Chemotherapy Before Surgery in Treating Patients With High Grade Upper Urinary Tract Cancer

• Sponsor: ECOG-ACRIN Cancer Research Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT02412670
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 36
• Locations: 134
• Arms: 2
• Actual Duration (Months): 85.3
• Patients Per Site: 0.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II trial studies how well giving chemotherapy before surgery works in treating patients with aggressive upper urinary tract cancer. Drugs used in chemotherapy, such as methotrexate, vinblastine, doxorubicin hydrochloride, cisplatin, gemcitabine hydrochloride, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Removing the affected upper urinary tract by surgery is the recommended treatment for upper urinary tract cancer, but can cause loss of kidney function and prevent patients from being able to receive chemotherapy after surgery. Giving chemotherapy before surgery, when the kidneys are working at their maximum, may allow less tissue to be removed during surgery and may be more effective in treating patients with high grade upper urinary tract cancer.

Condition or Disease	Intervention/Treatment	Phase
High Grade Upper Tract Urothelial Carcinoma	Drug: Methotrexate; Drug: Vinblastine; Drug: Doxorubicin; Drug: Cisplatin; Drug: Gemcitabine; Drug: Carboplatin; Drug: Pegfilgrastim; Procedure: Nephroureterectomy	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the rate of complete pathologic response (pCR = pT0pN0) as assessed by standard pathologic review attained by neoadjuvant systemic chemotherapy and nephroureterectomy.

SECONDARY OBJECTIVES:

1. To evaluate the safety of neoadjuvant systemic chemotherapy in patients with upper tract urothelial carcinoma preceding nephroureterectomy.

2. To evaluate distant recurrence-free survival of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy.

3. To evaluate event-free survival of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy.

4. To evaluate bladder cancer-free survival of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy.

5. To evaluate cancer specific survival of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy.

6. To evaluate renal functional outcomes of patients treated with neoadjuvant systemic chemotherapy preceding nephroureterectomy.

TERTIARY OBJECTIVES:

1. To collect pre-treatment and post-treatment tumor tissue, peripheral blood mononuclear cell (PBMC), peripheral blood plasma, and urine specimens for potential evaluations of markers of chemotherapy response/resistance.

OUTLINE: Patients are assigned to 1 of 2 treatment arms based on baseline renal function.

ARM A (CREATININE CLEARANCE [CRCL] > 50): Patients receive methotrexate intravenously (IV) over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.

ARM B (30 =< CRCL <= 50): Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery for Patients With High Grade Upper Tract Urothelial Carcinoma
• Actual Study Start Date: Apr 1, 2015
• Actual Primary Completion Date: Aug 23, 2018
• Actual Study Completion Date: May 10, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (methotrexate, vinblastine, doxorubicin, cisplatin) Patients receive methotrexate IV over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Pegfilgrastim at 6 mg is given once 24-48 hours after completion of chemotherapy. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.	Drug: Methotrexate; Given IV; Other Names: Folex abitrexate mexate ; Drug: Vinblastine; Given IV; Other Names: vinblastine sulfate ; Drug: Doxorubicin; Given IV; Other Names: Adriamycin R Rubex R Adriamycin RDF R Adriamycin PFS R hydroxydaunorubicin hydroxydaunomycin ADR ; Drug: Cisplatin; Given IV; Other Names: Cisdiaminedichloroplatinum Cis-diaminedichloroplatinum (II) diaminedichloroplatinum cis-platinum platinum Platinol Platinol-AQ DDP CDDP DACP NSC 119875 ; Drug: Pegfilgrastim; Administered subcutaneously; Other Names: Neulasta ; Procedure: Nephroureterectomy; Undergo nephroureterectomy and lymph node dissection
Experimental: Arm B (gemcitabine, carboplatin) Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.	Drug: Gemcitabine; Given IV; Other Names: 2'-Deoxy-2' 2'-difluorocytidine monohydrochloride Gemzar ; Drug: Carboplatin; Given IV; Other Names: Paraplatin ; Procedure: Nephroureterectomy; Undergo nephroureterectomy and lymph node dissection

Outcome Measures

Primary Outcome Measures

1. Complete Pathologic Response Rate [Assessed at nephroureterectomy or regional lymph node dissection (21-60 days from completion of chemotherapy; chemotherapy was administered for a total of 4 cycles; cycle length is 14 days and 21 days for arms A and B, respectively)]

   Complete pathologic response is defined as pT0pN0 (no evidence of disease) as assessed by pathologic evaluation of nephrectomy/ureterectomy and any identifiable regional lymph nodes.

Secondary Outcome Measures

1. Recurrence-free Survival [Assessed every 3 months for 2 years; and every 6 months for 3-5 years]

   Recurrence-free survival is defined as the time from the date of surgery to disease recurrence or death from any cause. Patients alive without documented recurrence will be censored at the date of last disease assessment.

2. Event-free Survival [Assessed every 3 months for 2 years, and every 6 months for 3-5 years]

   Event-free survival is defined as the time from registration to the earliest occurrence of recurrence of any type, disease progression, new invasive primary cancer, or death from any cause. Disease progression will be assessed using RECIST 1.1. Disease progression is defined as appearance of one or more new lesions, unequivocal progression of existing non-target lesions, or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

3. Bladder Cancer-free Survival [Assessed every 3 months for 2 years, and every 6 months for 3-5 years]

   Bladder cancer-free survival was defined as the time from the date of surgery to the earlier of a return of bladder cancer or death from any cause. Patients alive without documented bladder cancer were censored at the date of last disease assessment.

4. Cumulative Incidence of Cancer-specific Death at 24 Months [Assessed every 3 months for 2 years]

   Cancer-specific survival was defined as the time from registration to death due to cancer; deaths due to other causes are counted as competing events. Cancer-specific survival was analyzed using Gray's method and cumulative incidence of cancer-specific death at 24 months is reported.

5. Proportion of Patients With Renal Insufficiency at Completion of Chemotherapy [Assessed at completion of chemotherapy; at 8 weeks for Arm A and 12 weeks for Arm B]

   Renal insufficiency is defined as CrCl < 60 ml/min.

6. Proportion of Patients With Renal Insufficiency at Completion of Surgery [Assessed at completion of surgery (21-60 days from completion of chemotherapy; chemotherapy was administered for a total of 4 cycles; cycle length is 14 days and 21 days for arms A and B, respectively)]

   Renal insufficiency is defined as CrCl < 60 ml/min.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have high grade upper tract urothelial carcinoma proven by one of the following:

• Biopsy;

• Urinary cytology with a 3-dimensional upper urinary tract mass on cross-sectional imaging; or

• Urinary cytology and a mass visualized during upper urinary tract endoscopy

• Patients must have a creatinine clearance >= 30 ml/min as determined by Cockcroft-Gault calculation or 24-hour urine creatinine clearance measurement within 28 days of registration to be eligible for the study

• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Patients must have a left ventricular ejection fraction (LVEF) >= 50% by (either multigated acquisition [MUGA] or 2-dimensional [2-D] echocardiogram) within 28 days of registration

• Absolute neutrophil count (ANC) >= 1500/mm^3

• Platelets >= 100,000/mm^3

• Hemoglobin (HgB) >= 9

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2 X institutional upper limit of normal (ULN)

• Bilirubin within institutional normal limits (or < 2.5 X the ULN for patients with Gilbert's disease)

• Patients with concomitant primaries of the bladder/urethra are allowed, as long as these sites are surgically resected and non-invasive cancers (< cT1N0)

• Patients may have a history of resectable urothelial cancer (including neoadjuvant chemotherapy) as long as patients meet one of the following:

• pT0, Tis, or T1N0 and have no evidence of disease (NED) for more than 2 years from surgery or chemotherapy;

• pT2-3aN0 and NED for more than 3 years from surgery or chemotherapy; or

• pT3b, or N+ and NED for more than 5 years from surgery or chemotherapy

• Women of childbearing potential and sexually active males must use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study

Exclusion Criteria:

• Evidence of metastatic disease or clinically enlarged lymph nodes on computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis and CT chest obtained within 28 days of registration (a negative biopsy is required for lymph nodes > 1 cm in size to confirm lack of involvement); patients with lymph nodes > 1 cm in whom a biopsy is deemed not feasible are not eligible; patients with elevated alkaline phosphatase or suspicious bone pain should also undergo baseline bone scans to evaluate for bone metastasis

• Any component of small cell carcinoma; other variant histologies are permitted provided the predominant (>= 50%) subtype is urothelial carcinoma

• Peripheral neuropathy > grade 2

• History of allergy or hypersensitivity to methotrexate, vinblastine, doxorubicin (doxorubicin hydrochloride), cisplatin, gemcitabine (gemcitabine hydrochloride), carboplatin or filgrastim or pegfilgrastim

• Another active second malignancy other than non-melanoma skin cancers and biochemical relapsed prostate cancer; patients that have completed all necessary therapy and are considered to be at less than 30% risk of relapse are not considered to have an active second malignancy and are eligible for enrollment

• Prior systemic doxorubicin for patients who have creatinine clearance that meets >= 50 ml/min

• Uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, myocardial infarction in last 3 months, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Known to have human immunodeficiency virus (HIV) or are on combination antiretroviral therapy

• Prior radiation therapy to >= 25% of the bone marrow for other diseases or prior systemic anthracycline therapy; prior intravesical anthracycline therapy for non-muscle invasive urothelial carcinoma of the bladder is permitted

• Pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
2	University of Colorado Cancer Center - Anschutz Cancer Pavilion	Aurora	Colorado	United States	80045
3	Memorial Hospital Colorado Springs	Colorado Springs	Colorado	United States	80909
4	Poudre Valley Hospital	Fort Collins	Colorado	United States	80524
5	Saint Francis Hospital and Medical Center	Hartford	Connecticut	United States	06105
6	Beebe Medical Center	Lewes	Delaware	United States	19958
7	Christiana Gynecologic Oncology LLC	Newark	Delaware	United States	19713
8	Delaware Clinical and Laboratory Physicians PA	Newark	Delaware	United States	19713
9	Helen F Graham Cancer Center	Newark	Delaware	United States	19713
10	Medical Oncology Hematology Consultants PA	Newark	Delaware	United States	19713
11	Regional Hematology and Oncology PA	Newark	Delaware	United States	19713
12	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
13	Beebe Health Campus	Rehoboth Beach	Delaware	United States	19971
14	Nanticoke Memorial Hospital	Seaford	Delaware	United States	19973
15	Christiana Care Health System-Wilmington Hospital	Wilmington	Delaware	United States	19801
16	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia	United States	31405
17	Low Country Cancer Care Associates PC	Savannah	Georgia	United States	31405
18	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho	United States	83706
19	Saint Joseph Medical Center	Bloomington	Illinois	United States	61701
20	Illinois CancerCare-Bloomington	Bloomington	Illinois	United States	61704
21	Illinois CancerCare-Canton	Canton	Illinois	United States	61520
22	Memorial Hospital of Carbondale	Carbondale	Illinois	United States	62902
23	Illinois CancerCare-Carthage	Carthage	Illinois	United States	62321
24	Centralia Oncology Clinic	Centralia	Illinois	United States	62801
25	Carle on Vermilion	Danville	Illinois	United States	61832
26	Cancer Care Center of Decatur	Decatur	Illinois	United States	62526
27	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
28	Carle Physician Group-Effingham	Effingham	Illinois	United States	62401
29	Crossroads Cancer Center	Effingham	Illinois	United States	62401
30	Illinois CancerCare-Eureka	Eureka	Illinois	United States	61530
31	Illinois CancerCare Galesburg	Galesburg	Illinois	United States	61401
32	Western Illinois Cancer Treatment Center	Galesburg	Illinois	United States	61401
33	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois	United States	61443
34	Illinois CancerCare-Macomb	Macomb	Illinois	United States	61455
35	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois	United States	61938
36	Good Samaritan Regional Health Center	Mount Vernon	Illinois	United States	62864
37	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois	United States	61350
38	Radiation Oncology of Northern Illinois	Ottawa	Illinois	United States	61350
39	Illinois CancerCare-Pekin	Pekin	Illinois	United States	61554
40	Pekin Cancer Treatment Center	Pekin	Illinois	United States	61554
41	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61603
42	OSF Saint Francis Medical Center Radiation Oncology Service at the Central Illinois Comprehensive CC	Peoria	Illinois	United States	61615-7827
43	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
44	OSF Saint Francis Medical Center	Peoria	Illinois	United States	61637
45	Illinois CancerCare-Peru	Peru	Illinois	United States	61354
46	Valley Radiation Oncology	Peru	Illinois	United States	61354
47	Illinois CancerCare-Princeton	Princeton	Illinois	United States	61356
48	Central Illinois Hematology Oncology Center	Springfield	Illinois	United States	62702
49	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
50	Springfield Clinic	Springfield	Illinois	United States	62703
51	Memorial Medical Center	Springfield	Illinois	United States	62781
52	Cancer Care Specialists of Illinois-Swansea	Swansea	Illinois	United States	62226
53	Carle Cancer Center	Urbana	Illinois	United States	61801
54	The Carle Foundation Hospital	Urbana	Illinois	United States	61801
55	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana	United States	46360
56	Woodland Cancer Care Center	Michigan City	Indiana	United States	46360
57	Reid Hospital and Health Care Services	Richmond	Indiana	United States	47374
58	Oncology Hematology Care Inc-Crestview	Crestview Hills	Kentucky	United States	41017
59	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
60	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106-0995
61	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
62	Oakwood Hospital and Medical Center	Dearborn	Michigan	United States	48124
63	Saint John Hospital and Medical Center	Detroit	Michigan	United States	48236
64	Hurley Medical Center	Flint	Michigan	United States	48502
65	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
66	Allegiance Health	Jackson	Michigan	United States	49201
67	Sparrow Hospital	Lansing	Michigan	United States	48912
68	Saint Mary Mercy Hospital	Livonia	Michigan	United States	48154
69	Saint Joseph Mercy Oakland	Pontiac	Michigan	United States	48341
70	Saint Joseph Mercy Port Huron	Port Huron	Michigan	United States	48060
71	Saint Mary's of Michigan	Saginaw	Michigan	United States	48601
72	Saint John Macomb-Oakland Hospital	Warren	Michigan	United States	48093
73	Central Care Cancer Center-Carrie J Babb Cancer Center	Bolivar	Missouri	United States	65613
74	Parkland Health Center-Bonne Terre	Bonne Terre	Missouri	United States	63628
75	CoxHealth Cancer Center	Branson	Missouri	United States	65616
76	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
77	Southeast Cancer Center	Cape Girardeau	Missouri	United States	63703
78	Capital Region Medical Center-Goldschmidt Cancer Center	Jefferson City	Missouri	United States	65109
79	Freeman Health System	Joplin	Missouri	United States	64804
80	Mercy Hospital-Joplin	Joplin	Missouri	United States	64804
81	Phelps County Regional Medical Center	Rolla	Missouri	United States	65401
82	Saint John's Clinic-Rolla-Cancer and Hematology	Rolla	Missouri	United States	65401
83	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri	United States	63109
84	Missouri Baptist Medical Center	Saint Louis	Missouri	United States	63131
85	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
86	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri	United States	63670
87	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
88	CoxHealth South Hospital	Springfield	Missouri	United States	65807
89	Missouri Baptist Sullivan Hospital	Sullivan	Missouri	United States	63080
90	Missouri Baptist Outpatient Center-Sunset Hills	Sunset Hills	Missouri	United States	63127
91	Miami Valley Hospital South	Centerville	Ohio	United States	45459
92	Oncology Hematology Care Inc-Eden Park	Cincinnati	Ohio	United States	45202
93	Oncology Hematology Care Inc-Mercy West	Cincinnati	Ohio	United States	45211
94	Oncology Hematology Care Inc - Anderson	Cincinnati	Ohio	United States	45230
95	Oncology Hematology Care Inc - Kenwood	Cincinnati	Ohio	United States	45236
96	Oncology Hematology Care Inc-Blue Ash	Cincinnati	Ohio	United States	45242
97	Good Samaritan Hospital - Dayton	Dayton	Ohio	United States	45406
98	Miami Valley Hospital	Dayton	Ohio	United States	45409
99	Samaritan North Health Center	Dayton	Ohio	United States	45415
100	Oncology Hematology Care Inc-Healthplex	Fairfield	Ohio	United States	45014
101	Blanchard Valley Hospital	Findlay	Ohio	United States	45840
102	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
103	Wayne Hospital	Greenville	Ohio	United States	45331
104	Kettering Medical Center	Kettering	Ohio	United States	45429
105	Springfield Regional Cancer Center	Springfield	Ohio	United States	45504
106	Springfield Regional Medical Center	Springfield	Ohio	United States	45505
107	Flower Hospital	Sylvania	Ohio	United States	43560
108	Upper Valley Medical Center	Troy	Ohio	United States	45373
109	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
110	Tulsa Cancer Institute	Tulsa	Oklahoma	United States	74146
111	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania	United States	19317
112	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
113	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania	United States	18201
114	Geisinger Medical Oncology at Evangelical Community Hospital	Lewisburg	Pennsylvania	United States	17837
115	Lewistown Hospital	Lewistown	Pennsylvania	United States	17044
116	ECOG-ACRIN Cancer Research Group	Philadelphia	Pennsylvania	United States	19103
117	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
118	Geisinger Medical Oncology-Pottsville	Pottsville	Pennsylvania	United States	17901
119	Geisinger Medical Group	State College	Pennsylvania	United States	16801
120	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania	United States	18711
121	Medical University of South Carolina	Charleston	South Carolina	United States	29425
122	Vanderbilt-Ingram Cancer Center Cool Springs	Franklin	Tennessee	United States	37067
123	Vanderbilt Breast Center at One Hundred Oaks	Nashville	Tennessee	United States	37204
124	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
125	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
126	Aurora Cancer Care-Burlington	Burlington	Wisconsin	United States	53105
127	Aurora Cancer Care-Grafton	Grafton	Wisconsin	United States	53024
128	Vince Lombardi Cancer Clinic-Marinette	Marinette	Wisconsin	United States	54143
129	Aurora Advanced Healthcare Inc-Menomonee Falls	Menomonee Falls	Wisconsin	United States	53051
130	Aurora Cancer Care-Milwaukee	Milwaukee	Wisconsin	United States	53209
131	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin	United States	54904
132	Aurora Cancer Care-Racine	Racine	Wisconsin	United States	53406-5661
133	Aurora Medical Center in Summit	Summit	Wisconsin	United States	53066
134	Aurora Cancer Care-Waukesha	Waukesha	Wisconsin	United States	53188

Sponsors and Collaborators

• ECOG-ACRIN Cancer Research Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Vitaly Margulis, ECOG-ACRIN Cancer Research Group

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 11, 2019

More Information

Publications

None provided.

• Responsible Party: ECOG-ACRIN Cancer Research Group
• ClinicalTrials.gov Identifier: NCT02412670
• Other Study ID Numbers: EA8141; NCI-2014-02267; EA8141; EA8141; U10CA180820
• First Posted: Apr 9, 2015
• Last Update Posted: Aug 11, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by ECOG-ACRIN Cancer Research Group: carcinoma; drug therapy; nephroureterectomy; urinary tract; urothelium
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Transitional Cell; Gemcitabine; Cisplatin; Carboplatin; Doxorubicin; Liposomal doxorubicin; Methotrexate; Vinblastine

Study Results

Participant Flow

Recruitment Details	The study was activated on April 1, 2015. Arm A reached its accrual and was closed on May 31, 2017. Arm B was closed due to slow accrual on January 5, 2018.

Arm/Group Title	Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)	Arm B (Gemcitabine, Carboplatin)
Arm/Group Description	Patients receive methotrexate IV over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Pegfilgrastim at 6 mg is given once 24-48 hours after completion of chemotherapy. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.	Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.
Period Title: Overall Study
STARTED	30	6
Eligible and Treated	29	6
COMPLETED	23	5
NOT COMPLETED	7	1

Baseline Characteristics

Arm/Group Title	Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)	Arm B (Gemcitabine, Carboplatin)	Total
Arm/Group Description	Patients receive methotrexate IV over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Pegfilgrastim at 6 mg is given once 24-48 hours after completion of chemotherapy. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.	Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.	Total of all reporting groups
Overall Participants	29	6	35
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65	75	66
Sex: Female, Male (Count of Participants)
Female	6 20.7%	2 33.3%	8 22.9%
Male	23 79.3%	4 66.7%	27 77.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 33.3%	2 5.7%
Not Hispanic or Latino	27 93.1%	4 66.7%	31 88.6%
Unknown or Not Reported	2 6.9%	0 0%	2 5.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 3.4%	0 0%	1 2.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 3.4%	0 0%	1 2.9%
White	26 89.7%	4 66.7%	30 85.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 3.4%	2 33.3%	3 8.6%

Outcome Measures

1. Primary Outcome

Title	Complete Pathologic Response Rate
Description	Complete pathologic response is defined as pT0pN0 (no evidence of disease) as assessed by pathologic evaluation of nephrectomy/ureterectomy and any identifiable regional lymph nodes.
Time Frame	Assessed at nephroureterectomy or regional lymph node dissection (21-60 days from completion of chemotherapy; chemotherapy was administered for a total of 4 cycles; cycle length is 14 days and 21 days for arms A and B, respectively)

Outcome Measure Data

Analysis Population Description

Eligible and treated patients

Arm/Group Title	Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)	Arm B (Gemcitabine, Carboplatin)
Arm/Group Description	Patients receive methotrexate IV over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Pegfilgrastim at 6 mg is given once 24-48 hours after completion of chemotherapy. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.	Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.
Measure Participants	29	6
Number (80% Confidence Interval) [proportion of participants]	0.103 0.4%	0.167 2.8%

2. Secondary Outcome

Title	Recurrence-free Survival
Description	Recurrence-free survival is defined as the time from the date of surgery to disease recurrence or death from any cause. Patients alive without documented recurrence will be censored at the date of last disease assessment.
Time Frame	Assessed every 3 months for 2 years; and every 6 months for 3-5 years

Outcome Measure Data

Analysis Population Description

Eligible and treated patients who underwent radical nephro-ureterectomy and were rendered disease-free

Arm/Group Title	Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)	Arm B (Gemcitabine, Carboplatin)
Arm/Group Description	Patients receive methotrexate IV over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Pegfilgrastim at 6 mg is given once 24-48 hours after completion of chemotherapy. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.	Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.
Measure Participants	28	5
Median (90% Confidence Interval) [months]	NA	8.5

3. Secondary Outcome

Title	Event-free Survival
Description	Event-free survival is defined as the time from registration to the earliest occurrence of recurrence of any type, disease progression, new invasive primary cancer, or death from any cause. Disease progression will be assessed using RECIST 1.1. Disease progression is defined as appearance of one or more new lesions, unequivocal progression of existing non-target lesions, or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time Frame	Assessed every 3 months for 2 years, and every 6 months for 3-5 years

Outcome Measure Data

Analysis Population Description

Eligible and treated patients

Arm/Group Title	Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)	Arm B (Gemcitabine, Carboplatin)
Arm/Group Description	Patients receive methotrexate IV over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Pegfilgrastim at 6 mg is given once 24-48 hours after completion of chemotherapy. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.	Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.
Measure Participants	29	6
Median (90% Confidence Interval) [months]	NA	10.2

4. Secondary Outcome

Title	Bladder Cancer-free Survival
Description	Bladder cancer-free survival was defined as the time from the date of surgery to the earlier of a return of bladder cancer or death from any cause. Patients alive without documented bladder cancer were censored at the date of last disease assessment.
Time Frame	Assessed every 3 months for 2 years, and every 6 months for 3-5 years

Outcome Measure Data

Analysis Population Description

Eligible and treated patients who underwent radical nephro-ureterectomy and were rendered disease-free

Arm/Group Title	Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)	Arm B (Gemcitabine, Carboplatin)
Arm/Group Description	Patients receive methotrexate IV over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Pegfilgrastim at 6 mg is given once 24-48 hours after completion of chemotherapy. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.	Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.
Measure Participants	28	5
Median (90% Confidence Interval) [months]	NA	NA

5. Secondary Outcome

Title	Cumulative Incidence of Cancer-specific Death at 24 Months
Description	Cancer-specific survival was defined as the time from registration to death due to cancer; deaths due to other causes are counted as competing events. Cancer-specific survival was analyzed using Gray's method and cumulative incidence of cancer-specific death at 24 months is reported.
Time Frame	Assessed every 3 months for 2 years

Outcome Measure Data

Analysis Population Description

Eligible and treated patients

Arm/Group Title	Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)	Arm B (Gemcitabine, Carboplatin)
Arm/Group Description	Patients receive methotrexate IV over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Pegfilgrastim at 6 mg is given once 24-48 hours after completion of chemotherapy. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.	Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.
Measure Participants	29	6
Number (90% Confidence Interval) [proportion of patients died of cancer]	0.09	0.20

6. Secondary Outcome

Title	Proportion of Patients With Renal Insufficiency at Completion of Chemotherapy
Description	Renal insufficiency is defined as CrCl < 60 ml/min.
Time Frame	Assessed at completion of chemotherapy; at 8 weeks for Arm A and 12 weeks for Arm B

Outcome Measure Data

Analysis Population Description

All patients with chemotherapy

Arm/Group Title	Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)	Arm B (Gemcitabine, Carboplatin)
Arm/Group Description	Patients receive methotrexate IV over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Pegfilgrastim at 6 mg is given once 24-48 hours after completion of chemotherapy. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.	Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.
Measure Participants	30	6
Number (90% Confidence Interval) [proportion of participants]	0.2 0.7%	0.833 13.9%

7. Secondary Outcome

Title	Proportion of Patients With Renal Insufficiency at Completion of Surgery
Description	Renal insufficiency is defined as CrCl < 60 ml/min.
Time Frame	Assessed at completion of surgery (21-60 days from completion of chemotherapy; chemotherapy was administered for a total of 4 cycles; cycle length is 14 days and 21 days for arms A and B, respectively)

Outcome Measure Data

Analysis Population Description

All patients who underwent radical nephro-ureterectomy

Arm/Group Title	Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)	Arm B (Gemcitabine, Carboplatin)
Arm/Group Description	Patients receive methotrexate IV over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Pegfilgrastim at 6 mg is given once 24-48 hours after completion of chemotherapy. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.	Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.
Measure Participants	29	6
Number (90% Confidence Interval) [proportion of participants]	0.69 2.4%	0.833 13.9%

Adverse Events

Time Frame	Assessed every 2 weeks for arm A and every 3 weeks for arm B while on treatment and for 30 days after the end of treatment up to 5 years
Adverse Event Reporting Description	Serious adverse events are defined as treatment-related adverse events of grade 3 or higher. Other adverse events are treatment-related adverse events not included in the serious adverse events.
Arm/Group Title	Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)		Arm B (Gemcitabine, Carboplatin)
Arm/Group Description	Patients receive methotrexate IV over 2-3 minutes, vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV over 4 hours on day 1. Pegfilgrastim at 6 mg is given once 24-48 hours after completion of chemotherapy. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.		Patients receive gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without metastatic disease undergo nephroureterectomy and lymph node dissection 21-60 days after completion of chemotherapy.
All Cause Mortality
	Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)		Arm B (Gemcitabine, Carboplatin)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/30 (6.7%)		1/6 (16.7%)
Serious Adverse Events
	Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)		Arm B (Gemcitabine, Carboplatin)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/30 (23.3%)		3/6 (50%)
Blood and lymphatic system disorders
Anemia	2/30 (6.7%)		2/6 (33.3%)
Gastrointestinal disorders
Diarrhea	1/30 (3.3%)		0/6 (0%)
Lower gastrointestinal hemorrhage	1/30 (3.3%)		0/6 (0%)
Mucositis oral	1/30 (3.3%)		0/6 (0%)
Gastrointestinal disorders - Other, specify	1/30 (3.3%)		0/6 (0%)
General disorders
Fatigue	1/30 (3.3%)		0/6 (0%)
Injury, poisoning and procedural complications
Fall	1/30 (3.3%)		0/6 (0%)
Vascular access complication	1/30 (3.3%)		0/6 (0%)
Investigations
Alanine aminotransferase increased	1/30 (3.3%)		0/6 (0%)
Neutrophil count decreased	2/30 (6.7%)		2/6 (33.3%)
Platelet count decreased	1/30 (3.3%)		1/6 (16.7%)
White blood cell decreased	2/30 (6.7%)		2/6 (33.3%)
Investigations - Other, specify	1/30 (3.3%)		0/6 (0%)
Metabolism and nutrition disorders
Dehydration	3/30 (10%)		0/6 (0%)
Hypokalemia	1/30 (3.3%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain	1/30 (3.3%)		0/6 (0%)
Vascular disorders
Thromboembolic event	1/30 (3.3%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Arm A (Methotrexate, Vinblastine, Doxorubicin, Cisplatin)		Arm B (Gemcitabine, Carboplatin)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/30 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Anemia	20/30 (66.7%)		5/6 (83.3%)
Gastrointestinal disorders
Nausea	23/30 (76.7%)		4/6 (66.7%)
Vomiting	6/30 (20%)		2/6 (33.3%)
General disorders
Fatigue	22/30 (73.3%)		5/6 (83.3%)
Investigations
Creatinine increased	11/30 (36.7%)		2/6 (33.3%)
Neutrophil count decreased	2/30 (6.7%)		2/6 (33.3%)
Platelet count decreased	9/30 (30%)		3/6 (50%)
White blood cell decreased	2/30 (6.7%)		3/6 (50%)
Nervous system disorders
Peripheral sensory neuropathy	4/30 (13.3%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.