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

Recruiting now · Phase 1

Conditions studied: Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Breast Carcinoma, Metastatic Malignant Solid Neoplasm, Metastatic NUT Carcinoma, Unresectable Breast Carcinoma, Unresectable Malignant Solid Neoplasm, Unresectable NUT Carcinoma

In brief

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.

Key facts

Study ID: NCT05372640
Run by: National Cancer Institute (NCI)
People needed: 45
Starts: 2023-08-10
Expected to finish: 2027-06-07
Last updated by the study team: 2026-07-31

Who can join

Age: 12 and older. Sex: any. Healthy volunteers: not accepted.

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
Absolute neutrophil count >= 1.5 x 10\^9/L
Platelets >= 1 x 10\^11/L
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) for age. Patients with Gilbert's syndrome with a total bilirubin =< 2.0 times ULN and direct bilirubin within normal limits are permitted
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN for age
Serum or plasma creatinine =< 1.5 x institutional ULN OR calculated creatinine clearance >= 50 mL/min (via the chronic kidney disease epidemiology [CKD-EPI] glomerular filtration rate estimation) for participants >= 18 years old, or 60 mL/min/1.73m\^2 for patients 12-17 years as calculated based on bedside Schwartz formula
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Hepatitis C (HepC antibody) testing is required. Hepatitis C RNA is optional; however, a confirmatory negative Hepatitis C RNA test must be obtained to be able to enroll participants with positive Hepatitis C antibody due to prior resolved disease
Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression and has been clinically stable for at least 1 month. Patients must meet the following criteria:
Disease outside the CNS is present

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
Impairment of gastrointestinal function that may significantly alter the absorption of ZEN003694 and/or abemaciclib
The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest

Where it is running

Keck Medicine of USC Koreatown — Los Angeles, California, United States (enrolling)
Los Angeles General Medical Center — Los Angeles, California, United States (enrolling)
USC / Norris Comprehensive Cancer Center — Los Angeles, California, United States (enrolling)
USC Norris Oncology/Hematology-Newport Beach — Newport Beach, California, United States (enrolling)
Dana-Farber Cancer Institute — Boston, Massachusetts, United States (enrolling)
UPMC Hillman Cancer Center — Pittsburgh, Pennsylvania, United States (enrolling)
UT MD Anderson Cancer Center — Houston, Texas, United States (enrolling)

Full record on ClinicalTrials.gov

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