Tremelimumab + Durvalumab(MEDI4736)+ Belinostat in Urothelial Carcinoma

NCT05154994 | Active Not Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: HCI143952NCI-2021-12484P30CA042014
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial studies the side effects and best dose of belinostat when given together with durvalumab in treating patients with urothelial cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable) and has spread to nearby tissue or lymph nodes (locally advanced). 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. Belinostat is a potential anti-cancer drug, known as a histone deacetylase (HDAC) inhibitor, which means that belinostat stops the activity of HDAC enzymes (an enzyme is a protein that in small amounts can speed up a biological reaction). HDAC enzymes play an important role in cell growth and cell death. Giving durvalumab and belinostat may improve the body's ability to fight cancer.

Conditions

Locally Advanced Urothelial Carcinoma; Metastatic Urothelial Carcinoma; Unresectable Urothelial Carcinoma; Infiltrating Urothelial Carcinoma, Sarcomatoid Variant

Outcome Measures

Primary Outcomes (3)

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

  Rate of DLTs during the defined DLT period for belinostat dose escalation. The number and proportion of DLTs will be reported for each dose level. An exact 95% confidence interval will be reported for each dose level with more than one patient.

  Up to 21 days

• Incidence of DLTs (Phase 1A Part 2)

  Rate of DLTs during the defined DLT period for confirmation of belinostat for the phased triplet regimen.

  Up to 21 days

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

  The incidence and frequency of AEs characterized by type, severity (as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0), seriousness, duration, and relationship to study treatment. Will be tabulated by dose level and cohort. Exact 95% binomial confidence intervals.

  Up to 3 years

Secondary Outcomes (5)

• Rate of clinical benefit

  Up to 3 years

• Objective response rate

  Up to 3 years

• Duration of response

  Up to 3 years

• Progression-free survival

  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

• Overall survival

  From the initiation of study therapy until death from any cause, assessed up to 3 years

Study Arms (1)

Treatment (durvalumab, belinostat)

EXPERIMENTAL

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.

Drug: Belinostat; Biological: Durvalumab

Interventions

Durvalumab BIOLOGICAL

Given IV

Also known as: Imfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736

Treatment (durvalumab, belinostat)

Belinostat DRUG

Given IV

Also known as: Beleodaq, PXD 101, PXD101

Treatment (durvalumab, belinostat)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female subject aged \>= 18 years
• Histologically confirmed urothelial carcinoma with metastatic disease or with unresectable, locally advanced disease. Variant histology, including, but not limited to, neuroendocrine, sarcomatoid, and squamous differentiation are permitted to enroll
• Patients must meet one or more of the following criteria:
• Has progressed on at least one prior therapy; or
• Has declined standard therapy; or
• Is not a suitable candidate for standard therapy
• The discussion regarding the choice of standard therapy offered, if available, and patient's choice and reason(s) to decline standard therapy should be documented clearly in the research chart.
• Patients may have progressed on immune checkpoint inhibitor therapy
• Body weight \> 30 kg
• Subject must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria by computed tomography (CT) or magnetic resonance imaging (MRI)
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 1
• Absolute neutrophil count (ANC) \>= 1500/mm\^3
• Platelet count \>= 100,000/mm\^3
• Hemoglobin \>= 10 g/dL Hemoglobin \< 10 g/dL due to hematuria at the time of treatment is acceptable as long as there is evidence of adequate bone marrow function in the opinion of the investigator.
• Total Bilirubin =\< 1.5 x institutional upper limit of normal (ULN)

You may not qualify if:

• Homozygous for UGT1A1\*28 allele or heterozygous or homozygous for UGT1A1\*60 orGilbert syndrome
• Subject has received systemic antineoplastic therapy (including unconjugated therapeutic antibodies and toxin immunoconjugates) or any investigational therapy =\< 14 days or within 5 half-lives before starting study treatment, whichever is shorter
• Prior treatment with durvalumab
• Subject has received radiotherapy =\< 14 days before the first dose of study treatment. Localized radiation therapy for the treatment of symptomatic bone metastasis is allowed during that timeframe
• Subjects who have undergone major surgery =\< 3 weeks before starting study drug or who have not fully recovered from major surgery
• Known additional malignancy that is active and/or progressive and requiring treatment.
• Known brain metastases or cranial epidural disease
• Note: Brain metastases or cranial epidural disease adequately treated with radiotherapy and/or surgery and stable for at least 4 weeks before the first dose of study treatment will be allowed on trial. Subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the first dose of study treatment
• Current evidence of uncontrolled, clinically significant intercurrent illness including, but not limited to, the following conditions:
• Cardiovascular disorders:
• Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias
• Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic events, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before the first dose
• Uncontrolled hypertension defined as a sustained systolic blood pressure \>= 160 mmHg or a diastolic blood pressure \>= 100 mmHg despite optimal management
• Note: Patients with uncontrolled hypertension who are not optimally managed may be rescreened once controlled hypertension is achieved
• Note: Patients with uncorrectable prolonged corrected QT (QTc) (Bezet formula) \> 480 msec or concomitant use of medications(s) with a known risk of inducing Torsade de Pointes if such treatment cannot be discontinued or switched to a different medication before starting the study drug

Sponsors & Collaborators

• University of Utah: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112, United States

Location

MeSH Terms

Conditions

Carcinoma, Transitional Cell

Interventions

belinostat; durvalumab; Immunoglobulin G; Disulfides

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds; Organic Chemicals

Study Officials

• Sumati V Gupta

  Huntsman Cancer Institute/ University of Utah

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 30, 2021
• First Posted: December 13, 2021
• Study Start: January 14, 2022
• Primary Completion: April 1, 2026
• Study Completion (Estimated): November 30, 2027
• Last Updated: January 27, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)