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Patients receive durvalumab IV over 60 minutes on day 1 of chemotherapy cycles 1 and 3. Patients also receive methotrexate IV over 2-3 minutes, vinblastine sulfate IV, doxorubicin IV, cisplatin IV over at least 2 hours on day 1. Treatments repeat every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery. Patients also undergo tissue biopsy and blood sample collection on study, and CT or MRI throughout the trial.

Patients also receive methotrexate IV over 2-3 minutes, vinblastine sulfate IV, doxorubicin IV, cisplatin IV over at least 2 hours on day 1. Treatments repeat every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery. Patients also undergo tissue biopsy and blood sample collection on study, and CT or MRI throughout the trial.

Patients receive durvalumab IV over 60 minutes on day 1 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery. Patients also undergo tissue biopsy and blood sample collection on study, and CT or MRI throughout the trial.

Biopsy

Biospecimen Collection

Computed Tomography

Doxorubicin Hydrochloride

Gemcitabine Hydrochloride

Magnetic Resonance Imaging

Pegfilgrastim

Therapeutic Conventional Surgery

Vinblastine Sulfate

Site Public Contact

John A. Ellerton

Ari D. Baron

Abhishek Tripathi

Ali R. Khaki

Elizabeth R. Kessler

Suthee Rapisuwon

Jean H. Hoffman-Censits

Lance C. Pagliaro

Bassel Nazha

Thomas J. Saphner

Prem Sobti

Bryan A. Faller

Howard M. Gross

Yousef Zakharia

Patrick J. Hensley

Scott E. Delacroix

Lindsey Hathaway

Kriti Mittal

Elie G. Dib

Jean H Hoffman-Censits

This phase II/III trial compares the effect of adding durvalumab to chemotherapy versus chemotherapy alone before surgery in treating patients with upper urinary tract cancer. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as methotrexate, vinblastine, doxorubicin, cisplatin, and gemcitabine 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. Durvalumab in combination with chemotherapy before surgery may enhance the shrinking of the tumor compared to chemotherapy alone.

PRIMARY OBJECTIVES:

I. To compare event-free survival (EFS) between patients with upper tract urothelial cancer (UTUC) randomized to neoadjuvant accelerated methotrexate, vinblastine, adriamycin, cisplatin (aMVAC) alone or in combination with durvalumab. (Cisplatin eligible patients \[Arms A and B\]) II. Evaluation of pathologic complete response at radical nephroureterectomy (RNU) (pathologic complete response \[pCR\], pT0N0/ Nx). (Cisplatin ineligible patients \[Arm C\]).

SECONDARY OBJECTIVES:

I. To assess pathologic complete response (pCR) at surgery. (Cisplatin eligible cohort) II. Event-free survival (EFS) will be evaluated for the cisplatin ineligible cohort as a secondary endpoint. (Cisplatin ineligible cohort) III. Overall survival in all, and by post chemotherapy response (ypCR, yp =\< T1N0, yp \>= T2Nany). (All patients) IV. To evaluate disease-free survival (DFS) in each arm of the trial separately. (All patients) V. To evaluate cancer-specific survival of patients in each arm of the trial separately. (All patients) VI. To evaluate renal function outcomes following systemic treatment and following surgery (\[RNU) in each arm of the trial separately. (All patients) VII. To evaluate safety and tolerability of neoadjuvant aMVAC alone or in combination with durvalumab prior to RNU. (All patients)

OUTLINE: Patients eligible for cisplatin are randomized to Arms A or B. Patients ineligible for cisplatin are assigned to Arm C.

ARM A: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1 of chemotherapy cycles 1 and 3. Patients also receive methotrexate IV over 2-3 minutes, vinblastine sulfate IV, doxorubicin IV, cisplatin IV over at least 2 hours on day 1. Treatments repeat every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery.

ARM B: Patients also receive methotrexate IV over 2-3 minutes, vinblastine sulfate IV, doxorubicin IV, cisplatin IV over at least 2 hours on day 1. Treatments repeat every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery.

ARM C: Patients receive durvalumab IV over 60 minutes on day 1 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery.

Patients also undergo tissue biopsy and blood sample collection on study, and computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial.

After completion of study treatment, patients are followed up within 30 days and then every 3-6 months for up to 5 years from study entry.

Testing the Addition of MEDI4736 (Durvalumab) to Chemotherapy Before Surgery for Patients With High-Grade Upper Urinary Tract Cancer

A Phase II/III Trial of Durvalumab and Chemotherapy for Patients With High Grade Upper Tract Urothelial Cancer Prior to Nephroureterectomy

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Defined as muscle-invasive cancer or disease recurring outside of the bladder, urethra, or contralateral upper tract.

Will assess pathologic complete response at surgery (pCR, pT0N0/Nx) by local pathology review. Patients who drop out prior to surgery or who have unknown response status will be considered as non-responders.

Will be characterized using the Kaplan-Meier method.

OS will be evaluated by arm, post chemotherapy response (ypCR, stage yp =\< T1N0, yp \>= T2N0), as well as stage (ypCR and \> ypCR) within and across treatment arms. Will be estimated using Kaplan-Meier method.

A return of UTUC includes non-muscle invasive recurrences, pathologic T2 or higher muscle-invasive recurrences specifically in the urinary tract, metastatic disease outside the urinary tract, or death. Patients alive without documented UTUC will be censored at the date of last disease assessment.

Will be analyzed using Gray's method and cumulative incidence estimates will be reported.

The proportion of patients with renal insufficiency (creatinine \[CrCl\] \< 60 ml/min) post chemotherapy and post nephroureterectomy as well as the proportion of patients with renal function improvement (CrCl \< 60 ml/min at baseline and CrCl \>= 60 ml/min on study) will be reported along with exact binomial confidence intervals. The distribution of changes in renal function post chemotherapy as well as post surgery from baseline will also be reported. The analysis of renal function outcomes will be performed among patients who receive at least one dose of study therapy.

Toxicity will be evaluated in all treated patients.

National Cancer Institute (NCI)

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Pembrolizumab

Immunoconjugates

Immune Checkpoint Inhibitors

Patients receive pembrolizumab IV and enfortumab vedotin IV on study. Patients undergo radical nephroureterectomy and receive pembrolizumab IV on study Patients also undergo MRU imaging and undergo blood, urine and tissue sample collection throughout the study.

Enfortumab Vedotin

MR Urography

Nephroureterectomy

Karim Chamie

This phase II clinical trial tests how well pembrolizumab plus enfortumab vedotin prior to and after radical nephroureterectomy works in treating patients with high-risk upper tract urothelial cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Enfortumab vedotin (EV) is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of cancer cells. Enfortumab attaches to a protein called nectin-4 on cancer cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. Radical nephroureterectomy (RNU) is the surgical removal of a kidney and its ureter. Giving pembrolizumab plus enfortumab vedotin before surgery may make the tumor smaller and may reduce the amount of normal tissue that needs to be removed and giving pembrolizumab after surgery may kill any remaining cancer cells.

PRIMARY OBJECTIVES:

I. To assess pathologic objective response rate (ORR; complete response \[CR; pT0\] and partial response \[PR; \< pT2\] rate) at the time of radical nephroureterectomy.

II. To assess recurrence-free survival post radical nephroureterectomy.

SECONDARY OBJECTIVE:

I. To describe the side effect profile, tolerability, and surgical complications in patients receiving neoadjuvant pembrolizumab (pembro)/ enfortumab vedotin (EV) prior to RNU.

EXPLORATORY OBJECTIVE:

I. Correlative studies will evaluate the predictive potential of imaging and ureteroscopic response (visualization of tumor, biopsy, and cytology), and urinary, serum, and tissue biomarkers to pathologic response.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) and enfortumab vedotin IV on study. Patients undergo radical nephroureterectomy and receive pembrolizumab IV on study Patients also undergo magnetic resonance urogram (MRU) imaging and undergo blood, urine and tissue sample collection throughout the study.

Pembrolizumab and Enfortumab Vedotin With Pembrolizumab Prior to and After Radical Nephroureterectomy for High-Risk Upper Tract Urothelial Cancer

Neoadjuvant Combination Pembrolizumab / Enfortumab Vedotin With Adjuvant Pembrolizumab Prior to and After Radical Nephroureterectomy for High-Risk Upper Tract Urothelial Carcinoma

Will be assessed by the combination of partial response (PR) and complete response (CR). PR is defined as pathologic stage \<T2 disease. CR is defined as pT0 disease and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.

Will be assessed using the National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.

Will be assessed as completion of all infusions of both agents and successful completion of radical nephroureterectomy.

Will be assessed based on the Clavien-Dindo classification.

Merck Sharp & Dohme LLC

Seagen Inc.

Jonsson Comprehensive Cancer Center

Infigratinib

Patients receive infigratinib PO QD on days 1-21. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. During weeks 8-9 (at least 48 hours after last dose of infigratinib), patients undergo surgery.

Quality-of-Life Assessment

Questionnaire Administration

Surgical Procedure

Mehrad Adibi, MD

This phase Ib trial studies the side effects of infigratinib before surgery in treating patients with upper tract urothelial cancer. Infigratinib may stop the growth of tumor cells by blocking the activities of a gene called FGFR needed for cell growth. Giving infigratinib before surgery may cause the tumor to shrink, which may make the surgical procedure easier and/or reduce the need for more extensive surgery.

PRIMARY OBJECTIVE:

I. Evaluate the tolerability of infigratinib in patients with low-grade and high-grade platinum ineligible upper tract urothelial carcinoma (UTUC).

SECONDARY OBJECTIVES:

I. Assess tolerability in those with GFR 30-49. II. Evaluate the objective response rate (complete response \[CR\] + partial response \[PR\]) of infigratinib after 2 cycles in UTUC with and without FGFR3 alterations.

III. Correlate tumor tissue FGFR3 alteration (presence/absence, alteration type, and clonal status) with response and occurrence/severity of adverse events (AEs) such as hyperphosphatemia.

IV. Evaluate upper tract, bladder and local/distant recurrence within 12 months.

V. Evaluate renal function pre-treatment and after two treatments. VI. Evaluate patient-reported quality of life (QOL) outcomes during treatment.

EXPLORATORY OBJECTIVES:

I. Explore intra-tumor heterogeneity, gene expression profiles, and changes in tumor microenvironment using single cell ribonucleic acid (RNA) sequencing (scRNA-seq) and mass cytometry by time-of-flight (CyTOF) pre and post treatment to identify potential mechanisms of response and/or resistance, and correlation with the occurrence/severity of AEs.

II. Explore urinary/upper tract washing FGFR3 alterations as potential biomarker for detection and response.

III. Explore cell free deoxyribonucleic acid (cfDNA) for detection of FGFR3 alterations and as a predictor of response.

OUTLINE:

Patients receive infigratinib orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. During weeks 8-9 (at least 48 hours after last dose of infigratinib), patients undergo surgery.

After completion of study treatment, patients are followed up at 30 days, then every 3 months for up to 1 year after surgery.

Infigratinib Before Surgery for the Treatment of Upper Tract Urothelial Cancer

Tolerability and Activity of Neoadjuvant Infigratinib, an Inhibitor of FGFR, in Upper Tract Urothelial Carcinoma

Will estimate proportion of patients who are not able to complete treatment (discontinuation) due to excessive toxicity along with the 90% exact confidence interval. Toxicities will be tabulated using frequency and percentage by grade and their relations to treatment.

Will estimate the objective response rate along with the 90% confidence interval. Fisher's exact test will be used to explore the difference in response between the two cohorts of patients.

Wilcoxon rank sum test and Fisher's exact test will be used to explore the association between objective response and cfDNA.

Wilcoxon rank sum test and Fisher's exact test will be used to explore the association between objective response and expression of markers.

Wilcoxon rank sum test and Fisher's exact test will be used to explore the association between objective response and FGFR3 alteration type.

Will be summarized using proportion and 90% confidence interval as a binary outcome, and will also be estimated using the Kaplan-Meier method as a time to event variable.

Will be measured using a validated questionnaire (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Testing the Addition of MEDI4736 (Durvalumab) to Chemotherapy Before Surgery for Patients With High-Grade Upper Urinary Tract Cancer	NCT04628767	Renal Pelvis an...	Biopsy Biospecimen Col... Cisplatin Computed Tomogr... Doxorubicin Hyd... Durvalumab Gemcitabine Hyd... Magnetic Resona... Methotrexate Pegfilgrastim Therapeutic Con... Vinblastine Sul...	18 Years -	National Cancer Institute (NCI)
Pembrolizumab and Enfortumab Vedotin With Pembrolizumab Prior to and After Radical Nephroureterectomy for High-Risk Upper Tract Urothelial Cancer	NCT05775471	Renal Pelvis an...	Biopsy Biospecimen Col... Enfortumab Vedo... MR Urography Nephroureterect... Pembrolizumab	18 Years -	Jonsson Comprehensive Cancer Center
Infigratinib Before Surgery for the Treatment of Upper Tract Urothelial Cancer	NCT04228042	Renal Pelvis an...	Infigratinib Quality-of-Life... Questionnaire A... Surgical Proced...	18 Years -	M.D. Anderson Cancer Center
Testing the Addition of MEDI4736 (Durvalumab) to Chemotherapy Before Surgery for Patients With High-Grade Upper Urinary Tract Cancer	NCT04628767	Renal Pelvis an...	Biopsy Biospecimen Col... Cisplatin Computed Tomogr... Doxorubicin Hyd... Durvalumab Gemcitabine Hyd... Magnetic Resona... Methotrexate Pegfilgrastim Therapeutic Con... Vinblastine Sul...	18 Years -	National Cancer Institute (NCI)
Infigratinib Before Surgery for the Treatment of Upper Tract Urothelial Cancer	NCT04228042	Renal Pelvis an...	Infigratinib Quality-of-Life... Questionnaire A... Surgical Proced...	18 Years -	M.D. Anderson Cancer Center
Testing the Addition of MEDI4736 (Durvalumab) to Chemotherapy Before Surgery for Patients With High-Grade Upper Urinary Tract Cancer	NCT04628767	Renal Pelvis an...	Biopsy Biospecimen Col... Cisplatin Computed Tomogr... Doxorubicin Hyd... Durvalumab Gemcitabine Hyd... Magnetic Resona... Methotrexate Pegfilgrastim Therapeutic Con... Vinblastine Sul...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for renal pelvis and ureter urothelial carcinoma