What side effects are associated with this type of intervention?

Common treatments for bladder cancer, such as HDAC inhibitors like Belinostat and monoclonal antibody immunotherapies like Durvalumab, have distinct side effect profiles. Belinostat can cause fatigue, nausea, vomiting, and hematologic toxicities such as thrombocytopenia and neutropenia. Durvalumab, an immunotherapy, may lead to immune-related adverse events including colitis, pneumonitis, hepatitis, endocrinopathies, and skin reactions. Both treatments can also cause general side effects like infusion-related reactions and fatigue. Patients should discuss these potential side effects with their healthcare provider to manage and mitigate them effectively.

What prior FDA approvals exist?

The FDA has approved several treatments for bladder cancer that are similar to Belinostat and Durvalumab. Durvalumab, a monoclonal antibody targeting PD-L1, is approved for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy. Other similar immunotherapies include Atezolizumab, Pembrolizumab, and Nivolumab, which also target PD-1/PD-L1 pathways. While Belinostat, an HDAC inhibitor, is not specifically approved for bladder cancer, other HDAC inhibitors are being studied for their potential in treating various cancers, including urothelial carcinoma.

What other types of research exist?

Promising alternatives for bladder cancer treatment in 2024 include Enfortumab Vedotin, an antibody-drug conjugate targeting Nectin-4, and Sacituzumab Govitecan, a Trop-2 directed antibody-drug conjugate. Additionally, Pembrolizumab and Atezolizumab, both PD-1/PD-L1 inhibitors, continue to show efficacy in clinical trials. Novel HDAC inhibitors like 4SC-202 are also being investigated for their potential in urothelial carcinoma.

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Histone Deacetylase Inhibitor

Triple Therapy for Bladder Cancer (RESOLVE Trial)

Phase 1

Waitlist Available

Led By Sumati V Gupta

Research Sponsored by University of Utah

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Estimated creatinine clearance >= 30 mL/min by Cockcroft-Gault formula

Malignancy harboring ARID1A loss of function (lof) genomic alterations as determined by the standard of care next-generation sequencing

Must not have

Known brain metastases or cranial epidural disease

Current evidence of uncontrolled, clinically significant intercurrent illness including, but not limited to, the following conditions: Cardiovascular disorders, Uncontrolled hypertension, Adrenal insufficiency, Interstitial lung disease (ILD), Subjects with congenital long QT syndrome, Patients currently on or who will require valproic acid for any medical condition during the study

Timeline

Screening 3 weeks

Treatment Varies

Follow Up from the initiation of study therapy to disease progression per recist 1.1, initiation of alternative therapy, or death from any cause, assessed up to 3 years

Awards & highlights

No Placebo-Only Group

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects include reactions related to the immune system attacking normal organs, infusion-related reactions like fever or chills, fatigue, nausea, liver enzyme changes indicating liver damage, low blood cell counts increasing infection risk or bleeding tendency.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My kidneys are working well enough, with a creatinine clearance of at least 30 mL/min.

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My cancer has a specific genetic change called ARID1A loss of function.

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My liver enzymes are within acceptable limits despite having liver metastases.

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My body weight is over 30 kg.

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I am post-menopausal or not pregnant if pre-menopausal.

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I am fully active and can carry on all pre-disease activities without restriction.

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My bladder cancer has spread or cannot be surgically removed, and may include rare types.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have brain metastases or cranial epidural disease.

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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.

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I have been treated with durvalumab and tremelimumab before.

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I have a specific genetic variation related to Gilbert syndrome.

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I had major surgery less than 3 weeks ago or haven't fully recovered from one.

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I have previously received treatments targeting PD-1, PD-L1, or CTLA-4.

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I am not taking any medications that are not allowed in the study.

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I have another cancer that is growing and needs treatment.

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I have HIV with a detectable viral load.

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I do not have an active infection like TB, hepatitis B, or C.

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I have or had an autoimmune or inflammatory disorder.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ from the initiation of study therapy to disease progression per recist 1.1, initiation of alternative therapy, or death from any cause, assessed up to 3 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~from the initiation of study therapy to disease progression per recist 1.1, initiation of alternative therapy, or death from any cause, assessed up to 3 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and from the initiation of study therapy to disease progression per recist 1.1, initiation of alternative therapy, or death from any cause, assessed up to 3 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Incidence of DLTs (Phase 1A Part 2)

Incidence of adverse events (AEs) (Phase 1B)

Incidence of dose limiting toxicities (DLTs) (Phase 1A Part 1)

Secondary study objectives

Duration of response

Objective response rate

Overall survival

+2 more

Side effects data

From 2012 Phase 2 trial • 32 Patients • NCT00301756

88%

Fatigue

81%

Nausea

75%

Lymphocyte count decreased

72%

Constipation

Dyspnea

Lower gastrointestinal hemorrhage

Abdominal pain

Pleural infection

Urinary tract infection

Upper gastrointestinal hemorrhage

Activated partial thromboplastin time prolonged

Dehydration

Pneumonitis

Cytokine release syndrome

Arthralgia

Non-cardiac chest pain

Hypotension

Small intestinal obstruction

100%

80%

60%

40%

20%

Study treatment Arm

Treatment (Enzyme Inhibitor Therapy)

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Belinostat

2006

Completed Phase 2

~430

Durvalumab

2017

Completed Phase 2

~3750

0 / 18Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Bladder cancer treatments often include HDAC inhibitors like belinostat and monoclonal antibody immunotherapies such as durvalumab. HDAC inhibitors work by blocking histone deacetylase enzymes, which play a crucial role in cell growth and death, thereby potentially stopping cancer cell proliferation and inducing cancer cell death. Monoclonal antibody immunotherapies, on the other hand, help the immune system recognize and attack cancer cells by targeting specific proteins on the surface of these cells. For instance, durvalumab targets the PD-L1 protein, preventing it from inhibiting immune responses. These mechanisms are significant for bladder cancer patients as they offer targeted approaches to halt cancer progression and enhance the body's natural ability to fight the disease.

Combination therapy in advanced urothelial cancer: the role of PARP, HER-2 and mTOR inhibitors.[The role of immunotherapy in the modern treatment of urothelial carcinoma].