Entinostat + ZEN003694 for Cancer

Recruiting at 4 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: NK cell lymphoma, Uncontrolled illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two drugs, entinostat and ZEN003694, to evaluate their safety and potential side effects when combined to treat cancer. It targets individuals with solid tumors or lymphoma that have spread or resisted other treatments. Entinostat may inhibit cancer cell growth by blocking essential enzymes, while ZEN003694 targets proteins that aid tumor growth. Individuals with advanced or difficult-to-treat cancer unresponsive to standard therapies might be suitable for this study. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications that are strong inhibitors or inducers of CYP3A4 or substrates of CYP1A2 with narrow therapeutic windows at least 7 days before starting the study drugs. You should discuss your current medications with the trial team to ensure they don't interact with the study drugs.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that entinostat, a drug studied for its potential to stop cancer growth, is generally well-tolerated by patients. It belongs to a group of drugs called HDAC inhibitors, which have shown promise in treating various cancers. Although detailed information on entinostat's side effects is not provided here, it has been tested in conditions like non-small cell lung cancer, indicating some level of safety in humans.

Studies on ZEN003694, a drug targeting proteins that help tumor cells grow, have also shown it is generally tolerated by patients. Earlier research used it with other cancer drugs, and participants received it well. Some side effects were reported, but they were manageable and typical for cancer treatments.

Both entinostat and ZEN003694 are in phase 1 and 2 trials, meaning they are still being tested for safety and effectiveness. However, early studies have provided some safety evidence. Participating in clinical trials can help advance medical research and potentially offer new treatment options. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about entinostat and ZEN003694 because they offer a novel approach to cancer treatment. Unlike standard chemotherapy and targeted therapies that often focus on directly killing cancer cells, these treatments work by modulating gene expression and disrupting cancer cell growth mechanisms. Entinostat is a histone deacetylase inhibitor, which means it can alter the expression of genes involved in cancer progression. ZEN003694 is a bromodomain and extra-terminal (BET) inhibitor, targeting proteins that regulate gene expression crucial for cancer cell survival. This combination could potentially make cancer cells more vulnerable to treatment, offering a promising new pathway for those battling this disease.

What evidence suggests that this trial's treatments could be effective for advanced or refractory solid tumors or lymphoma?

Research shows that entinostat might stop cancer cells from growing by blocking certain necessary enzymes. It belongs to a group of drugs called HDAC inhibitors, which have shown promise in cancer treatment. ZEN003694 targets proteins called BET, often found in high amounts in cancer cells. Studies suggest that blocking these proteins can help stop tumor growth. This trial will explore the combination of entinostat and ZEN003694, as researchers believe they might work well together to fight cancer more effectively. Early results are promising, but more research is needed to confirm their effectiveness in treating advanced or hard-to-treat solid tumors or lymphoma. ^{1 4 6 7 8}

Who Is on the Research Team?

Patricia M Lorusso

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with advanced or treatment-resistant solid tumors or lymphoma, who have tried standard treatments without success. They must be in good enough health as shown by specific blood tests and organ function measures, not pregnant, able to take oral medication, and free of certain other medical conditions.

Inclusion Criteria

Your bilirubin levels are within a certain limit as measured in a recent test.

I have lymphoma and have undergone at least two treatments, including chemotherapy.

I have someone legally authorized to make decisions for me if I'm unable to.

Exclusion Criteria

I haven't had significant bleeding or bleeding disorders in the last 6 months.

I haven't had major surgery, except for diagnosis, dental work, or stenting, in the last 4 weeks.

I have had radiation therapy within the last 21 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Run-in Period

Patients receive ZEN003694 orally once daily during days -14 to 1 and undergo core needle biopsy within 30 days prior to starting therapy

2 weeks

1 visit (in-person)

Phase II Run-in Period

Patients receive ZEN003694 or entinostat based on enrollment order during days -14 to 1 and undergo core needle biopsy within 30 days prior to starting therapy

2 weeks

1 visit (in-person)

Combination Treatment

Patients receive entinostat once per week and ZEN003694 daily in 28-day cycles, with core needle biopsies on day 1 of cycle 1 and cycle 14

28 days per cycle

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Entinostat
• ZEN003694

Trial Overview The trial is testing the combination of two drugs: Entinostat (an enzyme blocker) and ZEN003694 (a protein inhibitor), for patients whose cancer has spread or doesn't respond to treatment. It's a phase I/II trial aimed at finding the safest dose with the fewest side effects.

How Is the Trial Designed?

Group I: Treatment (entinostat, ZEN003694) Experimental Treatment 3 Interventions

PHASE I RUN-IN PERIOD: Patients receive ZEN003694 PO QD during days -14 to 1. Patients also undergo core needle biopsy within 30 days prior to starting therapy. PHASE II RUN-IN PERIOD: Patients receive ZEN003694 PO QD or entinostat PO QW during days -14 to 1 based on the order to which they are enrolled to the study (e.g. every other patient starts by taking ZEN003694 alone for 14 days). Patients also undergo core needle biopsy within 30 days prior to starting therapy. PHASE I \& II COMBINATION TREATMENT: Patients receive entinostat PO QW on days 1, 8, 15, and 22, and ZEN003694 PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo core needle biopsy on day 1 of cycle 1, and on day 1 of cycle 14.

Entinostat is already approved in China, European Union for the following indications:

Approved in China as Entinostat for:

• Cancer

Approved in European Union as Entinostat for:

• Orphan Drug designation for cancer treatment

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Entinostat is a selective HDAC inhibitor that promotes histone hyperacetylation, leading to the activation of specific genes that inhibit cancer cell growth and induce apoptosis, making it a promising treatment for advanced malignancies.

Currently being evaluated in a Phase III trial for advanced breast cancer, entinostat has shown a potential overall survival advantage when combined with exemestane, based on earlier Phase II results, although it is not yet approved for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entinostat: a promising treatment option for patients with advanced breast cancer. Connolly, RM., Rudek, MA., Piekarz, R.[2022]

In a small phase I study involving 6 patients with metastatic castration-resistant prostate cancer (CRPC), the combination of entinostat and enzalutamide demonstrated a promising safety profile, with manageable side effects and no significant increase in fatigue.

Entinostat did not alter the plasma concentration of enzalutamide and showed biological activity by increasing histone H3 acetylation in peripheral blood mononuclear cells, suggesting potential mechanisms for its efficacy in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Entinostat in Combination with Enzalutamide for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer. Lin, J., Elkon, J., Ricart, B., et al.[2021]

In a study of 149 patients with high-risk myelodysplastic syndrome and acute myeloid leukemia, azacitidine (AZA) alone achieved a hematologic normalization (HN) rate of 32%, while the combination of AZA and entinostat resulted in a lower HN rate of 27%.

The addition of entinostat did not enhance the clinical response and was associated with less demethylation, indicating a potential antagonistic effect, while AZA alone showed promise with a median overall survival of 18 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. Prebet, T., Sun, Z., Figueroa, ME., et al.[2021]

Entinostat, an oral HDAC inhibitor, was well tolerated in a phase I trial with 21 pediatric patients, showing no dose-limiting toxicities at doses of 3 mg/m2 and 4 mg/m2, indicating a favorable safety profile for this age group.

The recommended phase 2 dose (RP2D) for entinostat in children with relapsed or refractory solid tumors is established at 4 mg/m2, with pharmacokinetic studies revealing a significantly higher drug exposure in children compared to adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 study of entinostat in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1513, Pediatric Early Phase-Clinical Trial Network (PEP-CTN). Bukowinski, A., Chang, B., Reid, JM., et al.[2022]

In a phase II study involving 130 postmenopausal women with ER+ advanced breast cancer, the combination of entinostat and exemestane improved median progression-free survival (PFS) to 4.3 months compared to 2.3 months with exemestane alone, suggesting enhanced efficacy of the combination treatment.

Entinostat was generally well tolerated, although there was a higher rate of treatment discontinuation due to adverse events in the entinostat group (11% vs. 2%). Additionally, changes in protein lysine acetylation were linked to prolonged PFS, indicating a potential biomarker for treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. Yardley, DA., Ismail-Khan, RR., Melichar, B., et al.[2022]

In a phase 3 trial involving 354 Chinese patients with hormone receptor-positive advanced breast cancer, the combination of entinostat and exemestane significantly improved progression-free survival (PFS) to a median of 6.32 months compared to 3.72 months with placebo (P = 0.046).

While the combination treatment showed efficacy, it was associated with a higher incidence of grade ≥3 adverse events (65.5% in the entinostat group vs. 19.3% in the placebo group), with neutropenia being the most common severe side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entinostat, a class I selective histone deacetylase inhibitor, plus exemestane for Chinese patients with hormone receptor-positive advanced breast cancer: A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Xu, B., Zhang, Q., Hu, X., et al.[2023]

Entinostat, both as a monotherapy and in combination with exemestane, was well tolerated in a phase 1 study involving 12 Japanese postmenopausal women with advanced hormone receptor-positive breast cancer, showing no dose-limiting toxicities or severe adverse events.

Half of the patients achieved stable disease for at least 6 months, with a median progression-free survival of 13.9 months, indicating that entinostat may be an effective treatment option for patients resistant to standard endocrine therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer. Masuda, N., Tamura, K., Yasojima, H., et al.[2022]

Citations

1. pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov/compound/Entinostat

Entinostat | C21H20N4O3 | CID 4261 - PubChem Entinostat is a member of the class of benzamides resulting from the formal condensation of the carboxy group of the pyridin-3-ylmethyl carbamate derivative ...

2. synapse.patsnap.com synapse.patsnap.com/drug/73864b8d082e4ee6a8e7f0560a2fa204

Entinostat - Drug Targets, Indications, Patents Entinostat: a HDAC inhibitors, Epigenetic drug Drug, Initially developed by Bayer AG, Now, its global highest R&D status is Approved, Mechanism: HDAC ...

3. precision.fda.gov precision.fda.gov/ginas/app/ui/substances/1ZNY4FKK9H

ENTINOSTAT Names and Synonyms ; ENTINOSTAT · CARBAMIC ACID, N-((4-(((2-AMINOPHENYL)AMINO)CARBONYL)PHENYL)METHYL)-, 3- PYRIDINYLMETHYL ESTER · entinostat [INN] ; Official Name ...

4. searchlf.ama-assn.org searchlf.ama-assn.org/usan/documentDownload?uri=/unstructured/binary/usan/entinostat.pdf

USAN ENTINOSTAT PRONUNCIATION en tin oh' stat STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL. USAN. ENTINOSTAT. PRONUNCIATION en tin oh' stat. THERAPEUTIC CLAIM. Antineoplastic.

5. newdrugapprovals.org newdrugapprovals.org/2015/01/09/entinostat/

Entinostat | New Drug Approvals The preparation of N-(2-aminophenyl)-4-[N- (pyridine-3-yl)methoxycarbonylaminomethyl]-benzamide is described on page 57, Example 48. The ...

6. pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov/compounds/4261

Entinostat | C21H20N4O3 | CID 4261 Entinostat is a member of the class of benzamides resulting from the formal condensation of the carboxy group of the pyridin-3-ylmethyl carbamate derivative ...

7. pharmaoffer.com pharmaoffer.com/api-excipient-supplier/enzyme-replacements-modifiers/entinostatum

Entinostatum (Entinostat) API Manufacturers & Suppliers Entinostat, identified by CAS number 209783-80-2, is a notable compound with significant therapeutic applications. Entinostat is under investigation for the ...

8. go.drugbank.com go.drugbank.com/drugs/DB11841

Entinostat: Uses, Interactions, Mechanism of Action Entinostat has been investigated for the treatment of Non-Small Lung Cancer, Epigenetic Therapy. Modality: Small Molecule; Groups ...