Neoplasms

All Conditions

Digestive System Diseases

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Carcinoma

Carcinoma, Hepatocellular

Lymphoma

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Neoplasms, Glandular and Epithelial

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

B-cell Lymphoma

Lymphosarcoma

Hematinics

All Drugs and Chemicals

Liver Extracts

Patients receive tazemetostat PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Pharmacological Study

Tazemetostat

Daniel J Renouf

This phase I trial studies the best dose and side effects of tazemetostat in treating patients with solid tumors or B-cell lymphomas with liver dysfunction that have spread to other places in the body or cannot be removed by surgery. Tazemetostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine safety, tolerability and recommended phase 2 dose (RP2D) of tazemetostat in patients with varying degrees of hepatic dysfunction.

SECONDARY OBJECTIVES:

I. To assess the pharmacokinetics (PK) profiles of tazemetostat in patients with varying degrees of hepatic dysfunction.

II. To observe preliminary antitumor activity of tazemetostat in this population, especially in tumors with aberrations in EZH2 or SWI/SNF complex pathways.

OUTLINE: This is a dose escalation study.

Patients receive tazemetostat orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks.

Tazemetostat in Treating Patients With Metastatic or Unresectable Solid Tumors or B-Cell Lymphomas With Liver Dysfunction

A Phase I Study of Single Agent Tazemetostat in Subjects With Advanced Solid Tumors and B-Cell Lymphomas With Hepatic Dysfunction

Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to study treatment.

Plasma concentrations will be measured by Q2 Solutions using a validated Liquid chromatography (LC)/mass spectrometry (MS)/MS assay. Molecular and clinical predictors of clinical outcomes will be investigated using logistic regression and Cox proportional hazards models. Potential predictors include clinical predictors and molecular correlates. Descriptive statistics and plotting of data will also be used to better understand potential relationships. Given the small sample size, and exploratory nature of these endpoints, all pharmacodynamic analyses conducted will be considered exploratory. All analyses will be considered exploratory and inference will be performed with appropriate caution.

Molecular and clinical predictors of clinical outcomes will be investigated using logistic regression and Cox proportional hazards models. Potential predictors include clinical predictors and molecular correlates. Descriptive statistics and plotting of data will also be used to better understand potential relationships. All analyses will be considered exploratory and inference will be performed with appropriate caution.

Response will be assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1

Response will be assessed using the RECIST criteria 1.1.

National Cancer Institute (NCI)

Antineoplastic Agents

Nivolumab

Sorafenib

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Participants receive sorafenib PO on days 1-28, and nivolumab IV over 30 minutes beginning on day 15 of course 1, then on days 1 and 15 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Course will continue until 1 dose-limiting toxicity occurs to establish maximum tolerated dose.

Participants receive sorafenib on days 1-28, and nivolumab IV over 30 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Robin K. Kelley, MD

This phase II trial studies the best dose and side effects of sorafenib tosylate and nivolumab in treating patients with liver cancer that cannot be removed by surgery (unresectable), has spread to nearby tissues or lymph nodes (locally advanced) or to other places in the body (metastatic). Sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving sorafenib tosylate and nivolumab may work better in treating patients with liver cancer.

PRIMARY OBJECTIVES:

I. Maximum tolerated dose (MTD) of sorafenib tosylate (sorafenib) in combination with standard dose nivolumab with Child Pugh A-B7 liver function. (Part 1: Escalation Cohort).

II. Safety in patients with Child Pugh B liver function. (Part 2: Child Pugh B Escalation Cohort)

SECONDARY OBJECTIVES:

I. Safety and tolerability of combination overall. (Parts 1 and 2).

II. Rate of immune-related adverse event (irAE) for combination overall and in patients with Child Pugh B liver function. (Parts 1 and 2).

III. Overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with Child Pugh B liver function. (Parts 1 and 2).

IV. Duration of response (DOR), progression free survival (PFS), and overall survival (OS) for escalation cohort and Child Pugh B expansion cohort and overall. (Parts 1 and 2).

EXPLORATORY OBJECTIVES:

I. Relationship between peripheral blood mononuclear cell (PBMC) immune cell subset frequencies, baseline liver function, and clinical outcomes.

II. Relationship between PBMC T cell receptor (TCR) clonotype frequency and diversity, baseline liver function, and clinical outcomes.

III. Tumor tissue immune cell subsets and TCR clonotype frequency and diversity in pre-treatment archival tumor tissue samples.

IV. Tumor and immune cell PD-L1 status in pre-treatment archival tumor tissue samples and relationship to clinical outcomes.

V. Changes in hepatitis B virus (HBV) and/or hepatitis C virus (HCV) viral load on treatment.

VI. Alpha-fetoprotein (AFP) changes on treatment and relationship to clinical outcomes.

VII. Relationship between clinical outcomes and clinicopathologic features including race/ethnicity, etiology of liver disease including HBV/HCV status, baseline liver function, presence of cirrhosis, macrovessel invasion, extrahepatic spread, site(s) of metastatic disease, prior treatment history including prior radiation and arterial therapies.

OUTLINE: This is a dose-escalation and expansion study of sorafenib tosylate.

DOSE-ESCALATION (Part 1 - CLOSED TO ENROLLMENT):

Between 3-12 patients will be enrolled in Part 1. Patients receive sorafenib tosylate orally (PO) once daily (QD) or twice daily (BID) on days 1-28, and nivolumab intravenously (IV) over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

EXPANSION COHORT (Part 2).

Patients receive nivolumab IV over 30 minutes on days 1 and 15, and sorafenib tosylate once daily (QD) or twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 100 days, then every 3 months for up to 2 years.

Sorafenib and Nivolumab in Treating Participants With Unresectable, Locally Advanced or Metastatic Liver Cancer

Multicenter Pilot Study of the Safety, Efficacy, and Immune Cell Profiling in Advanced Hepatocellular Carcinoma (HCC) Patients Treated With the Combination of Sorafenib Plus Nivolumab as First-Line of Systemic Therapy

Maximum tolerated dose is defined as the dose in which 1 or more dose limiting toxicities (DLT) is reported by the study participant within the first cycle of treatment. Subjects must receive 2 doses of nivolumab and at least 75% of sorafenib doses within 28 days (1 cycle), or experience a qualifying DLT event, to be evaluable for DLT. DLT will be defined as clinically-significant toxicities which are at least possibly treatment-related and meet criteria listed in NCI Common Terminology Criteria for Adverse Events (CTCAE) v.4.03

Defined as the proportion of subjects assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with measurable disease at study entry who have a evaluated complete response (CR) or partial response (PR) at any time during the main study.

Adverse event (AE) and serious adverse event (SAE) will be summarized based on proportion of total subjects, by system organ class, preferred term, and grade following CTCAE) v.4.03 criteria. Dose reductions and dose delays for toxicity will be summarized.

Delays in dosing due to adverse events will be summarized as proportion of all participants in each arm.

Dose reductions due to adverse events will be summarized as proportion of all participants in each arm.

Treatment discontinuations due to adverse events will be summarized as proportion of all participants in each arm.

ORR will be based on assessments using RECIST 1.15 using local radiographic review and analyzed for all efficacy-evaluable patients (Parts 1 and 2 combined) as well as for Part 1 and Part 2 individually. ORR defined as the proportion of subjects with RECIST 1.1-measurable disease at study entry who have a CR or PR at any time during the main study. Subjects with measurable disease at study entry who have unknown or missing response information will be treated as non-responders.

DOR is defined as the time from first documented evidence of CR or PR until the first documented sign of disease progression or death, assessed

PFS will be calculated in months from date of first dose of protocol therapy to date of first documented radiographic and/or clinical disease progression or death from any cause. For patients discontinued from study for other reasons than progression or death, PFS will be censored at the date last known to be progression-free.

OS is defined as the time from the date of first dose of protocol therapy to the date of death due to any cause. Censoring will be performed using the date of last known contact for those who are alive at the time of analysis.

Safety events assessed by treating investigator and/or Study Chair as being at least possibly Immune-related on nivolumab (irAE) will be summarized based on proportion of total subjects, by system organ class and preferred term as for overall safety

Safety events for participants with Chile Pugh B Liver Function assessed by treating investigator and/or Study Chair as being at least possibly Immune-related on nivolumab (irAE) will be summarized based on proportion of total subjects, by system organ class and preferred term as for overall safety

Bayer

Bristol-Myers Squibb

Robin Kate Kelley

Associate Professor

Symptoms and General Pathology

Gland and Hormone Related Diseases

Recurrence

Cholangiocarcinoma

Pancreatic Neoplasms

Carcinoma, Ductal

Gallbladder Neoplasms

Disease Attributes

Endocrine Gland Neoplasms

Pancreatic Diseases

Endocrine System Diseases

Biliary Tract Neoplasms

Biliary Tract Diseases

Gallbladder Diseases

Pancreatic Cancer

Bile Duct Cancer

Gallbladder Cancer

Intrahepatic Cholangiocarcinoma

Durvalumab

Guadecitabine

Patients receive guadecitabine SC QD on days 1-5 and durvalumab IV over 60 minutes on day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Anthony El-Khoueiry, MD

This phase Ib trial studies the side effects and best dose of guadecitabine and how well it works when given together with durvalumab in treating patients with liver, pancreatic, bile duct, or gallbladder cancer that has spread to other places in the body. Guadecitabine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as durvalumab, may block tumor growth in different ways by targeting certain cells. Giving guadecitabine and durvalumab may work better in treating patients with liver, pancreatic, bile duct, or gallbladder cancer.

PRIMARY OBJECTIVES:

I. To evaluate the dose limiting toxicities and determine the maximum tolerated dose/recommended phase 2 dose of the combination of guadecitabine and durvalumab. (Dose escalation part) II. To evaluate the objective response rate (per Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1) for the combination of guadecitabine and durvalumab in hepatocellular carcinoma, pancreatic cancer and cholangiocarcinoma cohorts, respectively. (Expansion part)

SECONDARY OBJECTIVES:

I. To describe the safety and tolerability of the combination of guadecitabine and durvalumab.

II. To estimate the progression-free and overall survival of patients with advanced hepatocellular carcinoma (HCC), pancreatic cancer and biliary cancers treated with the combination of guadecitabine and durvalumab.

TERTIARY OBJECTIVES:

I. Correlate programmed cell death ligand 1 (PD-L1) and programmed cell death protein 1 (PD1) expression on various cells within tumor samples and anti-tumor effect (response rate and survival).

II. Correlate effector T cells (Teff)/regulatory T cells (Treg) ratio in the tumor and anti-tumor effect.

III. Correlate granulocytic and monocytic myeloid-derived suppressor cells (MDSCs) level in the peripheral blood using fluorescence-activated cell sorting (FACS) and anti-tumor effect.

IV. Evaluate changes in inflammatory T cell signatures pre and post treatment and potential associations with anti-tumor effect.

V. Assess the induction, activation, expansion and tumor infiltration of tumor neo-epitope-specific T cells.

VI. Explore changes in gene methylation and expression with anti-tumor effect, with particular emphasis on the ancestry-informative marker (AIM) gene panel.

VII. Correlate immunologic changes in pre- and post-treatment peripheral blood mononuclear cell (PBMCs) and anti-tumor effect.

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

Patients receive guadecitabine subcutaneously (SC) once daily (QD) on days 1-5 and durvalumab intravenously (IV) over 60 minutes on day 8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months.

Guadecitabine and Durvalumab in Treating Patients With Advanced Liver, Pancreatic, Bile Duct, or Gallbladder Cancer

A Phase Ib Study of Guadecitabine (SGI-110) and Durvalumab (MEDI 4736) in Patients With Advanced Hepatocellular Carcinoma, Pancreatic Adenocarcinoma, and Cholangiocarcinoma/Gallbladder Cancer

Graded according to Common Terminology Criteria for Adverse Events version 4.03.

Will be calculated by the percentage of patients having complete or partial response among all patients who have been treated at maximum tolerated dose/recommended phase II dose in each cohort. Will be assessed according to Response Evaluation Criteria in Solid Tumors (RECIST).

Kaplan-Meier curves will be used to show overall survival in each cohort. Median overall survival and 95% confidence intervals will be derived from Kaplan-Meier curves.

Kaplan-Meier curves will be used to show progression-free survival in each cohort. Median progression-free survival and 95% confidence intervals will be derived from Kaplan-Meier curves.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Tazemetostat in Treating Patients With Metastatic or Unresectable Solid Tumors or B-Cell Lymphomas With Liver Dysfunction	NCT03217253	Ann Arbor Stage... Ann Arbor Stage... Metastatic Mali... Stage III Hepat... Stage IIIA Hepa... Stage IIIB Hepa... Stage IIIC Hepa... Stage IV Hepato... Stage IVA Hepat... Stage IVB Hepat... Unresectable So...	Laboratory Biom... Pharmacological... Tazemetostat	18 Years -	National Cancer Institute (NCI)
Sorafenib and Nivolumab in Treating Participants With Unresectable, Locally Advanced or Metastatic Liver Cancer	NCT03439891	Stage III Hepat... Stage IIIA Hepa... Stage IIIB Hepa... Stage IIIC Hepa... Stage IV Hepato... Stage IVA Hepat... Stage IVB Hepat...	Nivolumab Sorafenib	18 Years -	University of California, San Francisco
Guadecitabine and Durvalumab in Treating Patients With Advanced Liver, Pancreatic, Bile Duct, or Gallbladder Cancer	NCT03257761	Extrahepatic Bi... Gallbladder Ade... Metastatic Panc... Recurrent Chola... Recurrent Gallb... Recurrent Hepat... Recurrent Intra... Recurrent Pancr... Stage III Gallb... Stage III Hepat... Stage III Intra... Stage III Pancr... Stage IIIA Gall... Stage IIIA Hepa... Stage IIIB Gall... Stage IIIB Hepa... Stage IIIC Hepa... Stage IV Gallbl... Stage IV Hepato... Stage IV Pancre... Stage IVA Gallb... Stage IVA Hepat... Stage IVA Intra... Stage IVB Gallb... Stage IVB Hepat... Stage IVB Intra... Unresectable Ga... Unresectable Pa...	Durvalumab Guadecitabine	18 Years -	University of Southern California
Sorafenib and Nivolumab in Treating Participants With Unresectable, Locally Advanced or Metastatic Liver Cancer	NCT03439891	Stage III Hepat... Stage IIIA Hepa... Stage IIIB Hepa... Stage IIIC Hepa... Stage IV Hepato... Stage IVA Hepat... Stage IVB Hepat...	Nivolumab Sorafenib	18 Years -	University of California, San Francisco

Spots Global Cancer Trial Database for stage iiib hepatocellular carcinoma ajcc v7