A Phase 1 Study of BET Bromodomain Inhibitor ZEN003694 in Combination with the CDK4/6 Inhibitor Abemaciclib in Patients with NUT Carcinoma, Breast Cancer and Other Solid Tumors

This phase I trial tests the safety, side effects, and best dose of a 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.

Inclusion Criteria:

- 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

- 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

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

- Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial

- Patients should be New York Heart Association Functional Classification of class 2B or
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 be teratogenic,
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation. Women of child-bearing potential must have a
negative pregnancy test prior to study entry. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately. Men and women treated or enrolled on
this protocol must also agree to use adequate contraception prior to the study, for
the duration of study participation, and 3 weeks after completion of ZEN003694 and
abemaciclib administration

- For female subjects of child-bearing potentially receiving ZEN003694, hormonal
means of birth control alone, such as oral, injectable, dermal, subdermal or
topical contraceptives are NOT acceptable forms of birth control given that their
efficacy has not been evaluated when given in combination with the
investigational drugs. "Adequate contraception" is defined as the following:

- Contraceptive methods with a failure rate of =< 1% used in combination with
the barrier method. The following contraceptive methods are acceptable to
use in combination with the barrier method: intrauterine device (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 are met: male condoms are
required AND subjects are informed of the potential for reduced systemic
hormone levels from the IUD/OCP when taking ZEN003694. Alternatively, male
partner sterilization (vasectomy with documentation of azoospermia) prior to
the female subject's entry into the study, and this male is the sole partner
for that subject. For this definition, "documented" refers to the outcome of
the investigator's/designee's medical examination of the subject or review
of the subject's medical history for study eligibility, as obtained via a
verbal interview with the subject or from the subject's medical records

- Male subjects with female partners of child-bearing potential must use one of the
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, or hormonal
birth control such as contraceptive subdermal implant, combined estrogen 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 the
last dose of study medication. Male subjects whose partners are or become
pregnant must continue to use condoms for 12 weeks after the last dose of study
medication

- Women of childbearing potential must have a negative pregnancy test within 7 days of
starting treatment

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

Exclusion Criteria:

- 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 correction formula (QTcF) >= 450 msec on screening electrocardiogram
(ECG) (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