Clinical trial NCT02412670: Chemotherapy Before Surgery in Treating Patients With High Grade Upper Urinary Tract Cancer
Official title: A Prospective Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery for Patients With High Grade Upper Tract Urothelial Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: High Grade Upper Tract Urothelial Carcinoma
Keywords: carcinoma
drug therapy
nephroureterectomy
urinary tract
urothelium
Lead sponsor: Eastern Cooperative Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2015-04-09
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: PRIMARY OBJECTIVES:

I. 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:

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

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

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

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

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

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

TERTIARY OBJECTIVES:

I. 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Complete Pathologic Response Rate
timeFrame: 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)
Secondary outcomes:
measure: Recurrence-free Survival
timeFrame: Assessed every 3 months for 2 years; and every 6 months for 3-5 years
measure: Event-free Survival
timeFrame: Assessed every 3 months for 2 years, and every 6 months for 3-5 years
measure: Bladder Cancer-free Survival
timeFrame: Assessed every 3 months for 2 years, and every 6 months for 3-5 years
measure: Cumulative Incidence of Cancer-specific Death at 24 Months
timeFrame: Assessed every 3 months for 2 years
measure: Proportion of Patients With Renal Insufficiency at Completion of Chemotherapy
timeFrame: Assessed at completion of chemotherapy; at 8 weeks for Arm A and 12 weeks for Arm B
measure: Proportion of Patients With Renal Insufficiency at Completion of Surgery
timeFrame: 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)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: Aurora
country: United States
facility: University of Colorado Cancer Center - Anschutz Cancer Pavilion
state: Colorado
city: Colorado Springs
country: United States
facility: Memorial Hospital Colorado Springs
state: Colorado
city: Fort Collins
country: United States
facility: Poudre Valley Hospital
state: Colorado
city: Hartford
country: United States
facility: Saint Francis Hospital and Medical Center
state: Connecticut
city: Lewes
country: United States
facility: Beebe Medical Center
state: Delaware
city: Newark
country: United States
facility: Christiana Gynecologic Oncology LLC
state: Delaware
city: Newark
country: United States
facility: Delaware Clinical and Laboratory Physicians PA
state: Delaware
city: Newark
country: United States
facility: Helen F Graham Cancer Center
state: Delaware
city: Newark
country: United States
facility: Medical Oncology Hematology Consultants PA
state: Delaware
city: Newark
country: United States
facility: Regional Hematology and Oncology PA
state: Delaware
city: Newark
country: United States
facility: Christiana Care Health System-Christiana Hospital
state: Delaware
city: Rehoboth Beach
country: United States
facility: Beebe Health Campus
state: Delaware
city: Seaford
country: United States
facility: Nanticoke Memorial Hospital
state: Delaware
city: Wilmington
country: United States
facility: Christiana Care Health System-Wilmington Hospital
state: Delaware
city: Savannah
country: United States
facility: Lewis Cancer and Research Pavilion at Saint Joseph's/Candler
state: Georgia
city: Savannah
country: United States
facility: Low Country Cancer Care Associates PC
state: Georgia
city: Boise
country: United States
facility: Saint Alphonsus Cancer Care Center-Boise
state: Idaho
city: Bloomington
country: United States
facility: Saint Joseph Medical Center
state: Illinois
city: Bloomington
country: United States
facility: Illinois CancerCare-Bloomington
state: Illinois
city: Canton
country: United States
facility: Illinois CancerCare-Canton
state: Illinois
city: Carbondale
country: United States
facility: Memorial Hospital of Carbondale
state: Illinois
city: Carthage
country: United States
facility: Illinois CancerCare-Carthage
state: Illinois
city: Centralia
country: United States
facility: Centralia Oncology Clinic
state: Illinois
city: Danville
country: United States
facility: Carle on Vermilion
state: Illinois
city: Decatur
country: United States
facility: Cancer Care Center of Decatur
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Effingham
country: United States
facility: Carle Physician Group-Effingham
state: Illinois
city: Effingham
country: United States
facility: Crossroads Cancer Center
state: Illinois
city: Eureka
country: United States
facility: Illinois CancerCare-Eureka
state: Illinois
city: Galesburg
country: United States
facility: Illinois CancerCare Galesburg
state: Illinois
city: Galesburg
country: United States
facility: Western Illinois Cancer Treatment Center
state: Illinois
city: Kewanee
country: United States
facility: Illinois CancerCare-Kewanee Clinic
state: Illinois
city: Macomb
country: United States
facility: Illinois CancerCare-Macomb
state: Illinois
city: Mattoon
country: United States
facility: Carle Physician Group-Mattoon/Charleston
state: Illinois
city: Mount Vernon
country: United States
facility: Good Samaritan Regional Health Center
state: Illinois
city: Ottawa
country: United States
facility: Illinois CancerCare-Ottawa Clinic
state: Illinois
city: Ottawa
country: United States
facility: Radiation Oncology of Northern Illinois
state: Illinois
city: Pekin
country: United States
facility: Illinois CancerCare-Pekin
state: Illinois
city: Pekin
country: United States
facility: Pekin Cancer Treatment Center
state: Illinois
city: Peoria
country: United States
facility: Methodist Medical Center of Illinois
state: Illinois
city: Peoria
country: United States
facility: OSF Saint Francis Medical Center Radiation Oncology Service at the Central Illinois Comprehensive CC
state: Illinois
city: Peoria
country: United States
facility: Illinois CancerCare-Peoria
state: Illinois
city: Peoria
country: United States
facility: OSF Saint Francis Medical Center
state: Illinois
city: Peru
country: United States
facility: Illinois CancerCare-Peru
state: Illinois
city: Peru
country: United States
facility: Valley Radiation Oncology
state: Illinois
city: Princeton
country: United States
facility: Illinois CancerCare-Princeton
state: Illinois
city: Springfield
country: United States
facility: Central Illinois Hematology Oncology Center
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University School of Medicine
state: Illinois
city: Springfield
country: United States
facility: Springfield Clinic
state: Illinois
city: Springfield
country: United States
facility: Memorial Medical Center
state: Illinois
city: Swansea
country: United States
facility: Cancer Care Specialists of Illinois-Swansea
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Urbana
country: United States
facility: The Carle Foundation Hospital
state: Illinois
city: Michigan City
country: United States
facility: Franciscan Saint Anthony Health-Michigan City
state: Indiana
city: Michigan City
country: United States
facility: Woodland Cancer Care Center
state: Indiana
city: Richmond
country: United States
facility: Reid Hospital and Health Care Services
state: Indiana
city: Crestview Hills
country: United States
facility: Oncology Hematology Care Inc-Crestview
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Medical Center Jefferson
state: Louisiana
city: Ann Arbor
country: United States
facility: Saint Joseph Mercy Hospital
state: Michigan
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Dearborn
country: United States
facility: Oakwood Hospital and Medical Center
state: Michigan
city: Detroit
country: United States
facility: Saint John Hospital and Medical Center
state: Michigan
city: Flint
country: United States
facility: Hurley Medical Center
state: Michigan
city: Flint
country: United States
facility: Genesys Hurley Cancer Institute
state: Michigan
city: Jackson
country: United States
facility: Allegiance Health
state: Michigan
city: Lansing
country: United States
facility: Sparrow Hospital
state: Michigan
city: Livonia
country: United States
facility: Saint Mary Mercy Hospital
state: Michigan
city: Pontiac
country: United States
facility: Saint Joseph Mercy Oakland
state: Michigan
city: Port Huron
country: United States
facility: Saint Joseph Mercy Port Huron
state: Michigan
city: Saginaw
country: United States
facility: Saint Mary's of Michigan
state: Michigan
city: Warren
country: United States
facility: Saint John Macomb-Oakland Hospital
state: Michigan
city: Bolivar
country: United States
facility: Central Care Cancer Center-Carrie J Babb Cancer Center
state: Missouri
city: Bonne Terre
country: United States
facility: Parkland Health Center-Bonne Terre
state: Missouri
city: Branson
country: United States
facility: CoxHealth Cancer Center
state: Missouri
city: Cape Girardeau
country: United States
facility: Saint Francis Medical Center
state: Missouri
city: Cape Girardeau
country: United States
facility: Southeast Cancer Center
state: Missouri
city: Jefferson City
country: United States
facility: Capital Region Medical Center-Goldschmidt Cancer Center
state: Missouri
city: Joplin
country: United States
facility: Freeman Health System
state: Missouri
city: Joplin
country: United States
facility: Mercy Hospital-Joplin
state: Missouri
city: Rolla
country: United States
facility: Phelps County Regional Medical Center
state: Missouri
city: Rolla
country: United States
facility: Saint John's Clinic-Rolla-Cancer and Hematology
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis Cancer and Breast Institute-South City
state: Missouri
city: Saint Louis
country: United States
facility: Missouri Baptist Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: Mercy Hospital Saint Louis
state: Missouri
city: Sainte Genevieve
country: United States
facility: Sainte Genevieve County Memorial Hospital
state: Missouri
city: Springfield
country: United States
facility: Mercy Hospital Springfield
state: Missouri
city: Springfield
country: United States
facility: CoxHealth South Hospital
state: Missouri
city: Sullivan
country: United States
facility: Missouri Baptist Sullivan Hospital
state: Missouri
city: Sunset Hills
country: United States
facility: Missouri Baptist Outpatient Center-Sunset Hills
state: Missouri
city: Centerville
country: United States
facility: Miami Valley Hospital South
state: Ohio
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc-Eden Park
state: Ohio
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc-Mercy West
state: Ohio
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc - Anderson
state: Ohio
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc - Kenwood
state: Ohio
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc-Blue Ash
state: Ohio
city: Dayton
country: United States
facility: Good Samaritan Hospital - Dayton
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospital
state: Ohio
city: Dayton
country: United States
facility: Samaritan North Health Center
state: Ohio
city: Fairfield
country: United States
facility: Oncology Hematology Care Inc-Healthplex
state: Ohio
city: Findlay
country: United States
facility: Blanchard Valley Hospital
state: Ohio
city: Franklin
country: United States
facility: Atrium Medical Center-Middletown Regional Hospital
state: Ohio
city: Greenville
country: United States
facility: Wayne Hospital
state: Ohio
city: Kettering
country: United States
facility: Kettering Medical Center
state: Ohio
city: Springfield
country: United States
facility: Springfield Regional Cancer Center
state: Ohio
city: Springfield
country: United States
facility: Springfield Regional Medical Center
state: Ohio
city: Sylvania
country: United States
facility: Flower Hospital
state: Ohio
city: Troy
country: United States
facility: Upper Valley Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Tulsa
country: United States
facility: Tulsa Cancer Institute
state: Oklahoma
city: Chadds Ford
country: United States
facility: Christiana Care Health System-Concord Health Center
state: Pennsylvania
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Hazleton
country: United States
facility: Geisinger Medical Center-Cancer Center Hazleton
state: Pennsylvania
city: Lewisburg
country: United States
facility: Geisinger Medical Oncology at Evangelical Community Hospital
state: Pennsylvania
city: Lewistown
country: United States
facility: Lewistown Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: ECOG-ACRIN Cancer Research Group
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Pottsville
country: United States
facility: Geisinger Medical Oncology-Pottsville
state: Pennsylvania
city: State College
country: United States
facility: Geisinger Medical Group
state: Pennsylvania
city: Wilkes-Barre
country: United States
facility: Geisinger Wyoming Valley/Henry Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Franklin
country: United States
facility: Vanderbilt-Ingram Cancer Center Cool Springs
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Breast Center at One Hundred Oaks
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Burlington
country: United States
facility: Aurora Cancer Care-Burlington
state: Wisconsin
city: Grafton
country: United States
facility: Aurora Cancer Care-Grafton
state: Wisconsin
city: Marinette
country: United States
facility: Vince Lombardi Cancer Clinic-Marinette
state: Wisconsin
city: Menomonee Falls
country: United States
facility: Aurora Advanced Healthcare Inc-Menomonee Falls
state: Wisconsin
city: Milwaukee
country: United States
facility: Aurora Cancer Care-Milwaukee
state: Wisconsin
city: Oshkosh
country: United States
facility: Vince Lombardi Cancer Clinic - Oshkosh
state: Wisconsin
city: Racine
country: United States
facility: Aurora Cancer Care-Racine
state: Wisconsin
city: Summit
country: United States
facility: Aurora Medical Center in Summit
state: Wisconsin
city: Waukesha
country: United States
facility: Aurora Cancer Care-Waukesha
state: Wisconsin
Study officials:
affiliation: ECOG-ACRIN Cancer Research Group
name: Vitaly Margulis
role: PRINCIPAL_INVESTIGATOR
References:
citation: Margulis V, Puligandla M, Trabulsi EJ, Plimack ER, Kessler ER, Matin SF, Godoy G, Alva A, Hahn NM, Carducci MA, Hoffman-Censits J; Collaborators. Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery in Patients with High Grade Upper Tract Urothelial Carcinoma. J Urol. 2020 Apr;203(4):690-698. doi: 10.1097/JU.0000000000000644. Epub 2019 Nov 8.