Entinostat + ZEN003694 for Cancer

Recruiting at 3 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

Trial Summary

What is the purpose of this trial?

This phase I/II trial tests the safety, side effects, and best dose of entinostat and ZEN003694 in treating patients with solid tumors or lymphoma that has spread to other places in the body (advanced) or does not respond to treatment (refractory). Entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is in a class of drugs called histone deacetylase (HDAC) inhibitor. ZEN003694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). ZEN003694 may prevent the growth of tumor cells that produce high levels of BET protein. This trial aims to test the safety of combination therapy with entinostat and ZEN003694 in treating patients with advanced or refractory solid tumors or lymphoma.

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.

What data supports the effectiveness of the drug Entinostat + ZEN003694 for cancer?

Entinostat has shown promise in combination with other drugs for treating various cancers, such as prostate cancer and breast cancer, by inhibiting cancer growth and overcoming resistance to hormonal therapies. Additionally, it has been combined with azacitidine for myelodysplastic syndrome and acute myeloid leukemia, showing significant clinical activity. ^{1 2 3 4 5}

What makes the drug Entinostat + ZEN003694 unique for cancer treatment?

Entinostat + ZEN003694 is unique because it combines two oral inhibitors that target specific enzymes involved in cancer cell growth, potentially overcoming resistance to existing hormonal therapies. This combination is particularly novel as it includes Entinostat, a histone deacetylase inhibitor, which has shown promise in treating hormone-resistant breast cancer, and ZEN003694, which may enhance its effects. ^{1 3 4 6 7}

Research Team

Patricia M Lorusso

Principal Investigator

Yale University Cancer Center LAO

Eligibility Criteria

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 have had radiation therapy within the last 21 days.

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

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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 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]

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 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]

References

1. United States 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). [2022]

2. England pubmed.ncbi.nlm.nih.gov

Phase I Study of Entinostat in Combination with Enzalutamide for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer. [2021]

3. England 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. [2022]

4. United States 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. [2022]

5. United States 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. [2021]

6. Netherlands 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. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Entinostat: a promising treatment option for patients with advanced breast cancer. [2022]