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

Sponsor

Asan Medical Center (Other)

Overall Status

Unknown status

CT.gov ID

NCT03296306

Collaborator

Korean Cancer Study Group (Other)

330

Enrollment

Locations

Arms

Duration (Months)

17.4

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Bladder Cancer Ureter Cancer Urethral Cancer Transitional Cell Carcinoma	Drug: Treatment duration of cisplatin based chemotherapy	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

330 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Sep 1, 2016

Anticipated Primary Completion Date :

Aug 1, 2021

Anticipated Study Completion Date :

Feb 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 6 cycles arm 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)	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
Experimental: 4 cycles arm 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)	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

Arm

Intervention/Treatment

Active Comparator: 6 cycles arm

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)

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

Experimental: 4 cycles arm

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)

Drug: Treatment duration of cisplatin based chemotherapy

Outcome Measures

Primary Outcome Measures

Overall survival [5 years]
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 [Every 6-8 weeks, from date of enrollment until the date of first documented progression]
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 [Every 6-8 weeks, assess the tumor response from date of enrollment]
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) [Every 2-4 weeks, from date of enrollment until 30th days of last cycles treatment or initation of new regimen]
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 [0-1 week, 12-18 week, 24-34 week after enrollment]
Investigators measured Quality of life using EORTC-QoL-C30 and EORTC CIPN20 at the time of enrollment, 12-18 weeks, and 30 weeks

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kwonoh Park	Yangsan	Gyeongsangnam-do	Korea, Republic of	50612
2	Hallym University Medical Center, Hallym University College of Medicine	Anyang		Korea, Republic of
3	Fatima Hospital	Daegu		Korea, Republic of
4	Keimyeong University Dongsan Medical Center	Daegu		Korea, Republic of
5	Chungnam University Hospital	Daejeon		Korea, Republic of
6	National Health Insurance Service Ilsan Hospital	Goyang		Korea, Republic of
7	Gil Medical Center	Incheon		Korea, Republic of
8	Inje University Haeundae Paik Hospital	Pusan		Korea, Republic of
9	Kosin University Hospital	Pusan		Korea, Republic of
10	Pusan National University Hospital, Pusan National University School of Medicine	Pusan		Korea, Republic of
11	Asan Medical Center	Seoul		Korea, Republic of
12	Chung Ang University Hospital	Seoul		Korea, Republic of
13	Inje University Sanggye Paik Hospital	Seoul		Korea, Republic of
14	Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine	Seoul		Korea, Republic of
15	Korea University Anam Hospital	Seoul		Korea, Republic of
16	Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine	Seoul		Korea, Republic of
17	VHS medical center	Seoul		Korea, Republic of
18	Yonsei Cancer Center	Seoul		Korea, Republic of
19	St. Vincent's Hospital, The Catholic University of Korea	Suwon		Korea, Republic of