.
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.
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.
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

Full Information

First Posted
August 22, 2016
Last Updated
September 23, 2017
Sponsor
Asan Medical Center
Collaborators
Korean Cancer Study Group
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1. Study Identification

Unique Protocol Identification Number
NCT03296306
Brief Title
Four Cycles Versus Six Cycles of Cisplatin-based Chemotherapy in Metastatic Urothelial Carcinoma
Acronym
FOCUS
Official Title
Four Cycles of Cisplatin-Based Chemotherapy in Metastatic Urothelial Carcinoma Compared to Six Cycles: Randomized Phase III Trial - FOCUS Study -
Study Type
Interventional

2. Study Status

Record Verification Date
September 2017
Overall Recruitment Status
Unknown status
Study Start Date
September 2016 (undefined)
Primary Completion Date
August 2021 (Anticipated)
Study Completion Date
February 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Asan Medical Center
Collaborators
Korean Cancer Study Group

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief 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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bladder Cancer, Ureter Cancer, Urethral Cancer, Transitional Cell Carcinoma
Keywords
urothelial carcinoma, cisplatin, first-line chemotherapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
330 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
6 cycles arm
Arm Type
Active Comparator
Arm Description
Patients without evidence of disease progression or unacceptable toxicities after completion of two or four treatment cycles of cisplatin based chemotherapy (GP, GP-S, MVAC, HD-MVAC with GCSF) were randomly assigned to receive additional two to four cycles of chemotherapy (totally six cycles)
Arm Title
4 cycles arm
Arm Type
Experimental
Arm Description
Patients without evidence of disease progression or unacceptable toxicities after completion of two or four treatment cycles of cisplatin based chemotherapy (GP, GP-S, MVAC, HD-MVAC with GCSF) were randomly assigned to receive additional zero to two cycles of chemotherapy (totally four cycles)
Intervention Type
Drug
Intervention Name(s)
Treatment duration of cisplatin based chemotherapy
Intervention Description
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
Primary Outcome Measure Information:
Title
Overall survival
Description
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)
Time Frame
5 years
Secondary Outcome Measure Information:
Title
Progression free survival
Description
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.
Time Frame
Every 6-8 weeks, from date of enrollment until the date of first documented progression
Title
Tumor response rate
Description
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.
Time Frame
Every 6-8 weeks, assess the tumor response from date of enrollment
Title
safety using NCI Common Terminology Criteria for Adverse Events (version 4.03)
Description
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.
Time Frame
Every 2-4 weeks, from date of enrollment until 30th days of last cycles treatment or initation of new regimen
Title
Quality of life composite score of EORTC-QoL-C30 and EORTC CIPN20
Description
Investigators measured Quality of life using EORTC-QoL-C30 and EORTC CIPN20 at the time of enrollment, 12-18 weeks, and 30 weeks
Time Frame
0-1 week, 12-18 week, 24-34 week after enrollment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Patients with histologically or cytologically confirmed urothelial cancer Unresectable locally advanced (T3b, N2-3), metastatic (M1), or recurrent disease Age 18 years or older Eastern Cooperative Oncology Group performance status 0-1 Not progressed disease status after 2 or 4 cycles of platinum-based chemotherapy Adequate organ and bone marrow function for chemotherapy 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. 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. Patients should sign a written informed consent before study entry. Exclusion Criteria: Histologic types other than urothelial cell carcinoma should be excluded. However, urothelial cell types combined with squamous or glandular features are allowed. 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% Presence or history of CNS metastasis 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) Peripheral sensory neuropathy grade 2 or worse according to NCI CTCAE History of treatment with drugs of another clinical trial within 30 days before enrollment. 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 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). Pregnant or lactating women, women of childbearing potential not employing adequate contraception
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jae lyun Lee, MD., PhD.
Phone
+82-2-3010-5977
Email
jaelyun@amc.seoul.kr
First Name & Middle Initial & Last Name or Official Title & Degree
MiRan Kim
Phone
+82-2-3010-5576
Email
crnonc12@amc.seoul.kr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jae-Lyun Lee, MD., PhD.
Organizational Affiliation
Asan Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Kwonoh Park
City
Yangsan
State/Province
Gyeongsangnam-do
ZIP/Postal Code
50612
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kwonoh Park, MD, PhD
Phone
1033783529
Email
parkkoh@daum.net
Facility Name
Hallym University Medical Center, Hallym University College of Medicine
City
Anyang
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ho Young Kim
Email
ksfam@daum.net
Facility Name
Fatima Hospital
City
Daegu
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jung Lim Lee
Email
junglim3@gmail.com
Facility Name
Keimyeong University Dongsan Medical Center
City
Daegu
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jin Young Kim, MD
Email
takgu@dsmc.or.kr
Facility Name
Chungnam University Hospital
City
Daejeon
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hyo Jin Lee, MD, PhD.
Email
cymed@cnu.ac.kr
Facility Name
National Health Insurance Service Ilsan Hospital
City
Goyang
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Soo Jung Hong
Email
suzzy901@nhimc.or.kr
Facility Name
Gil Medical Center
City
Incheon
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Inkeun Park, MD, PhD
Email
ingni79@hanmail.net
Facility Name
Inje University Haeundae Paik Hospital
City
Pusan
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Il-Hwan Kim
Email
onelement@daum.net
Facility Name
Kosin University Hospital
City
Pusan
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sung-Hoon Shin
Email
ssh1533@daum.net
Facility Name
Pusan National University Hospital, Pusan National University School of Medicine
City
Pusan
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hyo Jung Kim
Email
leonkim80@naver.com
Facility Name
Asan Medical Center
City
Seoul
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jae-Lyun Lee, MD, PhD
Email
jaelyun@amc.seoul.kr
Facility Name
Chung Ang University Hospital
City
Seoul
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hee Joon Kim
Facility Name
Inje University Sanggye Paik Hospital
City
Seoul
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Byeong Seok Sohn
Email
imbs@paik.ac.kr
Facility Name
Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine
City
Seoul
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yun-Gyoo Lee
Email
gosciny@gmail.com
Facility Name
Korea University Anam Hospital
City
Seoul
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yoon Ji Choi
Email
yoonji23@hanmail.net
Facility Name
Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine
City
Seoul
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bhum Suk Keam
Email
bhumsuk@snu.ac.kr
Facility Name
VHS medical center
City
Seoul
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bong-Seog Kim
Facility Name
Yonsei Cancer Center
City
Seoul
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sang Joon Shin
Email
ssj338@yuhs.ac
Facility Name
St. Vincent's Hospital, The Catholic University of Korea
City
Suwon
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Byoung Yong Shim
Email
shimby@catholic.ac.kr

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
18685414
Citation
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.
Results Reference
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PubMed Identifier
11001674
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 methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77. doi: 10.1200/JCO.2000.18.17.3068.
Results Reference
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PubMed Identifier
16330205
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 high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. doi: 10.1016/j.ejca.2005.08.032. Epub 2005 Dec 5.
Results Reference
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PubMed Identifier
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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 metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. doi: 10.1200/JCO.1992.10.7.1066. Erratum In: J Clin Oncol 1993 Feb;11(2):384.
Results Reference
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PubMed Identifier
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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 Pharmacol. 2015 Jul;76(1):141-53. doi: 10.1007/s00280-015-2774-z. Epub 2015 May 23.
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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 platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007 Nov 20;25(33):5233-9. doi: 10.1200/JCO.2007.10.8134.
Results Reference
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Four Cycles Versus Six Cycles of Cisplatin-based Chemotherapy in Metastatic Urothelial Carcinoma

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