Testing the Safety and Efficacy of the Combination of Two Anti-cancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients (12-17 Years) With Metastatic or Unresectable NUT Carcinoma, Breast Cancer and Other Solid Tumors

NCT05372640 | Recruiting Phase 1 FDA Drug

• 3 other identifiers: NCI-2022-0410010509UM1CA186709
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 7

Brief Summary

This phase I trial tests the safety, side effects, and best dose of ZEN003694 when given together with abemaciclib in treating patients with NUT carcinoma, breast cancer or other solid tumors that have spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable). ZEN003694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). It may prevent the growth of tumor cells that overproduce BET protein. Abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving ZEN003694 and abemaciclib may help shrink or stabilize cancer in patients with NUT carcinoma, breast cancer or other solid tumors.

Conditions

Anatomic Stage III Breast Cancer AJCC v8; Anatomic Stage IV Breast Cancer AJCC v8; Metastatic Breast Carcinoma; Metastatic Malignant Solid Neoplasm; Unresectable Breast Carcinoma; Unresectable Malignant Solid Neoplasm; Metastatic NUT Carcinoma; Unresectable NUT Carcinoma

Outcome Measures

Primary Outcomes (8)

• Maximum tolerated dose or recommended phase 2 dose (Phase I dose escalation)

  The toxicity of the combination will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v). 5.0 criteria.

  During the first cycle of therapy (28 days)

• Incidence of adverse events (Phase I dose expansion)

  Safety will be reported with descriptive statistics. Toxicity will be graded according to National Cancer Institute CTCAE, v5.0. Toxicities will be summarized by maximum grade and by treatment arm. Incidence rate of each toxicity will be reported with 95% exact confidence intervals.

  Up to 5 years

• Overall response rate (Phase I dose expansion)

  Will be graded as complete response (CR), partial response (PR), stable disease (SD) and progressive disease.

  Up to 5 years

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

  Clinical benefit is defined as CR, PR or SD \>= 24 weeks according to Response Evaluation Criteria in Solid Tumors 1.1. CBR will be reported with 90% exact confidence intervals.

  Up to 5 years

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

  Median DoR will be reported with ranges.

  From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 5 years

• Time to response (Phase I dose expansion)

  From the time initiation of therapy to the time measurement criteria are met for CR or PR (whichever is first recorded), assessed up to 5 years

• Overall survival (Phase I dose expansion)

  From study enrollment until death due to any cause, assessed up to 5 years

• Progression free survival (Phase I dose expansion)

  From study enrollment until the identification of disease progression or death, assessed up to 5 years

Secondary Outcomes (2)

• Pharmacokinetics (PK)

  Up to 5 years

• Thymidine kinase (TK)

  Up to 5 years

Other Outcomes (1)

• Analysis of ATAC-sequence data

  Up to 5 years

Study Arms (1)

Treatment (ZEN003694, abemaciclib)

EXPERIMENTAL

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.

Drug: Abemaciclib; Drug: BET Bromodomain Inhibitor ZEN-3694; Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Diagnostic Imaging Testing

Interventions

Abemaciclib DRUG

Given PO

Also known as: LY 2835219, LY-2835219, LY2835219, Verzenio

Treatment (ZEN003694, abemaciclib)

Biopsy Procedure PROCEDURE

Undergo biopsy

Also known as: Biopsy, BIOPSY_TYPE, Bx

Treatment (ZEN003694, abemaciclib)

BET Bromodomain Inhibitor ZEN-3694 DRUG

Given PO

Also known as: BETi ZEN-3694, ZEN 3694, ZEN-3694, ZEN003694

Treatment (ZEN003694, abemaciclib)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (ZEN003694, abemaciclib)

Diagnostic Imaging Testing PROCEDURE

Undergo imaging evaluation

Also known as: Diagnostic Imaging, Medical Imaging

Treatment (ZEN003694, abemaciclib)

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Dose Escalation Cohort Only: Participants must have evaluable disease or measurable disease per RECIST 1.1 criteria
• Dose Expansion Cohort Only:
• Participants must have a diagnosis of NUT carcinoma (NC) based on standard criteria for the disease, with diagnostic testing performed in a Clinical Laboratory Improvement Act (CLIA) certified laboratory:
• Ectopic expression of NUT protein per World Health Organization (WHO) criteria as determined by immunohistochemistry (IHC) testing, OR
• Detection of the NUT gene translocation as determined by fluorescence in situ hybridization (FISH) testing, OR
• Detection of the NUT gene translocation as determined by either deoxyribonucleic acid (DNA) next-generation sequencing (NGS) or ribonucleic acid (RNA) sequencing.
• Participants must have measurable disease per RECIST 1.1 criteria
• Any number of prior lines of therapy in the metastatic setting are allowed, including prior BET inhibitor therapy and prior CDK4/6 inhibitor therapy
• Patients who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events \[CTCAE\] grade =\< 1) from the acute effects of chemotherapy except for residual alopecia or grade 2 peripheral neuropathy
• Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy
• Participants may have previously undergone surgical resection
• Age \>= 12 years. Patients 12-17 years of age must be \> 40 kg at enrollment. Patients 12-17 years of age will not participate in the mandatory tumor biopsies. Since there is no data on patients less than 18 years of age, this population may require lower doses and additional safety precautions and should be closely monitored. Because no dosing or adverse event data are currently available on the use of ZEN003694 in combination with abemaciclib in patients \< 12 years of age, younger children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 for participants \>= 16 years of age, Lansky \>= 50% if \< 16 years of age
• Hemoglobin \>= 8 g/dL; Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion

You may not qualify if:

• 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
• Participants who have had radiotherapy within at least 2 weeks prior to entering the study. Stereotactic radiosurgery (SRS) within 1 week prior to entering the study will be allowed
• Participants who have had major surgery within 3 weeks prior to entering the study
• Participants who have received tyrosine kinase inhibitors (TKIs) or small molecules within 5 half-lives or 1 week (whichever is shorter) of study entry
• 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
• Patients requiring medications or substances that are strong inhibitors or strong inducers of CYP3A4 or CYP3A enzymes are ineligible. Strong inhibitors or inducers of CYP3A4 must be discontinued at least 7 days prior to the first dose of ZEN003694 and abemaciclib. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. 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, including but not limited to: ongoing or active infection requiring systemic therapy, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment (e.g. estimated creatinine clearance \< 30ml/min), history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea that, in the judgment of the investigator, would preclude participation in this study
• Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 or substrates of CYP1A2 with narrow therapeutic windows are ineligible. Strong inhibitors or inducers of CYP3A4 must be discontinued at least 7 days prior to the first dose of ZEN003694. As proton pump inhibitors (PPIs), H2 receptor antagonists, and antacids may alter the pharmacokinetics of ZEN003694 by reducing ZEN003694 exposure, patients receiving proton pump inhibitors are ineligible. If H2 blockers or other acid reducing agents are used concomitantly with ZEN003694, a staggered dosing schedule should be used. 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
• Pregnant women are excluded from this study because ZEN003694 is a BETi agent 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 ZEN003694, breastfeeding should be discontinued if the mother is treated with ZEN003694. These potential risks may also apply to other agents used in this study
• Fridericia's formula-corrected QT interval (QTcF) \>= 450 msec on screening electrocardiogram (ECG) by Fredericia (machine or manual read allowed). Patients should avoid medications which prolong the QT
• Patients receiving any medications or substances that are Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) or Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed
• Patients with radiation to \> 25% of the bone marrow
• Patients who have had a bone-targeted radionuclide within 6 weeks of the first dose of ZEN003694
• Myocardial infarction or unstable angina within 6 months prior to the first dose of ZEN003694

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (7)

Keck Medicine of USC Koreatown

Los Angeles, California, 90020, United States

RECRUITING

Los Angeles General Medical Center

Los Angeles, California, 90033, United States

RECRUITING

USC / Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

RECRUITING

USC Norris Oncology/Hematology-Newport Beach

Newport Beach, California, 92663, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

M D Anderson Cancer Center

Houston, Texas, 77030, United States

RECRUITING

MeSH Terms

Conditions

Breast Neoplasms; Neoplasm Metastasis

Interventions

abemaciclib; Biopsy; Specimen Handling; X-Rays

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Electromagnetic Radiation; Electromagnetic Phenomena; Magnetic Phenomena; Physical Phenomena; Radiation; Radiation, Ionizing

Study Officials

• Jia Luo

  Dana-Farber - Harvard Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 12, 2022
• First Posted: May 13, 2022
• Study Start: August 10, 2023
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026
• Last Updated: April 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

US (7)