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.
Brief Title
Chemotherapy Before Surgery 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.
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
High Grade Upper Tract Urothelial Carcinoma
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)
* 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)
Inclusion 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
* 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
Gender
All
Gender Based
false
Keywords
carcinoma
drug therapy
nephroureterectomy
urinary tract
urothelium
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02412670
Org Class
Network
Org Full Name
Eastern Cooperative Oncology Group
Org Study Id
EA8141
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Prospective Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery for Patients With High Grade Upper Tract Urothelial Carcinoma
Primary Outcomes
Outcome 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.
Outcome Measure
Complete Pathologic Response Rate
Outcome 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)
Secondary Ids
Secondary Id
NCI-2014-02267
Secondary Id
EA8141
Secondary Id
EA8141
Secondary Id
U10CA180820
Secondary Outcomes
Outcome 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.
Outcome Time Frame
Assessed every 3 months for 2 years; and every 6 months for 3-5 years
Outcome Measure
Recurrence-free Survival
Outcome 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.
Outcome Time Frame
Assessed every 3 months for 2 years, and every 6 months for 3-5 years
Outcome Measure
Event-free Survival
Outcome 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.
Outcome Time Frame
Assessed every 3 months for 2 years, and every 6 months for 3-5 years
Outcome Measure
Bladder Cancer-free Survival
Outcome 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.
Outcome Time Frame
Assessed every 3 months for 2 years
Outcome Measure
Cumulative Incidence of Cancer-specific Death at 24 Months
Outcome Description
Renal insufficiency is defined as CrCl \< 60 ml/min.
Outcome Time Frame
Assessed at completion of chemotherapy; at 8 weeks for Arm A and 12 weeks for Arm B
Outcome Measure
Proportion of Patients With Renal Insufficiency at Completion of Chemotherapy
Outcome Description
Renal insufficiency is defined as CrCl \< 60 ml/min.
Outcome 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
Proportion of Patients With Renal Insufficiency at Completion of Surgery
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Benjamin Gartrell
Investigator Email
bgartrel@montefiore.org
Investigator Phone
718-405-8404