What side effects are associated with this type of intervention?

Common treatments for Neuroendocrine Tumors (NETs) include somatostatin analogs, targeted therapies like everolimus and sunitinib, and peptide receptor radionuclide therapy (PRRT). Somatostatin analogs can cause gastrointestinal disturbances, gallstones, and glucose metabolism disorders. Targeted therapies such as everolimus may lead to stomatitis, rash, diarrhea, fatigue, and infections, while sunitinib can cause hypertension, fatigue, diarrhea, and hand-foot syndrome. PRRT is associated with nausea, vomiting, and potential long-term renal and hematological toxicities. For treatments similar to BET inhibitors and CDK4/6 inhibitors, common side effects include gastrointestinal issues, fatigue, hematological toxicities, and potential liver enzyme elevations.

What prior FDA approvals exist?

The FDA has approved several treatments for Neuroendocrine Tumors (NETs), including somatostatin analogs like octreotide and lanreotide, which inhibit hormone secretion and tumor growth. Targeted therapies such as everolimus (an mTOR inhibitor) and sunitinib (a tyrosine kinase inhibitor) have also been approved for specific types of NETs. While there are no FDA-approved BET inhibitors or CDK4/6 inhibitors specifically for NETs, these classes of drugs are being explored in clinical trials for their potential efficacy in treating various cancers, including NETs.

What other types of research exist?

Promising novel alternatives for Neuroendocrine Tumors (NETs) patients include: 1) Everolimus, an mTOR inhibitor, which has shown a clinical benefit rate of 40% in a phase II study for recurrent, incurable endometrial cancer and is also used for progressive GINETs. 2) Surufatinib, a tyrosine kinase inhibitor (TKI), demonstrated significant improvement in progression-free survival (PFS) in a phase III trial for advanced nonpancreatic NETs. 3) Lenvatinib, another TKI, showed modest antitumor activity with a median PFS of 15.9 months in a phase II trial for GINETs. These agents represent promising alternatives for NETs treatment in 2024.

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CDK4/6 Inhibitor

ZEN003694 + Abemaciclib for Cancer

Q: What is the mechanism of action of this treatment?

BET inhibitors, such as ZEN003694, work by targeting the bromodomain and extra-terminal (BET) proteins, which play a crucial role in regulating gene expression that promotes tumor growth. By inhibiting these proteins, BET inhibitors can reduce the proliferation of cancer cells. CDK4/6 inhibitors, like Abemaciclib, block cyclin-dependent kinases 4 and 6, which are essential for cell cycle progression from the G1 to the S phase. This inhibition results in cell cycle arrest and reduced tumor growth. These mechanisms are particularly important for Neuroendocrine Tumors (NETs) because they address the uncontrolled cell proliferation characteristic of these tumors, potentially leading to better disease management and improved patient outcomes.

Phase 1

Recruiting

Led By Michael Cheng

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Dose Expansion Cohort Only: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN for age

Participants must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective

Must not have

Participants who have had cytotoxic chemotherapy, immunotherapy, or other investigational therapy within 2 weeks prior to entering the study. There is a two week required washout period for previous BET inhibitor therapy

Patients receiving any medications or substances that are Factor Xa inhibitors or Factor IIa inhibitors

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Awards & highlights

Summary

This trial tests the safety and best dose of two drugs, ZEN003694 and abemaciclib, in patients with advanced cancers. These drugs work together to stop cancer cells from growing and dividing. The goal is to find out if this combination can help treat cancers that have spread or cannot be removed by surgery.

Who is the study for?

This trial is for adults and kids aged 12-17 with NUT carcinoma or other solid tumors that have spread or can't be surgically removed. Participants need to meet specific health criteria, like normal organ function tests, controlled HIV or hepatitis if present, and a certain level of physical fitness. They should not have untreated brain metastases or conditions that could affect the trial's results.

What is being tested?

The trial is testing the combination of two drugs: ZEN003694 (a BET protein growth inhibitor) and abemaciclib (an enzyme blocker stopping tumor cell growth). It aims to find the safest dose that might help shrink or stabilize these cancers. The study includes biospecimen collection, imaging, and biopsies.

What are the potential side effects?

Possible side effects from ZEN003694 and abemaciclib may include fatigue, nausea, liver issues, blood count changes leading to infection risk increase or bleeding problems. There might also be risks related to taking pills and potential unknown effects on unborn babies.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My liver enzymes are within the normal range for my age.

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My cancer is advanced, cannot be surgically removed, and standard treatments are not effective.

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My kidney function, measured by creatinine levels or clearance, is within the required range.

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I have been diagnosed with NUT carcinoma confirmed by specific lab tests.

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I had hepatitis C but am cured, or I'm being treated with no detectable virus.

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I am 16 or older and can care for myself, or if under 16, I can do most activities.

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My brain metastases have been treated, stable for 1 month, and show no signs of getting worse.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I haven't had chemotherapy, immunotherapy, or experimental treatments in the last 2 weeks.

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I am taking medication that affects blood clotting.

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I am not taking strong medication that affects liver enzymes.

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I do not have any severe ongoing illnesses or conditions that are not under control.

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More than a quarter of my bone marrow has been exposed to radiation.

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I am not taking strong medication that affects liver enzymes.

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I haven't had a heart attack or unstable chest pain in the last 6 months.

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I have a history of fainting due to heart issues, irregular heartbeats, or sudden cardiac arrest.

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I have not had major surgery in the last 3 weeks.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Clinical benefit rate (CBR) (Phase I dose expansion)

Duration of response (DoR) (Phase I dose expansion)

Incidence of adverse events (Phase I dose expansion)

+3 more

Secondary study objectives

Pharmacokinetics (PK)

Thymidine

Other study objectives

Analysis of ATAC-sequence data

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (ZEN003694, abemaciclib)Experimental Treatment5 Interventions

Patients receive ZEN003694 PO QD on days 1-28 or 5 days on and 2 days off, and abemaciclib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo imaging evaluation, blood sample collection and tumor biopsy throughout the study.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Biopsy

2014

Completed Phase 4

~1090

Biospecimen Collection

2004

Completed Phase 3

~2020

Abemaciclib

2019

Completed Phase 2

~1800

0 / 16Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

BET inhibitors, such as ZEN003694, work by targeting the bromodomain and extra-terminal (BET) proteins, which play a crucial role in regulating gene expression that promotes tumor growth. By inhibiting these proteins, BET inhibitors can reduce the proliferation of cancer cells. CDK4/6 inhibitors, like Abemaciclib, block cyclin-dependent kinases 4 and 6, which are essential for cell cycle progression from the G1 to the S phase. This inhibition results in cell cycle arrest and reduced tumor growth. These mechanisms are particularly important for Neuroendocrine Tumors (NETs) because they address the uncontrolled cell proliferation characteristic of these tumors, potentially leading to better disease management and improved patient outcomes.

Selecting the optimal position of CDK4/6 inhibitors in hormone receptor-positive advanced breast cancer - the SONIA study: study protocol for a randomized controlled trial.The impact of ethnicity on efficacy and toxicity of cyclin D kinase 4/6 inhibitors in advanced breast cancer: a meta-analysis.