Symptoms and General Pathology

All Conditions

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Recurrence

Carcinoma

Carcinoma, Transitional Cell

Urinary Bladder Neoplasms

Urethral Neoplasms

Ureteral Neoplasms

Kidney Neoplasms

Pelvic Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Urethral Diseases

Ureteral Diseases

Kidney Diseases

Transitional Cell Carcinoma

Urethral Cancer

Antineoplastic Agents

All Drugs and Chemicals

Atezolizumab

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Immunologic Factors

Patients receive CYT107 IM on days 1, 8, 15, and 22, and atezolizumab IV over 60 minutes on day 8 of cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles with atezolizumab repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study.

Patients receive atezolizumab IV over 60 minutes on cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study.

Biopsy

Undergo collection of blood and stool samples

Biospecimen Collection

Computed Tomography

Glycosylated Recombinant Human Interleukin-7

Laboratory Biomarker Analysis

Magnetic Resonance Imaging

Positron Emission Tomography and Computed Tomography Scan

Evan Y Yu

This phase II trial studies how well atezolizumab when given with glycosylated recombinant human interleukin-7 (CYT107) works in treating patients with urothelial carcinoma that has spread to nearby tissue or lymph nodes (locally advanced), cannot be removed by surgery (inoperable), or has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. CYT107 is a biological product naturally made by the body that may stimulate the immune system to destroy tumor cells. Giving atezolizumab and CYT107 may work better in treating patients with locally advanced, inoperable, or metastatic urothelial carcinoma compared to atezolizumab alone.

PRIMARY OBJECTIVE:

I. To determine the clinical efficacy of the investigational treatment combination.

SECONDARY OBJECTIVES:

I. To determine the clinical activity and toxicity of the investigational treatment combination.

II. The clinical benefit rate (CBR), progression-free survival (PFS), duration of response (DOR), as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related (ir) RECIST, and overall survival (OS).

III. The CBR, PFS, DOR, and OS in all patients and patients stratified by PD-L1 expression levels in the tumor microenvironment.

IV. The safety and toxicity of addition of CYT107 to atezolizumab.

EXPLORATORY OBJECTIVES:

I. To determine the immune correlates of the clinical activity of the investigational treatment combination.

II. Explore the effect of the investigational treatment combination on the number and phenotype of tumor-specific T cells in the peripheral blood.

III. Investigate for evidence that the investigational treatment combination increases the exposure of bladder cancer-specific antigens (e.g., cancer/testis antigens or neoantigens).

IV. Investigate changes in tumor microenvironment that correlate with response or provide information on potential actionable causes for lack of clinical benefit.

V. Investigate the potential that administration of atezolizumab with CYT107 may perturb the pharmacokinetics and immunogenicity of CYT107.

OUTLINE: Safety Run-in phase - patients assigned to the experimental arm (atezolizumab + CYT107). If the treatment combination of the experimental arm demonstrates an acceptable safety profile in the Safety Run-In (one or fewer patient experiences a protocol-defined Dose Limiting-Toxicity), randomized enrollment into the trial will begin. The Run-in phase patients will be analyzed and reported separately both for safety and for efficacy.

Patients are randomized to 1 of 2 groups.

GROUP 1 (experimental arm): Patients receive CYT107 intramuscularly (IM) on days 1, 8, 15, and 22, and atezolizumab intravenously (IV) over 60 minutes on day 8 of cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles with atezolizumab repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study.

GROUP 2 (control arm): Patients receive atezolizumab IV over 60 minutes on cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks for up to 2 years.

Atezolizumab and CYT107 in Treating Participants With Locally Advanced, Inoperable, or Metastatic Urothelial Carcinoma

A Randomized Phase II Study of Atezolizumab (MPDL3280A) Plus Recombinant Human IL7 (CYT107) in Patients With Locally Advanced or Metastatic Urothelial Carcinoma

The evaluation of the effect of the investigation treatment combination on the immune-bias of the tumor microenvironment, based upon baseline and post-baseline tumor biopsy comparisons of number, distribution, and phenotype of tumor-infiltrating cells; PD-L1 expression, and expression of Interferon gamma (IFN-gamma) and associated proinflammatory gene expression in the tumor microenvironment.

ORR to be defined by complete response (CR) or partial response (PR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) version (v.) 1.1. The Cochran Mantel Haenszel test will be conducted to compare ORR in the experimental arm (atezolizumab + CYT107) to the ORR in the control arm (atezolizumab monotherapy). A one-sided significance level of 0.10 will be considered for the test.

CBR is defined as the percentage of patients with advanced or metastatic cancer who have achieved CR, PR, and stable disease (SD) to a therapeutic intervention in clinical trials of anticancer agents. A two-sided test for a difference in proportions will be conducted to compare the CBR in the experimental arm to the CBR in the control arm. A two-sided significance level of 0.05 will be considered for the test. Will also assess CBR in patients stratified by PD-L1 expression levels in the tumor microenvironment.

PFS to be measured by RECIST v1.1 and irRC. PFS will be summarized using Kaplan-Meier estimates. Long-rank tests will be conducted for overall survival (OS) and PFS to compare between the 2 arms. A one-sided significance level of 0.10 will be considered. Will also assess PFS in patients stratified by PD-L1 expression levels in the tumor microenvironment.

DOR is measured by RECIST v1.1 and irRC. DOR will be summarized using Kaplan-Meier estimates. Long-rank tests will be conducted for OS and PFS to compare between the 2 arms. A one-sided significance level of 0.10 will be considered. Will also assess DOR in patients stratified by PD-L1 expression levels in the tumor microenvironment.

OS will be summarized using Kaplan-Meier estimates. Long-rank tests will be conducted for OS and PFS to compare between the 2 arms. A one-sided significance level of 0.10 will be considered. Will also assess OS in patients stratified by PD-L1 expression levels in the tumor microenvironment.

National Cancer Institute (NCI)

Blood and Lymph Conditions

Immune System Diseases

Lymphoma, Large B-Cell, Diffuse

Lymphoma

Lymphoma, T-Cell

Lymphoma, T-Cell, Cutaneous

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

B-cell Lymphoma

Diffuse Large B-Cell Lymphoma

Lymphosarcoma

Cutaneous T-cell Lymphoma

Belinostat

Histone Deacetylase Inhibitors

Enzyme Inhibitors

Patients receive tazemetostat PO BID on days 2-21 of cycle 1 and days 1-21 of subsequent cycles, and belinostat IV over 30-180 minutes on days 1-5 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients may undergo a tumor biopsy during screening and on study (dose-expansion only). Patients undergo blood sample collection while on study and PET/CT scan throughout the study. Patients may also undergo CT scan alone throughout the study.

Pharmacokinetic Study

Tazemetostat

Site Public Contact

Joseph M. Tuscano

Tarsheen Sethi

Aung M. Tun

Yun Kyoung Tiger

Jennifer E. Amengual

Sami Ibrahimi

Lindsey Fitzgerald

Victor Y. Yazbeck

Jennifer E Amengual

This phase I trial tests the safety, side effects, and best dose of combination therapy with tazemetostat and belinostat in treating patients with lymphomas that have returned (relapsed) or resisted treatment (refractory). Tazemetostat is in a class of medications called EZH2 inhibitors. The EZH2 gene provides instructions for making a type of enzyme called histone methyltransferase which is involved in gene expression and cell division. Blocking EZH2 may help keep cancer cells from growing. Belinostat is in a class of medications called histone deacetylase inhibitors. Histone deacetylases are enzymes needed for cell division. Belinostat may kill cancer cells by blocking histone deacetylase. It may also prevent the growth of new blood vessels that tumors need to grow and may help make cancer cells easier to kill with other anticancer drugs. There is some evidence in animals and in living human cells that combination therapy with tazemetostat and belinostat can shrink or stabilize cancer, but it is not known whether this will happen in people. This trial may help doctors learn more about treatment of patients with relapsed or refractory lymphoma.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of tazemetostat and belinostat in combination in patients with relapsed or refractory lymphoma (Phase I: Dose escalation).

II. Evaluate the safety and toxicity of the combination tazemetostat and belinostat (Phase I: Dose escalation).

III. Assess the safety and tolerability of tazemetostat and belinostat in patients with germinal-center derived aggressive B-cell lymphoma (transformed disease, diffuse large B-cell lymphoma germinal center B-cell type \[GC-DLBCL\] defined by Hans criteria) (Phase I: Dose expansion).

IV. Assess the impact of EZH2, CREBBP, and EP300 mutations on response to dual epigenetic targeting (Phase I: Dose expansion).

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To evaluate the pharmacokinetic profile for tazemetostat and belinostat when given as a combination.

III. Define the overall response rate (ORR), progression free survival (PFS), and duration of response (DOR) in patients with relapsed or refractory EZH2 mutated and EZH2 wild-type aggressive germinal-center derived B-cell lymphoma (transformed disease, GC-DLBCL defined by Hans criteria).

IV. To describe the maximum number of cycles received, the number of dose reductions and delays at the MTD.

EXPLORATORY OBJECTIVES:

I. Determine a biomarker for response by assessing the basal mutation and gene expression status of key epigenetic regulators and correlating this signature with the response to the combination.

II. Determine the change in gene expression in tumor tissue following exposure the combined epigenetic therapy.

III. Determine the effect of combination epigenetic therapy on modulation of acetylation and methylation of histone K27.

IV. Determine the effect of combination epigenetic therapy on modulation of the immune response.

OUTLINE: This is a phase I dose-escalation study of tazemetostat and belinostat followed by a dose-expansion study.

Patients receive tazemetostat orally (PO) twice daily (BID) on days 2-21 of cycle 1 and days 1-21 of subsequent cycles, and belinostat intravenously (IV) over 30-180 minutes on days 1-5 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients may undergo a tumor biopsy during screening and on study (dose-expansion only). Patients undergo blood sample collection while on study and positron emission tomography/computed tomography(PET/CT) scan throughout the study. Patients may also undergo computed tomography (CT) scan alone throughout the study.

After completion of study treatment, patients are followed up at 4 weeks, then every 3 months for a year or until they begin a new treatment for their disease.

Testing the Safety of the Anti-cancer Drugs Tazemetostat and Belinostat in Patients With Lymphomas That Have Resisted Treatment

Phase 1/Expansion Study of Tazemetostat Plus Belinostat for the Treatment of Relapsed or Refractory Lymphoma

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Will be assessed separately for the wild type (WT) and the mutant (MUT) groups and will be compared using a two-sample Wilcoxon rank-sum test.

Will be evaluated next generation sequencing (NGS) and presented in descriptive terms. Gene signature biomarker data analysis will be completed using Lasso-based elastic net method.

Defined as the highest dose level at which \< 33% of the dose cohort (0 of 3 or 1 of 6) experience a dose-limiting toxicity (DLT) in the first cycle.

Will be assessed by positron emission tomography/computed tomography (PET/CT) scan following cycle 2 and 6, and then every 3-6 cycles. Response will be defined by the Lugano Classification.

Defined as complete response + partial response. Will be estimated and the exact 95% confidence interval will be constructed based on binomial distribution.

Will be estimated by the Kaplan-Meier method and compared by the log-rank test.

Will be estimated by the Kaplan-Meier method.

Plasma concentrations of both tazemetostat and belinostat using area under the "concentration time" curve (AUC), maximum concentration (Cmax), time to maximum concentration Tmax, and half-life (T1/2) will be calculated for the two study drugs.

National Cancer Institute (NCI) toxicity Grade 3 and Grade 4 laboratory abnormalities will be listed. Summary statistics will be provided for all laboratory values.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Atezolizumab and CYT107 in Treating Participants With Locally Advanced, Inoperable, or Metastatic Urothelial Carcinoma	NCT03513952	Advanced Bladde... Advanced Ureter... Metastatic Blad... Metastatic Rena... Metastatic Uret... Metastatic Uret... Metastatic Urot... Recurrent Bladd... Recurrent Renal... Recurrent Urete... Recurrent Ureth... Stage III Bladd... Stage III Renal... Stage III Urete... Stage III Ureth... Stage IV Bladde... Stage IV Renal ... Stage IV Ureter... Stage IV Urethr... Stage IVA Bladd... Stage IVB Bladd... Unresectable Bl... Unresectable Re... Unresectable Ur...	Atezolizumab Biopsy Biospecimen Col... Computed Tomogr... Glycosylated Re... Laboratory Biom... Magnetic Resona... Positron Emissi...	18 Years -	National Cancer Institute (NCI)
Testing the Safety of the Anti-cancer Drugs Tazemetostat and Belinostat in Patients With Lymphomas That Have Resisted Treatment	NCT05627245	Recurrent B-Cel... Recurrent Diffu... Recurrent Non-H... Recurrent Prima... Recurrent T-Cel... Recurrent Trans... Refractory B-Ce... Refractory Diff... Refractory Non-... Refractory Prim... Refractory T-Ce... Refractory Tran...	Belinostat Biopsy Biospecimen Col... Computed Tomogr... Pharmacokinetic... Positron Emissi... Tazemetostat	18 Years -	National Cancer Institute (NCI)

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