A Phase 1/2 Study of the Bromodomain Inhibitor ZEN003694 in Combination with Etoposide/Platinum in Patients with NUT Carcinoma

This phase I/II trial tests the safety, side effects, and best dose of a new combination of
drugs, BET bromodomain inhibitor ZEN-3694 (ZEN003694), cisplatin, and etoposide in treating
patients with NUT carcinoma (phase I), and identifies whether this combination therapy works
to shrink tumor in these patients (phase II). Another purpose of this study is to see whether
there are any changes in patient's tumor or blood characteristics (e.g. genes, molecules,
etc.) due to combination therapy. ZEN003694 inhibits the production of certain
growth-promoting proteins and may prevent proliferation of tumor cells that use those
proteins for their growth. Chemotherapy drugs, such as etoposide and cisplatin, work by
stopping or slowing the growth of cancer cells. Combination therapy with ZEN003694, etoposide
and cisplatin may be effective in treating patients with NUT carcinoma.

Inclusion Criteria:

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Participants must
have a diagnosis of 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 sequencing, eg. DNA next
generation sequencing (NGS) or RNA sequencing.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Participants must
have disease that is metastatic, unresectable, or for which a surgical approach would
not likely confer a survival benefit or would be otherwise contraindicated.
Participants who have already undergone surgical resection are eligible to participate
in Phase 1 and Phase 2.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Age >= 12 years.
Patients 12-17 years of age must be >= 40 kg at enrollment. Because no dosing or
adverse event data are currently available on the use of ZEN003694 in combination with
etoposide and cisplatin in patients < 12 years of age, younger children are excluded
from this study.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Eastern Cooperative
Oncology Group (ECOG) performance status of =< 2 (Karnofsky >= 60%) for patients >= 16
years of age, Lansky >= 50% if < 16 years of age.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Participants must
have measurable disease per RECIST version 1.1 criteria. Patients in the phase 1
portion do not need measurable disease if their disease is otherwise evaluable.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Ability to swallow
and retain oral medications.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Absolute neutrophil
count >= 1.5 x 10^9/L

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Platelets >= 125 x
10^9/L

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Hemoglobin >= 9.0
g/dL

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Albumin >= 2.5 g/dL

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Total bilirubin =<
1.5 x institutional upper limit of normal (ULN) for age

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Aspartate
aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine
aminotransferase(ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
institutional ULN for age

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Calculated creatinine
clearance >= 60 mL/min (based on the calculated Chronic Kidney Disease Epidemiology
Collaboration [CKD-EPI] glomerular filtration rate estimation for adults or 60
mL/min/1.73m^2 for patients 12-17 years as calculated based on bedside Schwartz
formula

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Prothrombin time
(PT)/international normalized ratio (INR) =< 1.5 x ULN

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Partial
thromboplastin time (PTT) =< 1.5 x ULN

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: QT interval by
Fridericia (QTcF) < 450 ms (machine or manual read allowed). Patients should avoid
medications which prolong the QT.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Human
immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy
with undetectable viral load within 3 months are eligible for this trial as long as
their anti-retroviral therapy does not have the potential for drug-drug interactions
as judged by the treating investigator.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: For patients with
evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be
undetectable on suppressive therapy, if indicated.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: 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.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: 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 treatment in the phase 1 portion, but not in the phase 2 or
non-thoracic, non-BRD4 exploratory cohort. Participants enrolling to the phase 2 or
non-thoracic, non-BRD4 exploratory cohort with a history of prior malignancy are
eligible only if they fit one or more of the following criteria: participants with
non-melanoma skin cancers that have been curatively treated; participants with
adequately treated carcinomas in situ of any type; or participants who were diagnosed
and curatively treated at least 3 years prior to the date of study entry and who are
considered by the treating investigator to be at low risk for recurrence.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: The effects of
ZEN003694 on the developing human fetus are unknown. For this reason and because the
chemotherapeutic agents used in this trial are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception (barrier
method of birth control; abstinence) prior to study entry and for the duration of
study participation and for 4 months after completion of study therapy. 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 treated or
enrolled on this protocol must also agree to use adequate contraception prior to the
study, for the duration of study participation, and 4 months after completion of study
therapy. 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.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Male subjects should
not donate sperm while on study and for 16 weeks after the last dose of study
medication. Male subjects whose partners are or become pregnant must continue to use
condoms for 16 weeks after the last dose of study medication.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Ability to understand
and the willingness to sign a written informed consent document (or parent or legally
authorized representative if minor). Participants with impaired decision-making
capacity (IDMC) who have a legally-authorized representative (LAR) and/or family
member available may be eligible after discussion with the Principal Investigator of
this study.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Women of childbearing
potential must have a negative pregnancy test within 7 days of starting treatment.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Participants who have
not had cytotoxic chemotherapy, oral tyrosine kinase inhibitor (TKI) or small molecule
therapy, or immunotherapy within 2 weeks prior to the first dose of study medication
or 5 half-lives, whichever is shorter. There is no required washout for previous EP
therapy.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Participants may have
had a maximum of 2 prior cycles of EP (cisplatin + etoposide). However, for
consistency, cycle 1 day 1 will be the first day of EP on the Phase 1 and 2 portions
of the study. There is no required washout for previous ZEN003694 therapy for patients
enrolling to the phase 1 or phase 2 portion of the study.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Participants who have
received prior radiation therapy can be enrolled at least 1 week after completing
radiation.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Participants who have
had major surgery can be enrolled at least 3 weeks after the surgery.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Any therapy-related
toxicities must have resolved to =< grade 1 or baseline (with the exception of
alopecia, peripheral neuropathy, or rash that will be permitted at =< grade 2). Other
grade 2 toxicities attributed to prior treatment may be permitted with agreement from
the overall principal investigator if they are toxicities not commonly attributed to
ZEN003694. Toxicities attributed to current EP therapy are excluded from this
requirement for participants enrolling to the dose escalation or phase 2 portion of
the study, as long as the participant meets all other eligibility criteria.

- NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Participants must have a diagnosis of NC
but lack BRD4-NUT rearrangement. If the fusion status is unknown after NC diagnosis,
the BRD4-NUT fusion status will be determined by centralized FISH testing at the BWH
Center for Advanced Molecular Diagnostics (CAMD).

Exclusion Criteria:

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Participants with
known untreated central nervous system (CNS) metastases. Patients with a history of
treated CNS metastases are eligible, provided they meet the following criteria:

- Radiologically stable for 4 weeks.

- Disease outside the CNS is present.

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

- Subjects currently taking enzyme-inducing anticonvulsants (EIAC) must be
transitioned to non-enzyme inducing anticonvulsants at least 14 days or 5
half-lives prior to the first dose of study medication

- No presence of symptomatic or untreated leptomeningeal metastases or spinal cord
compression

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: History of allergic
reactions attributed to compounds of similar chemical or biologic composition to
ZEN003694 or other agents used in study.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Uncontrolled
intercurrent illness including, but not limited to: ongoing or active infection
requiring systemic treatment, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements. Patients with myocardial infarction or
unstable angina within 6 months prior to the first dose of ZEN003694 will be excluded.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Any gastrointestinal
(GI) disorder that may affect absorption of ZEN003694 and other oral medications in
the opinion of the treating investigator, such as malabsorption syndrome or major
bowel or stomach resection.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Patients who are
receiving any other investigational agents.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: 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, either dose ZEN-3694 2 hours before the H2 blocker or 10-12 hours after an H2
blocker. 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.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Pregnant women are
excluded from this study because ZEN003694 is a bromodomain and extraterminal domain
(BET) inhibitor 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.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Patients receiving
therapeutic-dose anticoagulation (e.g., warfarin, low-molecular weight heparin [LMWH],
or novel oral anticoagulants) are not eligible. Use of oral Factor Xa inhibitors
(i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban)
and Factor IIa inhibitors (i.e., dabigatran) is not permitted. Prophylactic
anticoagulation, with low doses (per standard practice) of agents such as low
molecular weight heparin (LMWH) is permitted.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Patients with
radiation to > 25% of the bone marrow.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Cardiac abnormalities
as evidenced by any of the following:

- Clinically significant conduction abnormalities or arrhythmias.

- History or evidence of current >= class II congestive heart failure as defined by
New York Heart Association (NYHA).

- History of acute coronary syndromes (including unstable angina and myocardial
infarction), coronary angioplasty, or stenting within the past 3 months. Subjects
with a history of stent placement requiring ongoing antithrombotic therapy (e.g.,
clopidogrel, prasugrel) will not be permitted to enroll.

- Clinically significant cardiomegaly, ventricular hypertrophy, or cardiomyopathy.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Patients with
uncontrolled intercurrent illness.

- PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Patients with
psychiatric illness/social situations that would limit compliance with study
requirements.

- PHASE 1: Patients who are currently receiving EP or ZEN003694, or received EP or
ZEN003694 in the past, must be candidates to receive the study agents at the
protocol-defined dose level and schedule as judged by the treating investigator.
Patients who previously required dose reductions of their EP or ZEN003694 due to
unacceptable toxicities attributed to the agent(s) are not eligible.

- PHASE 1 OR PHASE 2: Patients ineligible for receiving EP.

- NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Patients with disease that definitively
originated in the thoracic cavity. In the case of patients with metastatic disease at
diagnosis where disease origin is uncertain, the patient may be allowed to enroll.

- PHASE 2 OR NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Patients who previously received
treatment with a BET inhibitor (BETi), including but not limited to previous ZEN003694
therapy.