ZEN003694 + Abemaciclib for Cancer

Recruiting at 8 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, Proton pump inhibitors

Disqualifiers: Uncontrolled illness, Severe renal impairment, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle, repeated until disease progression or unacceptable toxicity

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments, ZEN003694 and abemaciclib, to determine if they can safely shrink or control tumors in individuals with certain advanced or hard-to-remove cancers, such as NUT carcinoma and breast cancer. ZEN003694, an experimental treatment, aims to stop cancer cells by blocking a protein essential for their growth, while abemaciclib prevents cell growth. Individuals with cancers that have spread or cannot be surgically removed, and who have already tried standard treatments without success, might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering patients the opportunity to be among the first to receive this new treatment combination.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications that are strong inhibitors or inducers of certain liver enzymes (CYP3A4) at least 7 days before starting the study drugs. If you are on such medications, you will need to discuss alternatives with your doctor.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that ZEN003694, a drug under testing, has been used with other treatments like enzalutamide, a prostate cancer drug, and generally has a manageable safety profile. Studies suggest that while some side effects occur, they are usually tolerable. The FDA has granted ZEN003694 "orphan drug" status for NUT carcinoma, indicating its potential importance for conditions with limited treatment options.

Abemaciclib is already approved for certain breast cancers. It has been tested in numerous studies and is typically well-tolerated. Some side effects are common, but they are often manageable. Real-world data indicates that its side effects are less frequent and less severe than in some clinical trials.

Both treatments are still under study together, but current data suggests they are generally safe when used as intended. However, as this is a phase 1 trial, the primary focus is on safety, and much remains to be learned about their combined effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ZEN003694 and Abemaciclib because it targets cancer in a novel way. Unlike standard treatments that typically focus on one pathway, this duo employs a dual mechanism of action. ZEN003694 acts as a BET inhibitor, which can potentially suppress cancer cell growth by altering gene expression, while Abemaciclib, a CDK4/6 inhibitor, disrupts cancer cell division. This combination approach could enhance effectiveness and reduce the progression of the disease compared to treatments that target only a single pathway.

What evidence suggests that this trial's treatments could be effective for cancer?

Research has shown that ZEN003694, a BET inhibitor, might slow tumor growth by targeting proteins that cancer cells overproduce. Early studies suggest it could be effective when combined with other cancer drugs to treat tumors. Abemaciclib, known for its success in treating breast cancer, blocks enzymes necessary for cancer cell growth. Studies have found that it significantly improves survival rates in patients with advanced breast cancer. In this trial, participants will receive a combination of ZEN003694 and Abemaciclib, which together might help shrink or stabilize tumors in various types of cancer. ^{1 4 6 7 8}

Who Is on the Research Team?

Jia Luo

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

Dose Expansion Cohort Only: Absolute neutrophil count >= 1.5 x 10^9/L

Dose Expansion Cohort Only: Platelets >= 1 x 10^11/L

Dose Expansion Cohort Only: Participants must have measurable disease per RECIST 1.1 criteria

Exclusion Criteria

Patients who are receiving any other investigational agents

History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 or abemaciclib

Pregnant women are excluded from this study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ZEN003694 and abemaciclib orally in 28-day cycles, with imaging evaluation, blood sample collection, and tumor biopsy throughout the study

28 days per cycle, repeated until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

30 days, then every 3 months for 2 years, and every 6 months for 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Abemaciclib
• ZEN003694

Trial Overview 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.

How Is the Trial Designed?

Group I: Treatment (ZEN003694, abemaciclib) Experimental Treatment 5 Interventions

Patients receive ZEN003694 PO QD on days 1-28 or 5 days on and 2 days off of each cycle, 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.

Abemaciclib is already approved in United States, European Union for the following indications:

Approved in United States as Verzenio for:

• Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Approved in European Union as Verzenio for:

• HR+, HER2- advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

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

Abemaciclib is an oral medication that inhibits cyclin-dependent kinases 4 and 6, specifically approved in the USA for treating advanced or metastatic breast cancer that is hormone receptor-positive and HER2-negative.

It is effective both as a combination therapy with fulvestrant for patients who have progressed after endocrine therapy and as a standalone treatment for those who have also undergone chemotherapy, highlighting its role in advanced cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: First Global Approval. Kim, ES.[2019]

In a study involving 900 patients treated with abemaciclib for advanced breast cancer, patient-reported outcomes (PROs) such as physical function and pain were found to be significant predictors of progression-free survival (PFS), indicating their importance in treatment outcomes.

Patients with low physical function experienced a reduced benefit from abemaciclib compared to those with intermediate or high physical function, highlighting the need to consider PROs as independent prognostic markers in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-Reported Outcomes Predict Progression-Free Survival of Patients with Advanced Breast Cancer Treated with Abemaciclib. Badaoui, S., Kichenadasse, G., Rowland, A., et al.[2022]

A new ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to effectively monitor abemaciclib levels in patients with advanced breast cancer, showing high accuracy and precision in quantification.

This method allows for robust therapeutic drug monitoring (TDM) of abemaciclib, which can help personalize treatment and improve adherence in patients, addressing challenges in the emerging field of oral antitumor therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An UHPLC-MS/MS method for quantification of the CDK4/6 inhibitor abemaciclib in human serum. Habler, K., Vogeser, M., Teupser, D.[2022]

Interim results from the MONARCH3 study show that abemaciclib, a CDK4/6 inhibitor, is an effective first-line treatment for advanced ER-positive, HER2-negative breast cancer.

Patients receiving abemaciclib in combination with letrozole experienced significantly improved progression-free survival compared to those receiving a placebo with endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Abemaciclib Effective in ER+ Breast Cancer. [2019]

In a phase III trial, abemaciclib combined with endocrine therapy significantly reduced the risk of breast cancer recurrence in patients with hormone receptor positive (HR+), HER2-negative, node-positive early breast cancer, regardless of prior chemotherapy or tumor characteristics.

The combination treatment was generally well-tolerated, with manageable side effects such as diarrhea, infections, and neutropenia, making it a valuable option for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. Fung, S., Blair, HA.[2023]

In the nextMONARCH study involving women with endocrine-refractory HR+, HER2- metastatic breast cancer, abemaciclib showed a median progression-free survival (PFS) of 9.1 months when combined with tamoxifen, but this was not significantly better than the 7.4 months PFS with abemaciclib alone plus prophylactic loperamide.

The study found that the incidence and severity of diarrhea, a common side effect of abemaciclib, were manageable with dose adjustments and antidiarrheal medication, indicating that the treatment can be tolerated while maintaining its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

nextMONARCH: Abemaciclib Monotherapy or Combined With Tamoxifen for Metastatic Breast Cancer. Hamilton, E., Cortes, J., Ozyilkan, O., et al.[2021]

Abemaciclib, used for treating advanced breast cancer, was generally well tolerated, with the most common adverse event being diarrhea, affecting 42.8% of patients, which was manageable with medications and dose adjustments.

Importantly, dose reductions or early onset of adverse events like diarrhea and neutropenia did not negatively impact progression-free survival, indicating that patients can continue treatment effectively despite these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Abemaciclib-Associated Adverse Events in Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Safety Analysis of MONARCH 2 and MONARCH 3. Rugo, HS., Huober, J., García-Sáenz, JA., et al.[2023]

In a phase 1b study involving 50 patients with advanced non-small cell lung cancer (NSCLC), the combination of abemaciclib and pembrolizumab showed significant toxicity, with 80% of patients in cohort A and 76% in cohort B experiencing severe treatment-emergent adverse events.

Despite some antitumor activity, including a disease control rate of 56% in cohort A and 64% in cohort B, the overall risk-benefit profile of this combination therapy does not support further investigation in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib in Combination With Pembrolizumab for Stage IV KRAS-Mutant or Squamous NSCLC: A Phase 1b Study. Pujol, JL., Vansteenkiste, J., Paz-Ares Rodríguez, L., et al.[2022]

In a Phase 1b study involving 67 women with hormone receptor positive (HR+) and HER2 negative metastatic breast cancer, abemaciclib combined with endocrine therapies showed a median progression-free survival of 25.4 months and an objective response rate of 38.9%.

The treatment was generally well-tolerated, with manageable side effects such as diarrhea and fatigue, and no significant impact on the pharmacokinetics of the endocrine therapies used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study. Tolaney, SM., Beeram, M., Beck, JT., et al.[2022]

Abemaciclib, when combined with endocrine therapy, has been shown to improve invasive disease-free survival in patients with hormone receptor-positive, HER2-negative early breast cancer at high risk of recurrence, based on the MonarchE trial involving 5637 participants.

The cost-effectiveness analysis indicated that abemaciclib has an incremental cost-effectiveness ratio (ICER) of £9164 per quality-adjusted life-year gained, leading to its recommendation by NICE as a treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib in Combination with Endocrine Therapy for Adjuvant Treatment of Hormone Receptor-Positive, HER2-Negative, Node-Positive Early Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. Orozco Leal, G., Armstrong, N., Kernohan, A., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12550314/

metastatic breast cancer: A propensity-matched ... In this large, real-world cohort study, first-line abemaciclib was associated with a significant overall survival benefit compared to ...

2. prnewswire.com prnewswire.com/news-releases/lillys-verzenio-abemaciclib-prolonged-survival-in-hr-her2--high-risk-early-breast-cancer-with-two-years-of-treatment-302586849.html

Lilly's Verzenio® (abemaciclib) prolonged survival in HR+, ... In addition, treatment with Verzenio plus ET led to a sustained reduction in risk of recurrence at seven years, continuing to demonstrate the ...

3. onclive.com onclive.com/view/abemaciclib-plus-endocrine-therapy-provides-os-benefit-in-hr-her2-negative-breast-cancer

Abemaciclib Plus Endocrine Therapy Provides OS Benefit ... Abemaciclib plus endocrine therapy reduced death risk by 15.8% in high-risk early breast cancer patients compared to endocrine therapy alone.

4. cancernetwork.com cancernetwork.com/view/abemaciclib-endocrine-therapy-improves-os-in-hr-her2-early-breast-cancer

Abemaciclib/Endocrine Therapy Improves OS in HR+/HER2 Results from the monarchE study showed a statistically significant OS improvement with abemaciclib plus ET for patients with HR+/HER2– early ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04031885

NCT04031885 | A Study of Abemaciclib (LY2835219) in ... The reason for this study is to compare the efficacy of abemaciclib, in combination with fulvestrant, to that of physician's choice of chemotherapy in women ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41110697/

Overall Survival with Abemaciclib in Early Breast Cancer The 7-year OS was 86.8% with abemaciclib-ET and 85.0% with ET (absolute difference, 1.8%). OS benefit was consistent across prespecified ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03155997

Study Details | NCT03155997 | Endocrine Therapy With or ... The purpose of this study is to evaluate the safety and efficacy of the study drug abemaciclib in participants with high risk, node positive, early stage, ...

8. clinicaloncologyonline.net clinicaloncologyonline.net/article/S0936-6555(24)00059-1/fulltext

Real-world Data on Safety Outcome with Treatment of ... In a real-world setting, abemaciclib is generally well tolerated, and toxicity outcomes are less frequent and less severe than that seen in MONARCH E trial.