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

  • STATUS
    Recruiting
  • End date
    Sep 30, 2027
  • participants needed
    249
  • sponsor
    National Cancer Institute (NCI)
Updated on 27 October 2022

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.

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.

Details
Condition Renal Pelvis and Ureter Urothelial Carcinoma
Treatment methotrexate, cisplatin, gemcitabine hydrochloride, doxorubicin hydrochloride, durvalumab, pegfilgrastim, therapeutic conventional surgery, vinblastine sulfate
Clinical Study IdentifierNCT04628767
SponsorNational Cancer Institute (NCI)
Last Modified on27 October 2022

Eligibility

Yes No Not Sure

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 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
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
therapy with undetectable viral load within 6 months are eligible for this
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
trial
NOTE: Testing for HIV, hepatitis B or hepatitis C is not required unless clinically indicated
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
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
Patients with a history of hepatitis C virus (HCV) infection must have been treated
Patient must have a creatinine clearance > 15 ml/min as by Crockroft-Gault or 24-hour creatinine clearance within 28 days prior to registration
and have undetectable viral load. For patients with HCV infection who are
currently on treatment, they are eligible if they have an undetectable HCV
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
viral load
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
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
Patients that meet the following criteria will be randomized to
cisplatin-eligible Arm A or Arm B

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
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 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 another active (or within 2 years) second malignancy other than
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
resected non-melanoma skin cancers, resected in situ breast, cervical or other
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
in situ carcinoma, and either clinically insignificant per the investigator
(e.g. =< Gleason 3+4) on surveillance or previously treated prostate cancer
Steroids as premedications for hypersensitivity reactions (e.g. computed tomography [CT] scan premedication)
with no rising prostate specific antigen (PSA) and no plan to treat
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 any uncontrolled illness including, but not limited to, ongoing
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
or active infection including tuberculosis (clinical evaluation that includes
clinical history, physical examination and radiographic findings, and
Patient must not have had a major surgical procedure (as defined by the Investigator) within 28 days prior to registration
tuberculosis [TB] testing in line with local practice), symptomatic congestive
heart failure (CHF), myocardial infarction (MI) in last 3 months, or unstable
Patient must not have a history of allogenic organ transplantation
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 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 have a concomitant primary urothelial carcinoma of the bladder and/or
urethra
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
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)
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