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Advanced LymphomaPhase 1NCT03925428

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

A Phase 1 study testing Entinostat and Molibresib in people with Advanced Lymphoma and Advanced Malignant Solid Neoplasm, run by National Cancer Institute (NCI).

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 12 years and older
What is being tested?
Entinostat and Molibresib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
18 Sep 2020to 18 Sep 2020
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 12 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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.
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  • 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).
  • Creatinine =< institutional ULN (within 14 days prior to administration of study treatment) OR
  • Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73m^2 as measured by the Cockcroft-Gault equation (within 14 days prior to administration of study treatment).
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
  • Patients with treated brain metastases are eligible if follow-up brain imaging at least 4 weeks after central nervous system (CNS)-directed therapy shows no evidence of progression.
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification. To be eligible for this trial, patients should be class 2B or better.
  • Patients must be able to swallow and retain orally administered medication.
  • Women of childbearing potential must have a negative pregnancy test within 7 days of starting treatment.
  • The effects of entinostat and GSK525762C on the developing human fetus are unknown. For this reason and because HDAC inhibitor (HDACi) and BET inhibitor (BETi) agents are known to be teratogenic, women of child-bearing potential and their male partner must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for 7 months after completion of entinostat and GSK525762C administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of entinostat and GSK525762C administration.
  • Patients must have tumors determined to be easily accessible for biopsy and must be willing to have serial biopsies. Tumor biopsies will be performed on the most accessible biopsiable site of disease. All possible precautions to avoid complications will be taken, including discussions in multidisciplinary meetings, if needed. If a biopsy cannot be performed safely (e.g. there is no safely accessible biopsiable tumor tissue) or biopsy does not yield sufficient tissue for analysis, participation is still allowed.
  • Patients on both therapeutic and prophylactic anticoagulation may participate as long as they have no history of clinically significant bleeding while on anticoagulation.
  • Ability to understand and the willingness to sign a written informed consent document.

Who cannot join

  • 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.
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  • 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.

About this study

Official title: Phase I Study of GSK525762C and Entinostat in Advanced and Refractory Solid Tumors and Lymphomas

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the maximum tolerated dose (MTD) of GSK525762C and entinostat in combination in patients with advanced and refractory solid tumors and lymphomas based on dose limiting toxicities (DLTs) of the combination of GSK525762C and entinostat.

SECONDARY OBJECTIVES:

  1. To describe the safety profile of GSK525762C and entinostat in advanced and refractory solid tumors and lymphomas.

II. To determine the overall response rate (ORR) of GSK525762C and entinostat in advanced and refractory solid tumors and lymphomas.

III. To determine the progression-free survival (PFS), duration of response (DOR), and overall survival (OS) of GSK525762C and entinostat in this patient population.

EXPLORATORY OBJECTIVES:

  1. To assess the effect of GSK525762C and entinostat therapy on apoptosis, as measured by an apoptosis multiplex immunoassay.

II. To assess the effect of GSK525762C and entinostat therapy on c-MYC and YAP1 as measured by ribonucleic acid (RNA) and protein expression.

III. To assess the effect of GSK525762C and entinostat therapy on tumor burden and gene expression patterns as measured by whole exome sequencing (WES) and RNA sequencing (RNASeq) on circulating tumor deoxyribonucleic acid (DNA) (ctDNA) specimens.

OUTLINE: This is a dose-escalation study.

Patients receive entinostat orally (PO) on days 1, 8, 15, and 22, and molibresib PO once daily (QD) 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 for 4 weeks.

Being tested
Entinostat, Molibresib
Medical subject headings
Lymphoma, B-Cell, Lymphoma, Pancreatic Neoplasms, Lymphoma, T-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EntinostatDrug

    Also called HDAC inhibitor SNDX-275, MS 27-275, MS-275, SNDX-275

    Given PO

  • MolibresibDrug

    Also called GSK-525762A, GSK525762, I-BET 762

    Given PO

Study groups in NCT03925428
Study groupRoleWhat they receive
Treatment (entinostat, molibresib)ExperimentalPatients 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.
Receives: Drug: Entinostat; Drug: Molibresib

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: At 28 days

Secondary outcomes (5)

  1. Incidence of adverse events

    Graded per Common Terminology Criteria for Adverse Events version 5.0. National Cancer Institute toxicity grade 3 and grade 4 laboratory abnormalities will be listed.

    Measured: Up to 2 years

  2. Overall response rate (ORR)

    The exact two-sided 95% confidence intervals (CIs) for the RR will be reported.

    Measured: Up to 2 years

  3. Progression-free survival

    Will be estimated using the Kaplan-Meier method with the 95% CIs. The CI based on Greenwood's variance will be reported. In addition, the possible risk factors will be compared for survival with log-rank test.

    Measured: Up to 2 years

  4. Overall survival

    Will be estimated using the Kaplan-Meier method with the 95% CIs. The CI based on Greenwood's variance will be reported. In addition, the possible risk factors will be compared for survival with log-rank test.

    Measured: Up to 2 years

  5. Duration of response

    The 95% CIs for the duration of response will be reported.

    Measured: Up to 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Apr 2019
  2. Study start18 Sep 2020
  3. Primary completion18 Sep 2020
  4. Study completion18 Sep 2020

Why it stopped: Other - Protocol moved to Disapproved

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03925428
Sponsor's protocol ID
NCI-2019-02419
Other IDs
NCI-2019-02419, 10244, 10244, UM1CA186689
Status last verified
Sep 2020
First submitted
23 Apr 2019
Last updated
28 Sep 2020
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: 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.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Entinostat and Molibresib in people with Advanced Lymphoma and Advanced Malignant Solid Neoplasm, run by National Cancer Institute (NCI).

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 29 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 28 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose (time frame: At 28 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03925428.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Sep 2020.

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