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

Inclusion Criteria:

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

• Dose Escalation Cohort Only: Participants must have evaluable disease or measurabledisease per RECIST 1.1 criteria

• Dose Expansion Cohort Only:

• Participants must have a diagnosis of NUT carcinoma (NC) based on standardcriteria for the disease, with diagnostic testing performed in a ClinicalLaboratory 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 insitu hybridization (FISH) testing, OR

• Detection of the NUT gene translocation as determined by eitherdeoxyribonucleic acid (DNA) next-generation sequencing (NGS) orribonucleic 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 Criteriafor Adverse Events [CTCAE] grade =< 1) from the acute effects of chemotherapy exceptfor residual alopecia or grade 2 peripheral neuropathy

• Patients who received radiotherapy must have completed and fully recovered from theacute effects of radiotherapy. A washout period of at least 14 days is requiredbetween 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 thereis no data on patients less than 18 years of age, this population may require lowerdoses and additional safety precautions and should be closely monitored. Because nodosing or adverse event data are currently available on the use of ZEN003694 incombination with abemaciclib in patients < 12 years of age, younger children areexcluded 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 thishemoglobin level at the discretion of the investigator. Initial treatment must notbegin 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. Patientswith Gilbert's syndrome with a total bilirubin =< 2.0 times ULN and direct bilirubinwithin 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 creatinineclearance >= 50 mL/min (via the chronic kidney disease epidemiology [CKD-EPI]glomerular filtration rate estimation) for participants >= 18 years old, or 60mL/min/1.73m^2 for patients 12-17 years as calculated based on bedside Schwartzformula

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load. Hepatitis C (HepC antibody)testing is required. Hepatitis C RNA is optional; however, a confirmatory negativeHepatitis C RNA test must be obtained to be able to enroll participants withpositive Hepatitis C antibody due to prior resolved disease

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression andhas been clinically stable for at least 1 month. Patients must meet the followingcriteria:

• Disease outside the CNS is present

• Recovery from acute toxicity associated with the treatment to =< CTCAE grade 1or baseline (with the exception of alopecia), with no requirement forescalating doses of corticosteroids over the past 7 days

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients should be New York Heart Association Functional Classification of class 2Bor better

• Ability to swallow and retain oral medications

• The effects of ZEN00364 and abemaciclib on the developing human fetus are unknown.For this reason and because BETi and CDKi-inhibiting agents are known to beteratogenic, women of child-bearing potential and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation. Women of child-bearingpotential must have a negative pregnancy test prior to study entry. Should a womanbecome pregnant or suspect she is pregnant while she or her partner is participatingin this study, she should inform her treating physician immediately. Men and womentreated or enrolled on this protocol must also agree to use adequate contraceptionprior to the study, for the duration of study participation, and 3 weeks aftercompletion of ZEN003694 and abemaciclib administration

• For female subjects of child-bearing potentially receiving ZEN003694, hormonalmeans of birth control alone, such as oral, injectable, dermal, subdermal ortopical contraceptives are NOT acceptable forms of birth control given thattheir efficacy has not been evaluated when given in combination with theinvestigational drugs. "Adequate contraception" is defined as the following:

• Contraceptive methods with a failure rate of =< 1% used in combinationwith the barrier method. The following contraceptive methods areacceptable to use in combination with the barrier method: intrauterinedevice (IUD), intrauterine system (IUS), or oral contraceptive pills (OCPs) that meet the < 1% failure rate as stated in the product label.Note: Hormonal IUDs/OCPs may only be used if the following criteria aremet: male condoms are required AND subjects are informed of the potentialfor reduced systemic hormone levels from the IUD/OCP when takingZEN003694. Alternatively, male partner sterilization (vasectomy withdocumentation of azoospermia) prior to the female subject's entry into thestudy, and this male is the sole partner for that subject. For thisdefinition, "documented" refers to the outcome of theinvestigator's/designee's medical examination of the subject or review ofthe subject's medical history for study eligibility, as obtained via averbal interview with the subject or from the subject's medical records

• Male subjects with female partners of child-bearing potential must use one ofthe following contraceptive methods:

• Vasectomy with documentation of azoospermia OR

• Condom use PLUS partner use of a highly effective contraceptive (=< 1%rate of failure per year) such as intrauterine device or system, orhormonal birth control such as contraceptive subdermal implant, combinedestrogen and progestogen oral contraceptive, injectable progestogen,contraceptive vaginal ring, or percutaneous contraceptive patches

• Male subjects should not donate sperm while on study and for 12 weeks after thelast dose of study medication. Male subjects whose partners are or becomepregnant must continue to use condoms for 12 weeks after the last dose of studymedication

• Women of childbearing potential must have a negative pregnancy test within 7 days ofstarting treatment

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity who have alegally-authorized representative (LAR) and/or family member available may beeligible after discussion with the Principal Investigator of this study. There willbe a separate assent process for minors

Exclusion Criteria:

• Participants who have had cytotoxic chemotherapy, immunotherapy, or otherinvestigational therapy within 2 weeks prior to entering the study. There is atwo-week required washout period for previous BET inhibitor therapy

• Participants who have had radiotherapy within at least 2 weeks prior to entering thestudy. Stereotactic radiosurgery (SRS) within 1 week prior to entering the studywill 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 moleculeswithin 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 orbiologic composition to ZEN003694 or abemaciclib

• Patients requiring medications or substances that are strong inhibitors or stronginducers of CYP3A4 or CYP3A enzymes are ineligible. Strong inhibitors or inducers ofCYP3A4 must be discontinued at least 7 days prior to the first dose of ZEN003694 andabemaciclib. Because the lists of these agents are constantly changing, it isimportant to regularly consult a frequently-updated list such ashttp://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such asthe Physicians' Desk Reference may also provide this information. As part of theenrollment/informed consent procedures, the patient will be counseled on the risk ofinteractions with other agents, and what to do if new medications need to beprescribed or if the patient is considering a new over-the-counter medicine orherbal product

• Patients with uncontrolled intercurrent illness, including but not limited to:ongoing or active infection requiring systemic therapy, symptomatic congestive heartfailure, 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 resectioninvolving the stomach or small bowel, or preexisting Crohn's disease or ulcerativecolitis or a preexisting chronic condition resulting in baseline grade 2 or higherdiarrhea that, in the judgment of the investigator, would preclude participation inthis study

• Patients receiving any medications or substances that are strong inhibitors orinducers of CYP3A4 or substrates of CYP1A2 with narrow therapeutic windows areineligible. Strong inhibitors or inducers of CYP3A4 must be discontinued at least 7days prior to the first dose of ZEN003694. As proton pump inhibitors (PPIs), H2receptor antagonists, and antacids may alter the pharmacokinetics of ZEN003694 byreducing ZEN003694 exposure, patients receiving proton pump inhibitors areineligible. If H2 blockers or other acid reducing agents are used concomitantly withZEN003694, a staggered dosing schedule should be used. Because the lists of theseagents are constantly changing, it is important to regularly consult afrequently-updated medical reference. As part of the enrollment/informed consentprocedures, the patient will be counseled on the risk of interactions with otheragents, and what to do if new medications need to be prescribed or if the patient isconsidering a new over-the-counter medicine or herbal product

• Pregnant women are excluded from this study because ZEN003694 is a BETi agent withthe potential for teratogenic or abortifacient effects. Because there is an unknownbut potential risk for adverse events in nursing infants secondary to treatment ofthe mother with ZEN003694, breastfeeding should be discontinued if the mother istreated with ZEN003694. These potential risks may also apply to other agents used inthis study

• Fridericia's formula-corrected QT interval (QTcF) >= 450 msec on screeningelectrocardiogram (ECG) by Fredericia (machine or manual read allowed). Patientsshould 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 weightheparin 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 doseof ZEN003694

• Myocardial infarction or unstable angina within 6 months prior to the first dose ofZEN003694

• Impairment of gastrointestinal function that may significantly alter the absorptionof ZEN003694 and/or abemaciclib

• The patient has a personal history of any of the following conditions: syncope ofcardiovascular etiology, ventricular arrhythmia of pathological origin (including,but not limited to, ventricular tachycardia and ventricular fibrillation), or suddencardiac arrest