Testing a New Anti-cancer Drug Combination, Entinostat and GSK525762C, for Advanced and Refractory Solid Tumors and Lymphomas

NCT03925428 | Withdrawn Phase 1 DMC FDA Drug

• 3 other identifiers: NCI-2019-0241910244UM1CA186689
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase I trial studies the side effects and best dose of GSK525762C (molibresib besylate) and entinostat in treating patients with solid tumors or lymphomas that have spread to other parts of the body (advanced) or are not responding to treatment (refractory). GSK525762C and entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. This study may help doctors find out if giving the combination of GSK525762C and entinostat is better or worse than the usual approach for treating solid tumors or lymphomas.

Conditions

Advanced Lymphoma; Advanced Malignant Solid Neoplasm; Ann Arbor Stage III B-Cell Non-Hodgkin Lymphoma; Ann Arbor Stage III T-Cell Non-Hodgkin Lymphoma; Ann Arbor Stage IV B-Cell Non-Hodgkin Lymphoma; Ann Arbor Stage IV T-Cell Non-Hodgkin Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Lymphoma; Refractory Malignant Solid Neoplasm; Refractory Pancreatic Carcinoma; Refractory T-Cell Non-Hodgkin Lymphoma; Stage II Pancreatic Cancer AJCC v8; Stage IIA Pancreatic Cancer AJCC v8; Stage IIB Pancreatic Cancer AJCC v8; Stage III Pancreatic Cancer AJCC v8; Stage IV Pancreatic Cancer AJCC v8; Unresectable Pancreatic Carcinoma

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose

  Assesses with dose limiting toxicities. Descriptive statistics, including means, standard deviations, and ranges for continuous parameters, as well as percentages and frequencies for categorical parameters, will be presented.

  At 28 days

Secondary Outcomes (5)

• Incidence of adverse events

  Up to 2 years

• Overall response rate (ORR)

  Up to 2 years

• Progression-free survival

  Up to 2 years

• Overall survival

  Up to 2 years

• Duration of response

  Up to 2 years

Other Outcomes (5)

• Effect of GSK525762C and entinostat combination therapy on apoptosis rate

  Up to 2 years

• Effect of GSK525762C and entinostat combination therapy on c-MYC expression

  Up to 2 years

• Effect of GSK525762C and entinostat combination therapy on YAP1 expression

  Up to 2 years

Study Arms (1)

Treatment (entinostat, molibresib)

EXPERIMENTAL

Patients receive entinostat PO on days 1, 8, 15, and 22 and molibresib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Entinostat; Drug: Molibresib

Interventions

Entinostat DRUG

Given PO

Also known as: HDAC inhibitor SNDX-275, MS 27-275, MS-275, SNDX-275

Treatment (entinostat, molibresib)

Molibresib DRUG

Given PO

Also known as: GSK-525762A, GSK525762, I-BET 762

Treatment (entinostat, molibresib)

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have advanced or refractory solid tumor or lymphoma (all B cell lymphomas and T cell lymphomas other than natural killer \[NK\]-cell lymphoma).
• For patients in the dose expansion cohort:
• Cohort A: Patients must have locally advanced, unresectable OR metastatic pancreatic cancer refractory to standard therapy.
• Patients must have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
• Patients should have received previous therapy with at least one combination chemotherapy regimen for metastatic disease.
• Patients with lymphoma must have exhausted or refused potential curative therapy prior to enrolling.
• Weight of \>= 35 kg.
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 50%).
• Hemoglobin \>= 9.0 g/dL (within 14 days prior to administration of study treatment).
• Absolute neutrophil count (ANC) \>= 1,500/mcL (within 14 days prior to administration of study treatment).
• Platelets \>= 100,000/mcL (within 14 days prior to administration of study treatment).
• Total bilirubin =\< institutional upper limit of normal (ULN) (within 14 days prior to administration of study treatment).
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional ULN (within 14 days prior to administration of study treatment).
• Serum creatinine clearance \> 50 mL/min (within 14 days prior to administration of study treatment).
• Serum bilirubin =\< 1.5 x institutional ULN (within 14 days prior to administration of study treatment).

You may not qualify if:

• Patients who have had any anti-cancer therapy within 14 days (or 5 half-lives, whichever is longer) prior to the first dose of the investigational products.
• Patients who have received radiation therapy within 21 days prior to the first dose of the investigational products.
• Patients who have a diagnosis of NK cell lymphoma.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy. Toxicities should have recovered to =\< grade 1, excluding alopecia, or should be stable chronic grade 2 toxicities that do not overlap with presumed toxicities of entinostat or GSK525762C.
• Patients who are receiving any other investigational agents.
• Patients with known untreated or symptomatic brain or leptomeningeal metastases are excluded. Patients with previously treated central nervous system (CNS) metastasis may be included provided that they have stable CNS disease for at least 4 weeks (confirmed by imaging) without symptoms and are off corticosteroids (above physiologic dose) for that indication.
• Patients with significant malabsorption or nausea and vomiting that would interfere with oral therapies.
• Patients with bleeding diathesis or clinically significant bleeding within the prior 6 months.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to entinostat (e.g. medications that have a benzamide structure \[tiapride, remoxipride, clebopride\] or GSK525762C \[e.g. benzodiazepines\]).
• Patients receiving any medications or substances that are strong inhibitors or strong inducers of CYP3A4 are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Patients with uncontrolled intercurrent illness.
• Patients with a history of clinically significant bleeding.
• Patients with psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because entinostat is an HDACi and GSK525762C is a BETi with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with entinostat or GSK525762C, breastfeeding should be discontinued throughout the treatment period and for at least 28 days following the last dose of study treatment if the mother is treated with entinostat or GSK525762C.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

MeSH Terms

Conditions

Lymphoma, B-Cell; Lymphoma; Pancreatic Neoplasms; Lymphoma, T-Cell

Interventions

entinostat; molibresib

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Study Officials

• Patricia M LoRusso

  Yale University Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: April 23, 2019
• First Posted: April 24, 2019
• Study Start: September 18, 2020
• Primary Completion: September 18, 2020
• Study Completion: September 18, 2020
• Last Updated: September 28, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will share