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

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ClinicalTrials.gov Identifier: NCT02412670
Recruitment Status : Active, not recruiting
First Posted : April 9, 2015
Last Update Posted : July 29, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group )

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
Localized Urothelial Carcinoma of the Renal Pelvis and Ureter Recurrent Urothelial Carcinoma of the Renal Pelvis and Ureter Regional Urothelial Carcinoma of the Renal Pelvis and Ureter Drug: Methotrexate Drug: Vinblastine Drug: Doxorubicin Hydrochloride Drug: Cisplatin Drug: Gemcitabine Hydrochloride Drug: Carboplatin Procedure: Therapeutic Conventional Surgery Other: Laboratory Biomarker Analysis Phase 2

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 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.


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Study Type : Interventional  (Clinical Trial)
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
Study Start Date : April 2015
Estimated Primary Completion Date : February 2020
Estimated Study Completion Date : February 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Vinblastine

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. 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

Drug: Vinblastine
Given IV
Other Names:
  • Velban
  • Velsar
  • VLB

Drug: Doxorubicin Hydrochloride
Given IV

Drug: Cisplatin
Given IV

Procedure: Therapeutic Conventional Surgery
Undergo nephroureterectomy and lymph node dissection

Other: Laboratory Biomarker Analysis
Correlative studies

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 Hydrochloride
Given IV
Other Names:
  • dFdC
  • dFdCyd

Drug: Carboplatin
Given IV

Procedure: Therapeutic Conventional Surgery
Undergo nephroureterectomy and lymph node dissection

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. pCR rates [ Time Frame: Up to 5 years ]
    Analyzed using a one-sided exact binomial test.


Secondary Outcome Measures :
  1. Recurrence-free survival [ Time Frame: From the date of surgery to disease recurrence or death from any cause, assessed up to 5 years ]
    Characterized using the method of Kaplan and Meier.

  2. Event-free survival [ Time Frame: From registration to the earlier of recurrence, disease progression, new invasive primary cancer, or death from any cause, assessed up to 5 years ]
    Characterized using the method of Kaplan and Meier.

  3. Bladder cancer-free survival [ Time Frame: From the date of surgery to the earlier of a return of bladder cancer or death from any cause, assessed up to 5 years ]
    Characterized using the method of Kaplan and Meier.

  4. Cancer-specific survival [ Time Frame: From registration to death due to cancer, assessed up to 5 years ]
    Will be analyzed using Gray's method and cumulative incidence estimates will be reported.

  5. The proportion of patients with renal insufficiency (CrCl < 60 ml/min) post chemotherapy and post nephroureterectomy [ Time Frame: Up to 60 days after completion of chemotherapy ]
    Will be reported along with exact binomial confidence intervals.

  6. The proportion of patients with renal function improvement (CrCl < 60 ml/min at baseline and CrCl >= 60 ml/min on study) [ Time Frame: Up to 60 days after completion of chemotherapy ]
    Will be reported along with exact binomial confidence intervals.

  7. Distribution of changes in renal function post chemotherapy and post surgery [ Time Frame: Baseline up to 60 days after completion of chemotherapy ]
  8. Incidence of toxicities [ Time Frame: Up to 30 days from date of surgery ]
    The percent of patients with various toxicities will be tabulated.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 no 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
  • Patients with any component of small cell carcinoma are not eligible; other variant histologies are permitted provided the predominant (>= 50%) subtype is urothelial carcinoma
  • Patients must not have peripheral neuropathy > grade 2
  • Patients must not have a history of allergy or hypersensitivity to methotrexate, vinblastine, doxorubicin (doxorubicin hydrochloride), cisplatin, gemcitabine (gemcitabine hydrochloride), carboplatin or filgrastim or pegfilgrastim
  • 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 must not have 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
  • For patients who have creatinine clearance that meets >= 50 ml/min they must not have received prior systemic doxorubicin
  • Patients with 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 are not eligible
  • Patients who are known to have human immunodeficiency virus (HIV) or are on combination antiretroviral therapy are ineligible
  • Patients must have no 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
  • 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 must not be 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)
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02412670


  Show 134 Study Locations
Sponsors and Collaborators
ECOG-ACRIN Cancer Research Group
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Vitaly Margulis ECOG-ACRIN Cancer Research Group

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Responsible Party: ECOG-ACRIN Cancer Research Group
ClinicalTrials.gov Identifier: NCT02412670     History of Changes
Other Study ID Numbers: EA8141
NCI-2014-02267 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EA8141 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
EA8141 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
First Posted: April 9, 2015    Key Record Dates
Last Update Posted: July 29, 2019
Last Verified: July 2018
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Transitional Cell
Kidney Neoplasms
Ureteral Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Ureteral Diseases
Gemcitabine
Cisplatin
Carboplatin
Doxorubicin
Liposomal doxorubicin
Methotrexate
Vinblastine
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs