Neoplasms

All Conditions

Rare Diseases

Carcinoma

Carcinoma, Transitional Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Transitional Cell Carcinoma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Durvalumab

Belinostat

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Tremelimumab

Antibodies, Monoclonal

Antineoplastic Agents, Immunological

Immunologic Factors

Histone Deacetylase Inhibitors

Enzyme Inhibitors

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.

Susan Sharry

Sumati V. Gupta

Sumati V Gupta

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.

PRIMARY OBJECTIVES:

I. To assess the recommended phase 2 dose of belinostat in combination with tremelimumab and durvalumab or belinostat in combination with durvalumab alone in advanced solid tumors harboring ARID1A mutations with focus on urothelial carcinoma. (Phase 1A) II. To assess the ongoing safety of belinostat in combination with durvalumab in patients with advanced solid tumors with ARID1A mutation with focus on urothelial cancer. (Phase 1B)

SECONDARY OBJECTIVES:

I. To assess the efficacy of belinostat in combination with tremelimumab and durvalumab or belinostat in combination with durvalumab in patients with advanced urothelial cancer with ARID1A mutation.

EXPLORATORY OBJECTIVES:

I. To assess the mechanism of action of belinostat in combination with tremelimumab and durvalumab or belinostat in combination with durvalumab.

II. To explore possible mechanisms of treatment resistance. III. Determine the feasibility of establishing patient-derived xenografts from tumor cells collected from enrolled subjects at baseline, and progression to better explore mechanisms of response and resistance. IIII. To explore possible biomarkers predictive of treatment benefit.

OUTLINE: This is a dose-escalation study of belinostat.

Patients receive durvalumab intravenously (IV) over 30 minutes on day 1. Patients also receive tremelimumab IV over 60 minutes on day 1 of cycle 1. Beginning cycle 2, patients receive belinostat IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 7 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 2 years.

Tremelimumab + Durvalumab(MEDI4736)+ Belinostat in ARID1A Mutated Cancer Focus on Urothelial Carcinoma

RESOLVE : A Phase I Trial of Tremelimumab + Durvalumab(MEDI4736)+ Belinostat in ARID1A Mutated Cancers With Focus on Urothelial Carcinoma

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.

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

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.

Defined as the proportion of evaluable patients achieving stable disease, a partial response, or a complete response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Will be tabulated by dose level and cohort. Exact 95% binomial confidence intervals.

Defined as the proportion of evaluable patients achieving a partial response or a complete response per RECIST 1.1 criteria. Will be tabulated by dose level and cohort. Exact 95% binomial confidence intervals.

Defined as the time from documented tumor response to disease progression as defined by RECIST 1.1. Will be analyzed using Kaplan-Meier methodology and associated 95% confidence intervals.

Will be analyzed using Kaplan-Meier methodology and associated 95% confidence intervals.

Spots Global Cancer Trial Database for infiltrating urothelial carcinoma, sarcomatoid variant