Clinical trial NCT03296306: Four Cycles Versus Six Cycles of Cisplatin-based Chemotherapy in Metastatic Urothelial Carcinoma
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
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Bladder Cancer
Ureter Cancer
Urethral Cancer
Transitional Cell Carcinoma
Keywords: urothelial carcinoma
cisplatin
first-line chemotherapy
Lead sponsor: Asan Medical Center
Sponsor class: OTHER
Collaborators: name: Korean Cancer Study Group
First posted: 2017-09-28
Enrollment: 330
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall survival
timeFrame: 5 years
Secondary outcomes:
measure: Progression free survival
timeFrame: Every 6-8 weeks, from date of enrollment until the date of first documented progression
measure: Tumor response rate
timeFrame: Every 6-8 weeks, assess the tumor response from date of enrollment
measure: safety using NCI Common Terminology Criteria for Adverse Events (version 4.03)
timeFrame: Every 2-4 weeks, from date of enrollment until 30th days of last cycles treatment or initation of new regimen
measure: Quality of life composite score of EORTC-QoL-C30 and EORTC CIPN20
timeFrame: 0-1 week, 12-18 week, 24-34 week after enrollment
Other outcomes:
Locations:
city: Yangsan
country: Korea, Republic of
facility: Kwonoh Park
state: Gyeongsangnam-do
city: Anyang
country: Korea, Republic of
facility: Hallym University Medical Center, Hallym University College of Medicine
city: Daegu
country: Korea, Republic of
facility: Fatima Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyeong University Dongsan Medical Center
city: Daejeon
country: Korea, Republic of
facility: Chungnam University Hospital
city: Goyang
country: Korea, Republic of
facility: National Health Insurance Service Ilsan Hospital
city: Incheon
country: Korea, Republic of
facility: Gil Medical Center
city: Pusan
country: Korea, Republic of
facility: Inje University Haeundae Paik Hospital
city: Pusan
country: Korea, Republic of
facility: Kosin University Hospital
city: Pusan
country: Korea, Republic of
facility: Pusan National University Hospital, Pusan National University School of Medicine
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Chung Ang University Hospital
city: Seoul
country: Korea, Republic of
facility: Inje University Sanggye Paik Hospital
city: Seoul
country: Korea, Republic of
facility: Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine
city: Seoul
country: Korea, Republic of
facility: VHS medical center
city: Seoul
country: Korea, Republic of
facility: Yonsei Cancer Center
city: Suwon
country: Korea, Republic of
facility: St. Vincent's Hospital, The Catholic University of Korea
Study officials:
affiliation: Asan Medical Center
name: Jae-Lyun Lee, MD., PhD.
role: PRINCIPAL_INVESTIGATOR
References:
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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.
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.