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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Renal Pelvis and Ureter Urothelial Carcinoma

Intervention / Treatment
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* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Drug: Cisplatin
* Procedure: Computed Tomography
* Drug: Doxorubicin Hydrochloride
* Biological: Durvalumab
* Drug: Gemcitabine Hydrochloride
* Procedure: Magnetic Resonance Imaging
* Drug: Methotrexate
* Biological: Pegfilgrastim
* Procedure: Therapeutic Conventional Surgery
* Drug: Vinblastine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: STEP 1 REGISTRATION AND RANDOMIZATION Patients must be >= 18 years of age Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible Patient must have a diagnosis of high grade upper tract urothelial carcinoma proven by biopsy within 12 weeks (84 days) prior to registration/randomization with one of the following: Upper urinary tract mass on cross-sectional imaging or Tumor directly visualized during upper urinary tract endoscopy before referral to medical oncology NOTE: Biopsy is standard of care (SOC) and required for enrollment to study. This is vital for best practice Leukocytes >= 3,000/mcL (obtained =< 14 days prior to registration/randomization) Platelets >= 100,000/mcL (obtained =< 14 days prior to registration/randomization) Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (or =< 2.5 x ULN for patients with Gilbert's disease) (obtained =< 14 days prior to registration/randomization) Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained =< 14 days prior to registration/randomization) Hemoglobin (Hgb) >= 9 g/dL (obtained =< 14 days prior to registration/randomization) NOTE: Packed red blood transfusion is allowed to achieve this parameter as per treating investigator Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration/randomization are eligible for this trial NOTE: These patients must be stable on their anti-retroviral regimen with evidence of at least two undetectable viral loads within the past 6 months on the same regimen; the most recent undetectable viral load must be within the past 12 weeks. They must have a CD4 count of greater than 250 cells/mcL over the past 6 months on this same anti-retroviral regimen and must not have had a CD4 count < 200 cells/mcL over the past 2 years, unless it was deemed related to the cancer and/or chemotherapy induced bone marrow suppression. They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months NOTE: For patients who have received chemotherapy in the past 6 months, a CD4 count < 250 cells/mcL during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy. They must have an undetectable viral load and a CD4 count >= 250 cells/mcL within 7 days of registration/randomization For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated NOTE: Testing for HIV, hepatitis B or hepatitis C is not required unless clinically indicated Patients with a history of hepatitis C virus (HCV) infection must have been treated and have undetectable viral load. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better Patient must have a body weight of > 30 kg Patient must have life expectancy of >= 12 weeks Patient must have creatinine clearance > 15 ml/min as by Crockroft-Gault formula or 24-hour creatinine clearance within 28 days prior to registration/randomization NOTE: Patients will be assigned to cisplatin-ineligible and cisplatin-eligible cohorts based on their creatinine clearance, Eastern Cooperative Oncology Group (ECOG) performance status, and grade (if any) of peripheral neuropathy and/or hearing loss in keeping with SOC cisplatin contraindications. Patients that are cisplatin-eligible will be randomized to either Arm A or Arm B Patients that meet any of the following criteria will be registered and assigned to the cisplatin-ineligible Arm C if they meet other eligibility criteria: Creatinine clearance > 15 ml/min and =< 50 ml/min or hearing loss grade >= 3, or neuropathy >= 2, or ECOG PS 2 Patient must have an absolute neutrophil count (ANC) >= 1,000/mcL obtained =< 14 days prior to registration Patient must have ECOG performance status 0-2 Patients that meet the following criteria will be randomized to the cisplatin-eligible Arm A or Arm B: Patient must have creatinine clearance of > 50ml/min, PS ECOG 0-1, absence of hearing loss grade >= 3, and/or neuropathy >= 2 Patient must have an absolute neutrophil count (ANC) >= 1,500/mcL obtained =< 14 days prior to randomization Patient must have left ventricular ejection fraction (LVEF) >= 50% by (either multigated acquisition scan [MUGA] or 2-D echocardiogram) obtained within obtained within 28 days prior to randomization Exclusion Criteria: Patients must not have any component of small cell/neuroendocrine carcinoma. Other variant histologic types are permitted provided the predominant (>= 50%) subtype is urothelial carcinoma Patients must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy. A patient of childbearing potential is defined as any patient, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Patients of childbearing potential and sexually active patients must not expect to conceive or father children, either by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse from the time of registration, while on study treatment and for at least 6 months after the last dose of protocol treatment Patients must have no evidence of metastatic disease or clinically enlarged regional lymph nodes (>= 1.5 cm short axis) on imaging required within 28 days prior to registration (Non-regional findings >=1.5 cm short axis that in the opinion of the investigator are not concerning for involvement based on radiographic characteristics, chronicity, avidity on positron emission tomography (PET) or other imaging or other criteria can be eligible based on investigator discretion). NOTE: Patients with elevated alkaline phosphatase, calcium or suspicious bone pain/tenderness can also undergo baseline bone scans to evaluate for bone metastasis at the discretion of local provider. Patient must meet below criteria for prior/current malignancy history: Non-urothelial cancer malignancy history: Patient must not have another active (or within two years) second malignancy other than resected non-melanoma skin cancers, resected in situ breast, cervical or other in situ carcinoma, and either clinically insignificant per the investigator (e.g. =< Gleason 3+4) on active surveillance (or watchful waiting) or previously treated prostate cancer with no rising prostate specific antigen (PSA) and no plan to treat NOTE: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients in whom concomitant or prior bladder/urethra predominant (>= 50%) urothelial carcinoma have been surgically resected and demonstrated to be only non-invasive cancer (< cT1N0) are eligible regardless of time elapsed Urothelial cancer malignancy history: Patient may have a history of resectable urothelial cancer as long as patients meet one of the following: T0, Ta or Tis at any time T1-4a N0 and no evidence of disease (NED) for more than 2 years from the latest therapy [e.g., radical surgery, transurethral resection of bladder tumor (TURBT), radiation, chemotherapy (neoadjuvant or adjuvant, or with radiation)]. Prior immune checkpoint inhibitor is not allowed. Patient with history of >= pT4b, N+, and/or M1 is not eligible. NOTE: Patients in whom concomitant or prior bladder/urethra predominant (>= 50%) urothelial carcinoma have been surgically resected and demonstrated to be only Ta or carcinoma in situ (CIS) (< cT1 N0) are eligible regardless of time elapsed Patient must not have any uncontrolled illness including, but not limited to, ongoing or active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), symptomatic congestive heart failure (CHF), myocardial infarction (MI) in last three months, or unstable angina pectoris, significant uncontrolled cardiac arrhythmia, clinically relevant liver cirrhosis, interstitial lung disease, or psychiatric illness/social situations that would limit compliance with study requirements Patient must not have received prior radiation therapy to >= 25% of the bone marrow for other diseases Patient must not have received prior systemic anthracycline therapy NOTE: Patients who have received prior intravesical chemotherapy at any time for non-muscle invasive urothelial carcinoma of the bladder are eligible Patient must not have either history of or active autoimmune disease requiring immunosuppressive therapy within 2 years prior to registration/randomization or any history of inflammatory bowel disease (inflammatory bowel disease [IBD], colitis, or Crohn's disease), neuromuscular autoimmune condition, immune-related pneumonitis or interstitial lung disease. Patients with well-controlled hyper/hypothyroidism, celiac controlled by diet alone, diabetes mellitus type I, vitiligo, alopecia, psoriasis, eczema, lichen planus, or similar skin/mucosa condition are eligible Patient must not be on or have used immunosuppressive medication within 14 days prior to the first dose of durvalumab. The following are exceptions to this criterion: Intranasal, inhaled, intra-auricular, topical steroids, or local steroid injections (e.g. intra-articular injection Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent at the time of enrollment Steroids as premedications for hypersensitivity reactions (e.g. computed tomography [CT] scan premedication) Patient must not have received live attenuated vaccine within 30 days prior to the first dose of durvalumab, while on protocol treatment and within 30 days after the last dose of durvalumab Patient must not have had a major surgical procedure within 28 days prior to registration/randomization NOTE: Cystoscopy/ureteroscopy, stent placement or nephrostomy tube is not considered major surgery Patient must not have history of allogenic organ transplantation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (durvalumab, chemotherapy)<br>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. | Procedure: Biopsy<br>* Undergo tissue biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Drug: Doxorubicin Hydrochloride<br>* Given Iv<br>* Other names: Rubex;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Biological: Pegfilgrastim<br>* Given via injection<br>* Other names: Ziextenzo;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Drug: Vinblastine Sulfate<br>* Given Iv<br>* Other names: VINCALEUKOBLASTINE;|
| Active Comparator: Arm B (chemotherapy)<br>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. | Procedure: Biopsy<br>* Undergo tissue biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Drug: Doxorubicin Hydrochloride<br>* Given Iv<br>* Other names: Rubex;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Biological: Pegfilgrastim<br>* Given via injection<br>* Other names: Ziextenzo;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Drug: Vinblastine Sulfate<br>* Given Iv<br>* Other names: VINCALEUKOBLASTINE;|
| Experimental: Arm C (durvalumab, gemcitabine hydrochloride)<br>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. | Procedure: Biopsy<br>* Undergo tissue biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) (Cisplatin eligible cohort: Arms A and B) | Defined as muscle-invasive cancer or disease recurring outside of the bladder, urethra, or contralateral upper tract. | From registration/randomization to the earliest of systemic recurrence outside urinary tract, cancer progression, or death from any cause, assessed up to 5 years | 
| Pathologic complete response (pCR) (Cisplatin ineligible cohort: Arm C) | 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. | At surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pCR (Cisplatin-eligible cohort: Arms A and B) |  | Up to 5 years | 
| EFS (cisplatin-ineligible cohort: Arm C) | Will be characterized using the Kaplan-Meier method. | From registration/randomization to the earliest of systemic recurrence outside urinary tract, cancer progression, or death from any cause, assessed up to 5 years | 
| Overall survival (OS) (All Patients) | 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. | From registration/randomization to death from any cause, assessed up to 5 years | 
| Urothelial cancer-free survival or disease-free survival (All Patients) | 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. | From the date of surgery to the earlier of a return of upper tract urothelial cancer (UTUC) or death from any cause, assessed up to 5 years | 
| Cancer-specific survival (All Patients) | Will be analyzed using Gray's method and cumulative incidence estimates will be reported. | From registration/randomization to death due to cancer; deaths due to other causes will be counted as competing events, assessed up to 5 years | 
| Renal function outcomes following systemic treatment and following radical nephroureterectomy (All Patients) | 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. | Post chemotherapy and post surgery | 
| Incidence of adverse events (All Patients) | Toxicity will be evaluated in all treated patients. | Up to 30 days post surgery |