Durvalumab + Chemotherapy for Urothelial Carcinoma
Recruiting in Palo Alto (17 mi)
+217 other locations
Overseen ByJean H Hoffman-Censits
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2 & 3
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Immunosuppressants, Anthracyclines
Disqualifiers: Pregnancy, Metastatic disease, Autoimmune disease, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?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.
Will I have to stop taking my current medications?
The trial protocol does not specify whether you need to stop taking your current medications. However, you must not be on immunosuppressive medication within 14 days before starting durvalumab, except for certain low-dose steroids and specific types of steroid use.
What data supports the effectiveness of the drug combination used in the Durvalumab + Chemotherapy for Urothelial Carcinoma trial?
Research shows that combinations like methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and gemcitabine with cisplatin (GC) are effective as neoadjuvant chemotherapy for bladder cancer, suggesting potential effectiveness of similar drug combinations in treating urothelial carcinoma.
12345Is the combination of Durvalumab and chemotherapy safe for treating urothelial carcinoma?
The combination of gemcitabine and cisplatin (GC) chemotherapy, which is part of the treatment regimen with Durvalumab, has been shown to have a better safety profile compared to the traditional MVAC regimen, with fewer severe side effects like mucositis (mouth sores), neutropenic fever (fever due to low white blood cells), and neutropenic sepsis (infection due to low white blood cells).
16789What makes the drug combination of Durvalumab and chemotherapy unique for treating urothelial carcinoma?
This treatment combines Durvalumab, an immunotherapy drug that helps the immune system attack cancer cells, with chemotherapy drugs like Doxorubicin and Gemcitabine, which kill cancer cells directly. This combination aims to enhance the overall effectiveness by using both the body's immune response and traditional chemotherapy to target the cancer.
610111213Eligibility Criteria
Adults with high-grade upper urinary tract cancer who are fit for chemotherapy and surgery. They must have a life expectancy of at least 12 weeks, adequate organ function, no severe hearing loss or neuropathy, not be pregnant or breastfeeding, and willing to use contraception. Excluded if they have small cell/neuroendocrine carcinoma components in their cancer, other active cancers (with some exceptions), uncontrolled illnesses, recent major surgeries, certain autoimmune diseases or treatments.Inclusion Criteria
I was diagnosed with a severe type of urinary tract cancer within the last 12 weeks.
I understand a biopsy is necessary for my participation in the study.
I can take care of myself and am up and about more than half of my waking hours.
I had hepatitis C but am now treated with no detectable virus, or I am currently being treated with no detectable virus.
I am 18 years old or older.
I weigh more than 30 kilograms.
My hepatitis B virus is undetectable with treatment.
I have a tumor in my upper urinary tract seen on imaging or during an endoscopy.
Exclusion Criteria
I have never been treated with anthracycline drugs.
I've been cancer-free for over 2 years after treatment and haven't had immune therapy.
I have a history of bladder cancer.
I do not have any serious health issues that are not under control.
I am taking no more than 10 mg/day of prednisone or its equivalent.
My scans show no signs of cancer spread or large lymph nodes.
My cancer is mostly urothelial and does not have small cell/neuroendocrine parts.
I have a history of cancer that is not related to the bladder.
I have not had radiation on more than 25% of my bone marrow.
My cancer has not spread extensively to other parts of my body.
Participant Groups
The trial is testing the addition of Durvalumab (an immunotherapy drug) to standard chemotherapy before surgery compared to chemotherapy alone. The goal is to see if combining Durvalumab with chemo can better shrink tumors before they're surgically removed.
3Treatment groups
Experimental Treatment
Active Control
Group I: Arm C (durvalumab, gemcitabine hydrochloride)Experimental Treatment7 Interventions
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.
Group II: Arm A (durvalumab, chemotherapy)Experimental Treatment11 Interventions
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.
Group III: Arm B (chemotherapy)Active Control10 Interventions
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.
Doxorubicin Hydrochloride is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Adriamycin for:
- Breast cancer
- Ovarian cancer
- Bladder cancer
- Leukemia
- Lymphoma
🇪🇺 Approved in European Union as Doxorubicin Hydrochloride for:
- Breast cancer
- Ovarian cancer
- Bladder cancer
- Leukemia
- Lymphoma
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Springfield ClinicSpringfield, IL
Trinity Health Medical Center - CantonCanton, MI
Hematology Oncology Consultants-ClarkstonClarkston, MI
UW Cancer Center at ProHealth CareWaukesha, WI
More Trial Locations
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Who is running the clinical trial?
National Cancer Institute (NCI)Lead Sponsor
References
A systematic review and meta-analysis of neoadjuvant chemotherapy for bladder cancer between ddMVAC and GC regimen. [2022]The purpose of this systematic literature review and meta-analysis was to compare the pathological response rate and prognosis of the dose dense Methotrexate, vinblastine, doxorubicin and cisplatin (ddMVAC) regimen and gemcitabine and cisplatin (GC) regimen as neoadjuvant chemotherapy choices for bladder cancer.
Comparison of clinical outcomes in patients with localized or locally advanced urothelial carcinoma treated with neoadjuvant chemotherapy involving gemcitabine-cisplatin and high dose-intensity MVAC. [2022]To compare the efficacy and safety of high dose-intensity combination of methotrexate, vinblastine, adriamycin and cisplatin (HD MVAC) with gemcitabine plus cisplatin (GC) as a neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) or locally advanced upper tract urothelial cancer (UTUC).
Neoadjuvant chemotherapy in urothelial bladder cancer: impact of regimen and variant histology. [2022]We compared the efficacy of methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) versus gemcitabine/cisplatin in urothelial cancer and neoadjuvant chemotherapy (NACT) efficacy in variant histology (VH).
Downstaging of Muscle-Invasive Bladder Cancer Using Neoadjuvant Gemcitabine and Cisplatin or Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin as Single Regimens or as Switch Therapy Modalities. [2022]Consensus guidelines recommend gemcitabine and cisplatin (GC) or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) as equally preferable neoadjuvant chemotherapy before cystectomy for muscle-invasive bladder cancer. This study sought to compare the ability of GC and ddMVAC to achieve pathologic response; and to evaluate the benefit of switching regimens after 1 or 2 cycles of the other.
Adjuvant chemotherapy for locally advanced urothelial carcinoma: an overview of the USC experience. [2022]To describe the tolerability of two chemotherapy regimens, gemcitabine and cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) for adjuvant treatment of patients with locally advanced urothelial cancer after radical cystectomy.
Perioperative Chemoimmunotherapy With Durvalumab for Muscle-Invasive Urothelial Carcinoma: Primary Analysis of the Single-Arm Phase II Trial SAKK 06/17. [2023]The integration of immunotherapy in the perioperative setting of muscle-invasive urothelial carcinoma (MIUC) appears promising. SAKK 06/17 investigated the addition of neoadjuvant durvalumab to gemcitabine/cisplatin (GC) chemotherapy followed by radical surgery and adjuvant checkpoint inhibition with durvalumab.
Gemcitabine in advanced bladder cancer. [2022]The methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) regimen has been considered standard therapy for advanced bladder cancer. However, the toxicity of this regimen motivated the development of safer and/or more effective therapy. Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) is a promising new agent with activity in advanced disease. Early phase studies yielded response rates of 23% to 29% with single-agent treatment and 41% to 57% with the combination of gemcitabine/cisplatin (GC). In a randomized phase III trial involving 405 randomized patients with locally advanced or metastatic bladder cancer, data comparing gemcitabine at 1,000 mg/m(2) on days 1, 8, and 15 plus cisplatin at 70 mg/m(2) on day 2 every 28 days with standard MVAC demonstrated that the two regimens were associated with comparable response rates, time to disease progression, and overall survival. The GC regimen was associated with superior safety and tolerability, including reduced frequencies of grade 3/4 mucositis (1% v 22%), neutropenic fever (2% v 14%), and neutropenic sepsis (1% v 12%). These findings suggested that on the basis of superior risk to benefit ratio, the GC regimen should be favored as standard treatment in advanced bladder cancer. Other promising combinations include gemcitabine/cisplatin/paclitaxel, and a phase III trial comparing this triple-agent combination with the GC regimen in advanced bladder cancer patients has been initiated. Semin Oncol 28 (suppl 7):11-14.
Gemcitabine in the treatment of bladder cancer. [2022]New agents are available for the treatment of metastatic transitional cell carcinoma of the bladder. In the US, the combination of methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) remains the standard chemotherapy regimen for advanced bladder cancer. Gemcitabine (2',2'-difluorodeoxycytidine [dFdC]) is a relatively new agent with a favourable toxicity profile that has demonstrated activity against a number of solid tumours in both preclinical and clinical studies. Single-agent gemcitabine has shown activity in bladder cancer in both pretreated and chemotherapy-naïve patients. The combination of gemcitabine plus cisplatin is a regimen with significant activity and moderate toxicity in bladder cancer patients. A randomised trial of gemcitabine plus cisplatin versus M-VAC has completed accrual but has not yet been reported. New combination studies of gemcitabine with other chemotherapy agents, including the taxanes, are ongoing.
Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. [2022]In advanced urothelial cancer, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) results in a high response rate, less toxicity, and few dosing delays. We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive urothelial cancer (MIUC).
Durvalumab: First Global Approval. [2022]Intravenous durvalumab (Imfinzi™; AstraZeneca) is a fully human monoclonal antibody that blocks programmed cell death ligand-1 binding to its receptors (PD-1 and CD80), resulting in enhanced T-cell responses against cancer cells. The US FDA has granted durvalumab accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Durvalumab ± tremelimumab is under phase III clinical trials in urothelial carcinoma, non-small cell lung cancer, small cell lung cancer and head and neck squamous cell carcinoma. The drug is also being evaluated in phase I or II clinical trials in a wide range of solid tumours and haematological malignancies. This article summarizes the milestones in the development of durvalumab leading to this first approval for urothelial carcinoma.
Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. [2021]Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma.
Chemotherapy of Metastatic Bladder Cancer. [2019]Recent disease-oriented phase II clinical trials in advanced transitional cell carcinoma of the urothelial tract have defined the therapeutic efficacy of cis-diamminedichloride platinum II, Adriamycin and methotrexate. Other agents which may have some activity include cyclophosphamide, the podophyllotoxins, hexamethylmelamine, and possibly 5-flourouracil. While combination drug regimens have been reported to induce higher remission rates when compared to single agents, prospective randomized trials will be needed to document enhanced therapeutic benefit. The problems in selecting appropriate patients and in defining response criteria in clinical trials in urothelial tumors are discussed. Chemotherapy data in the treatment of bladder cancer is summarized, using strict response criteria.
Cabozantinib Plus Durvalumab in Patients With Advanced Urothelial Carcinoma After Platinum Chemotherapy: Safety and Preliminary Activity of the Open-Label, Single-Arm, Phase 2 ARCADIA Trial. [2021]Durvalumab and cabozantinib have shown single-agent activity in patients with metastatic urothelial carcinoma (UC). ARCADIA is a phase 2 study evaluating their combination in patients with platinum-treated, advanced UC (NCT03824691). Herein, we report the results of the planned interim safety analysis and the preliminary activity.