Triple Therapy for Bladder Cancer (RESOLVE Trial)
Recruiting in Palo Alto (17 mi)
Overseen BySumati V Gupta
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of Utah
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This trial tests a combination of two drugs, durvalumab and belinostat, for treating advanced urothelial cancer. It targets patients whose cancer has spread or cannot be surgically removed. Durvalumab helps the immune system attack cancer, and belinostat stops proteins that help cancer cells grow.
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, there is a requirement for a washout period (time without taking certain medications) of at least 5 half-lives for prohibited medications before starting the trial treatment.
How is the triple therapy for bladder cancer unique?
The triple therapy for bladder cancer combines Belinostat, Durvalumab, and Tremelimumab, which is unique because it uses a combination of drugs that target different pathways in the immune system to fight cancer. Durvalumab and Tremelimumab are immune checkpoint inhibitors that help the immune system recognize and attack cancer cells, while Belinostat is a histone deacetylase inhibitor that can modify gene expression to stop cancer cell growth.
12345Eligibility Criteria
Adults (18+) with advanced urothelial carcinoma that's spread or can't be surgically removed, who've tried at least one therapy or declined/aren't suitable for standard treatments. They must have ARID1A gene alterations, measurable disease, good organ function and blood counts, and a life expectancy of over 12 weeks. Women must not be pregnant and use effective contraception.Inclusion Criteria
My kidneys are working well enough, with a creatinine clearance of at least 30 mL/min.
My cancer has a specific genetic change called ARID1A loss of function.
My liver enzymes are within acceptable limits despite having liver metastases.
My body weight is over 30 kg.
I am post-menopausal or not pregnant if pre-menopausal.
I am fully active and can carry on all pre-disease activities without restriction.
My bladder cancer has spread or cannot be surgically removed, and may include rare types.
Exclusion Criteria
I have brain metastases or cranial epidural disease.
I do not have any uncontrolled illnesses like heart problems, high blood pressure, adrenal issues, lung disease, long QT syndrome, or need for valproic acid.
I have been treated with durvalumab and tremelimumab before.
I have a specific genetic variation related to Gilbert syndrome.
I had major surgery less than 3 weeks ago or haven't fully recovered from one.
I have previously received treatments targeting PD-1, PD-L1, or CTLA-4.
I am not taking any medications that are not allowed in the study.
I have another cancer that is growing and needs treatment.
I have HIV with a detectable viral load.
I do not have an active infection like TB, hepatitis B, or C.
I have or had an autoimmune or inflammatory disorder.
Participant Groups
The trial is testing the combination of two drugs: Belinostat (an HDAC inhibitor that may stop cancer cells from growing) and Durvalumab (a monoclonal antibody designed to help the immune system attack cancer). It aims to find the safest dose with acceptable side effects for patients with specific genetic changes in their tumors.
1Treatment groups
Experimental Treatment
Group I: Treatment (durvalumab, belinostat)Experimental Treatment2 Interventions
Phased Doublet Therapy
Eligible patients enrolled will be administered durvalumab 1120 mg every 3 weeks C1 through C7 followed by durvalumab 1500 mg every four weeks C8 through C15 (T300+D). Belinostat administration will begin with Cycle 2 for 6 cycles. From cycle 8 on, durvalumab will be administered in 28-day cycles to complete up to a total of 15 cycles of treatment or until treatment discontinuation criteria is met. Belinostat will be administered at the assigned dose level on days one through five of every applicable cycle. Belinostat administration on five consecutive days is preferred. Administration within seven days of Day 1 is allowed as needed to accommodate holidays and infusion schedules.
Durvalumab will be infused over 60 minutes (±10 minutes). For Cycles 2-7, belinostat will be infused over 30 minutes (-5 minutes/+15 minutes) and will be administered after durvalumab. Separate infusion bags and filters must be used for each infusion.
Belinostat is already approved in United States for the following indications:
🇺🇸 Approved in United States as Beleodaq for:
- Peripheral T-cell lymphoma (PTCL)
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Huntsman Cancer Institute/University of UtahSalt Lake City, UT
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Who is running the clinical trial?
University of UtahLead Sponsor
National Cancer Institute (NCI)Collaborator
References
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.
ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer. [2020]Immune checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma. In cisplatin-eligible muscle-invasive bladder cancer (MIBC), cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy improves overall survival. Tumor PD-L1 expression increases in MIBC after NAC, suggesting potential synergy in combining PD1/PD-L1 inhibitors with NAC. IDO1 is overexpressed in bladder cancer and is associated with poor outcomes. Linrodostat mesylate (BMS-986205) - a selective, potent, oral IDO1 inhibitor - combined with nivolumab has demonstrated safety and preliminary evidence of clinical activity in metastatic urothelial carcinoma. Here, we discuss the rationale and trial design of the ENERGIZE, a Phase III trial investigating the efficacy of NAC in combination with nivolumab with or without linrodostat followed by postsurgery nivolumab or nivolumab with linrodostat in cisplatin-eligible patients with MIBC. Clinical trial registration number: NCT03661320.
Neoadjuvant Immunotherapy for Muscle-Invasive Bladder Cancer. [2021]Background and Objectives: Facing neoadjuvant chemotherapy followed by surgery, neoadjuvant immunotherapy is an innovative concept in localized muscle-invasive bladder cancer. Herein, we performed a review of the available and ongoing evidence supporting immune checkpoint inhibitor (ICI) administration in the early stages of bladder cancer treatment. Materials and Methods: A literature search was performed on Medline and clinical trials databases, using the terms: "bladder cancer" OR "urothelial carcinoma", AND "neoadjuvant immunotherapy" OR "preoperative immunotherapy". We restricted our investigations to prospective clinical trials evaluating anti-PD-(L)1 and anti-CTLA-4 monoclonal antibodies. Data on efficacy, toxicity and potential biomarkers of response were retrieved. Results: The search identified 6 ICIs that were tested in the neoadjuvant setting for localized bladder cancer-4 anti-PD-(L)1 inhibitors (Pembrolizumab, Atezolizumab, Nivolumab and Durvalumab) and 2 anti-CTLA-4 inhibitors (Ipilimumab and Tremelimumab). Most of the existing literature was based on single-arm phase 2 clinical trials that included from 23 to 143 patients. The pathological complete response rate (pCR) and pathological response rate (pRR) ranged from 31% to 46% and from 55.9% to 66%, respectively. Survival data were immature at this time. The safety profile was acceptable, with severe treatment-related adverse events ranging from 6% to 41%. Conclusions: The results of early phase trials are encouraging, and more investigations are needed to strengthen the rationale for immune checkpoint inhibitor administration in localized muscle-invasive bladder cancer.
Muscle invasive bladder cancer: where is the field headed? [2023]The standard treatment for muscle-invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy or upfront radical cystectomy for cisplatin-ineligible patients. In those who are ineligible for or refuse radical cystectomy, trimodal therapy with chemoradiation is offered. However, with the success of immune checkpoint inhibitors (ICI) and antibody-drug conjugates such as enfortumab vedotin in the metastatic setting, several trials are implementing these drugs in the neoadjuvant setting for cisplatin ineligible patients. Indeed, nivolumab is approved as adjuvant therapy for high-risk muscle-invasive urothelial carcinoma.
Phase 1 Trial of Atezolizumab Plus Trimodal Therapy in Patients With Localized Muscle-Invasive Bladder Cancer. [2021]Immune checkpoint programmed death-ligand 1 inhibitor therapy has shown response in metastatic muscle invasive bladder cancer (MIBC). We evaluated the safety and tolerability of atezolizumab (anti-programmed death-ligand 1) in combination with trimodal therapy in patients with localized MIBC.