A Phase II/III Trial of MEDI4736 (Durvalumab) and Chemotherapy for Patients with High Grade Upper Tract Urothelial Cancer Prior to Nephroureterectomy.

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