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BRIEF TITLE: MEDI4736 (Durvalumab) and Chemotherapy for Patients With High Grade Upper Tract Urothelial Cancer Prior to Nephroureterectomy

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


  • Org Study ID: NCI-2020-09850
  • Secondary ID: NCI-2020-09850,EA8192,EA8192,U10CA180820
  • NCT ID: NCT04628767
  • NCT Alias:
  • Sponsor: National Cancer Institute (NCI) - NIH
  • Source: National Cancer Institute (NCI)

Brief Summary

This phase 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


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 MEDI4736 (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 separately. (All patients) V. To evaluate
cancer-specific survival of patients in each arm separately. (All patients) VI. To evaluate
renal function outcomes following systemic treatment and following surgery ([RNU) in each arm
separately. (All patients) VII. To evaluate safety and tolerability of neoadjuvant aMVAC
alone or in combination with MEDI4736 (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.

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.

Overal Status Start Date Phase Study Type
Recruiting May 6, 2021 Phase 3 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Event-free survival (EFS) (Cisplatin eligible cohort: Arms A and B)

Primary Outcome 1 - Time Frame: From randomization to the earliest of systemic recurrence, disease progression, or death from any cause, assessed up to 5 years

Primary Outcome 2 - Measure: Pathologic complete response (pCR) (Cisplatin ineligible cohort: Arm C)

Primary Outcome 2 - Time Frame: At surgery

Condition:

  • Renal Pelvis and Ureter Urothelial Carcinoma

Eligibility

Criteria:
Inclusion Criteria:

- STEP 1 REGISTRATION AND RANDOMIZATION

- 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<br/> 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 60 days prior to registration 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)

- Platelets >= 100,000/mcL (obtained =< 14 days prior to registration)

- 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)

- 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)

- Hemoglobin (Hgb) >= 9 g/dL (obtained =< 14 days prior to registration)

- 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 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

- 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 a life expectancy of >= 12 weeks

- Patient must have a creatinine clearance > 15 ml/min as by Crockroft-Gault or 24-hour
creatinine clearance within 28 days prior to registration

- 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
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 the following criteria will be assigned to the
cisplatin-ineligible Arm C:

- Creatinine clearance of > 15 ml/min and =< 50 ml/min

- 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
cisplatin-eligible Arm A or Arm B:

- Patient must have an absolute neutrophil count (ANC) >= 1,500/mcL
obtained =< 14 days prior to randomization

- Patient must have ECOG performance status 0-1

- Patient must have left ventricular ejection fraction (LVEF) >= 50% by
(either multigated acquisition scan [MUGA] or 2-D echocardiogram)
obtained within 28 days prior to randomization

- Patient must not have peripheral neuropathy >= grade 2 or hearing loss
>= grade 3

Exclusion Criteria:

- Patients must not have any component of small cell 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 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

- Patient must have no evidence of metastatic disease or clinically enlarged lymph nodes
(>= 1.0 cm short axis) on imaging required within 28 days prior to registration
(solitary slightly enlarged lymph node with negative biopsy is allowed)

- NOTE: Patients with elevated alkaline phosphatase, calcium or suspicious bone
pain/tenderness should also undergo baseline bone scans to evaluate for bone
metastasis

- Patient must not have another active (or within 2 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 surveillance 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

- 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 3 months, or unstable angina pectoris, significant
uncontrolled cardiac arrhythmia, 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 an active autoimmune disease requiring immunosuppressive therapy
within 2 years prior to registration or a history of inflammatory bowel disease
(inflammatory bowel disease [IBD], colitis, or Crohn's disease), systemic lupus
erythematosus, Sarcoidosis syndrome, Wegener syndrome or immune-related pneumonitis or
interstitial lung disease. Patients with well-controlled hyper/hypothyroidism, celiac
controlled by diet alone, diverticulosis, 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 MEDI4736 (MEDI4736 (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 a concomitant primary urothelial carcinoma of the bladder and/or
urethra

- NOTE: 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

- Patient must not have prior history of muscle-invasive urothelial carcinoma with or
without systemic chemotherapy (T2-4a and/or N1) within 2 years prior to registration

- NOTE: Patients who have no evidence of disease (NED) for more than 2 years from
the latest therapy (surgery, radiation, chemotherapy, or clinical trial) are
eligible

- Patient must not have received live attenuated vaccine within 30 days prior to the
first dose of MEDI4736 (durvalumab), while on protocol treatment and within 30 days
after the last dose of MEDI4736 (durvalumab)

- Patient must not have had a major surgical procedure (as defined by the Investigator)
within 28 days prior to registration

- Patient must not have a history of allogenic organ transplantation
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: Jean H Hoffman-Censits

Role: Principal Investigator

Affiliation: ECOG-ACRIN Cancer Research Group

Locations

Facility Status Contact
Sibley Memorial Hospital
Washington, District of Columbia 20016
United States
Recruiting Site Public Contact
202-243-2373
jquiver1@jhmi.edu
Mary Greeley Medical Center
Ames, Iowa 50010
United States
Recruiting Site Public Contact
515-956-4132
McFarland Clinic PC - Ames
Ames, Iowa 50010
United States
Recruiting Site Public Contact
515-239-4734
ksoder@mcfarlandclinic.com
McFarland Clinic PC-Boone
Boone, Iowa 50036
United States
Recruiting Site Public Contact
515-956-4132
McFarland Clinic PC-Trinity Cancer Center
Fort Dodge, Iowa 50501
United States
Recruiting Site Public Contact
515-956-4132
McFarland Clinic PC-Jefferson
Jefferson, Iowa 50129
United States
Recruiting Site Public Contact
515-956-4132
McFarland Clinic PC-Marshalltown
Marshalltown, Iowa 50158
United States
Recruiting Site Public Contact
515-956-4132
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland 21287
United States
Recruiting Site Public Contact
410-955-8804
jhcccro@jhmi.edu
Fairview Ridges Hospital
Burnsville, Minnesota 55337
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Minnesota Oncology - Burnsville
Burnsville, Minnesota 55337
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Cambridge Medical Center
Cambridge, Minnesota 55008
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Mercy Hospital
Coon Rapids, Minnesota 55433
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Fairview Southdale Hospital
Edina, Minnesota 55435
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Unity Hospital
Fridley, Minnesota 55432
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Fairview Clinics and Surgery Center Maple Grove
Maple Grove, Minnesota 55369
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Minnesota Oncology Hematology PA-Maplewood
Maplewood, Minnesota 55109
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Saint John's Hospital - Healtheast
Maplewood, Minnesota 55109
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Abbott-Northwestern Hospital
Minneapolis, Minnesota 55407
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Hennepin County Medical Center
Minneapolis, Minnesota 55415
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Health Partners Inc
Minneapolis, Minnesota 55454
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Monticello Cancer Center
Monticello, Minnesota 55362
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
New Ulm Medical Center
New Ulm, Minnesota 56073
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Fairview Northland Medical Center
Princeton, Minnesota 55371
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
North Memorial Medical Health Center
Robbinsdale, Minnesota 55422
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Park Nicollet Clinic - Saint Louis Park
Saint Louis Park, Minnesota 55416
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Regions Hospital
Saint Paul, Minnesota 55101
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
United Hospital
Saint Paul, Minnesota 55102
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Saint Francis Regional Medical Center
Shakopee, Minnesota 55379
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Lakeview Hospital
Stillwater, Minnesota 55082
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Ridgeview Medical Center
Waconia, Minnesota 55387
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Rice Memorial Hospital
Willmar, Minnesota 56201
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Minnesota Oncology Hematology PA-Woodbury
Woodbury, Minnesota 55125
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Fairview Lakes Medical Center
Wyoming, Minnesota 55092
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com
Cancer Center of Western Wisconsin
New Richmond, Wisconsin 54017
United States
Recruiting Site Public Contact
952-993-1517
mmcorc@healthpartners.com