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

Plain English Summary

Testing the Addition of MEDI4736 (Durvalumab) to Chemotherapy Before Surgery for Patients With High-Grade Upper Urinary Tract Cancer is a Phase 3 clinical trial sponsored by National Cancer Institute (NCI) studying Renal Pelvis and Ureter Urothelial Carcinoma. Tests Durvalumab plus chemotherapy before surgery to shrink tumors in patients with high-grade upper urinary tract cancer. For patients 18+ with high-grade upper urinary tract cancer, expected within 14 weeks of registration. Participation involves biopsies, blood tests, and chemotherapy treatments before surgery. Alternative treatments include standard chemotherapy without Durvalumab. The trial aims to enroll 249 participants.

Official Summary

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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Eligible if 18+ years old, able to understand and sign consent, and have high-grade upper urinary tract cancer. Must have certain blood and organ function tests within normal limits. HIV patients on effective anti-retroviral therapy with undetectable viral load are eligible. Patients with chronic hepatitis B or C must have undetectable viral load. This trial is studying Renal Pelvis and Ureter Urothelial Carcinoma, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures the time until the cancer returns or spreads, which is crucial for patient survival. The specific primary outcome measures are: Event-free survival (EFS) (Cisplatin eligible cohort: Arms A and B) (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) (At surgery). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial aims to improve outcomes for patients with upper urinary tract cancer by combining immunotherapy with chemotherapy before surgery. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Renal Pelvis and Ureter Urothelial Carcinoma, where improved treatment options are needed.

Investor Insight

The market for advanced urothelial cancer treatments is growing, with this trial potentially leading to new approved therapies. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor if you have high-grade upper urinary tract cancer and are expected to have surgery within 14 weeks. Undergo biopsies, blood tests, and chemotherapy treatments before surgery as part of the trial. This trial is currently recruiting participants. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 249 participants

Interventions

• PROCEDURE: Biopsy Procedure — Undergo tissue biopsy
• PROCEDURE: Biospecimen Collection — Undergo blood sample collection
• DRUG: Cisplatin — Given IV
• PROCEDURE: Computed Tomography — Undergo CT
• DRUG: Doxorubicin Hydrochloride — Given Iv

Primary Outcomes

• Event-free survival (EFS) (Cisplatin eligible cohort: Arms A and B) (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) (At surgery)

Secondary Outcomes

• pCR (Cisplatin-eligible cohort: Arms A and B) (Up to 5 years)
• EFS (cisplatin-ineligible cohort: Arm C) (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) (From registration/randomization to death from any cause, assessed up to 5 years)
• Urothelial cancer-free survival or disease-free survival (All Patients) (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) (From registration/randomization to death due to cancer; deaths due to other causes will be counted as competing events, assessed up to 5 years)

Full Eligibility Criteria

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 expected within 14 weeks (98 days) prior to registration/randomization with one of the following:

  * Biopsy (gold standard, preferred) and either upper urinary tract mass on cross-sectional imaging or
  * Tumor directly visualized during upper urinary tract endoscopy
  * High grade cytology and clinically estimated invasive upper urinary tract mass on cross-sectional imaging (e.g., including presence of tumor-related hydronephrosis) or tumor directly visualized during upper urinary tract endoscopy

    * NOTE: Universal histologic testing of UTUC with additional studies, such as immunohistochemistry or microsatellite instability, is strongly recommended to identify patients with high probability of Lynch-related or other germline mutation related cancers whom clinicians should refer for genetic counseling and germline testing (this is not required for eligibility)

      * Due to the anatomy of upper urinary tract and lack of muscularis propria, pathologic evidence of cT2 on biopsy is usually not possible
* Leukocytes \>= 3,000/mcL (obtained =\< 14 days prior to registration/randomization)
* Platelets \>= 100,000/mcL (obtained =\< 14 days prior to registration/randomization)
* Total bilirubin =\< 1.2 mg/dL (or ≤ 2 mg/dLfor patients with Gilbert's disease)
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2 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 estimated by Cockcroft-Gault formula or glomerular filtration rate (GFR) \> 15 ml/min/1.73m\^2 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 recommended cisplatin contraindications. Patients who are cisplatin-eligible will be randomized to either Arm A or Arm B and patients who are cisplatin-ineligible will be registered to Arm 

Trial Locations

• Kingman Regional Medical Center, Kingman, Arizona, United States
• Mercy Hospital Fort Smith, Fort Smith, Arkansas, United States
• University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
• Sutter Auburn Faith Hospital, Auburn, California, United States
• Alta Bates Summit Medical Center-Herrick Campus, Berkeley, California, United States
• City of Hope Comprehensive Cancer Center, Duarte, California, United States
• Palo Alto Medical Foundation-Fremont, Fremont, California, United States
• UC San Diego Moores Cancer Center, La Jolla, California, United States
• Memorial Medical Center, Modesto, California, United States
• Palo Alto Medical Foundation-Camino Division, Mountain View, California, United States
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Renal Pelvis and Ureter Urothelial Carcinoma
• Upper Urinary Tract Cancer
• Bladder Cancer
• Kidney Cancer
• Urological Cancers
• Cancer Immunotherapy
• Chemotherapy
• Surgery for Cancer
• Advanced Urothelial Carcinoma
• Upper Urinary Tract Tumors

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