A Phase 1 Study of ZEN003694 in Combination with Binimetinib in Solid Tumors with RAS Pathway Alterations and Triple Negative Breast Cancer

This phase I trial tests the safety, side effects, and best dose of ZEN003694 in combination
with binimetinib in treating patients with solid tumors that carry RAS alterations and that
have spread to other places in the body (advanced/metastatic) or cannot be removed by surgery
(unresectable). ZEN003694 is an oral medication with potential anticancer activity. It is an
inhibitor of a family of proteins called bromodomain and extra-terminal (BET) which play
important role during development and cellular growth. ZEN003694 may stop the growth of tumor
cells that produce BET. Binimetinib is in a class of medications called kinase inhibitors. It
works by blocking the action proteins called MEK1 and MEK2, that signal cancer cells to
multiply. It may help keep cancer cells from growing and spreading. There is pre-clinical
evidence that using ZEN003694 and binimetinib together may shrink or stabilize cancers
studied in this trial. There are two parts of this study; dose escalation and dose expansion.
In the dose escalation part of this study, different people will get different doses of the
study drugs ZEN003694 and binimetinib. In the dose expansion part of this study, the highest
dose with manageable side effects will be given to additional people. This will help to
understand the side effects that may happen with this drug combination.

Inclusion Criteria:

- Patients must have histologically confirmed advanced/metastatic or unresectable solid
tumor that is refractory to standard therapy or has relapsed after standard therapy

- Patients must have one of the following:

- For Part 1 and 2 -

- Triple negative breast cancer (TNBC) (estrogen receptor =< 1%, progesterone
receptor =< 1%, human epidermal growth factor receptor 2 0-1+ or
non-amplified)

- Solid tumor with genomic alteration(s) activating RAS signaling including
activating KRAS, NRAS, HRAS, or BRAF mutations, inactivating NF1 mutations,
or BRAF fusions

- Genomic alterations should be identified locally by next generation
sequencing (NGS). Patient genomic reports will be reviewed by the MD
Anderson Cancer Center (MDACC) Precision Oncology Decision Support team
prior to initiation of study treatment

- For Part 1, patients can have evaluable or measurable disease. For Part 2, patients
must have measurable disease by the Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1

- Patients must be >= 4 weeks beyond treatment with any chemotherapy (6 weeks for
nitrosoureas or mitomycin C) or other investigational therapy to include hormonal,
biological, or targeted agents; or at least 5 half-lives from hormonal, biological, or
targeted agents, whichever is shorter at the time of study treatment initiation.
Patients must be >= 4 weeks beyond radiotherapy

- Age >= 18 years. Because no dosing or adverse events (AE) data are currently available
on the use of binimetinib and ZEN003694 (ZEN-3694) in patients < 18 years of age,
children are excluded from this study

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 125,000/mcL

- Hemoglobin >= 8 g/dL or >= 5.6 mmol/L

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) OR < 2.0 x ULN in
patients with documented Gilbert's syndrome

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN

- Calculated creatinine clearance >= 60 mL/min/1.73 m^2 (based on the calculated Chronic
Kidney Disease-Epidemiology collaboration [CKD-EPI] glomerular filtration rate
estimation)

- Prothrombin time =< 1.5 x ULN

- Partial thromboplastin time =< 1.5 x ULN

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this study

- 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

- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression by
imaging for at least 4 weeks prior to the first dose of study treatment and any
neurologic symptoms have returned to baseline, have no evidence of new or enlarging
brain metastases, and are not using steroids for at least 7 days prior to the first
dose of study treatment. This exception does not include carcinomatous meningitis and
primary CNS cancers, which are excluded regardless of clinical stability

- 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 study

- Patients should be New York Heart Association Functional Classification of class 2B or
better

- Patients must have corrected QT (QTcF) < 450 msec

- The effects of ZEN003694 (ZEN-3694) and binimetinib on the developing human fetus are
unknown. For this reason and because BETi agents are known to be teratogenic, women of
childbearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry, for the duration of
study participation, and 4 months after the completion of ZEN003694 (ZEN-3694) and
binimetinib administration. 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 ZEN003694 (ZEN-3694) and binimetinib
administration

- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a legally
authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria:

- Patients who have not recovered from adverse events (AEs) due to prior anticancer
therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia and
peripheral neuropathy

- Patients who are receiving any other investigational agents

- Breast cancer patients with a prior history of hormone receptor positivity will not be
eligible

- Patients with PI3K pathway activating genomic alterations including inactivating
mutations/deletions in PTEN and PIK3R1, amplifications in PIK3CA, and activating
mutations in PIK3CA, Akt, or mTOR will not be eligible

- Prior therapy with BET, RAF, MEK, or ERK inhibitor

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ZEN003694 (ZEN-3694) and binimetinib

- Patients requiring therapeutic doses of anticoagulation are excluded. Patients taking
low-dose (prophylactic) anticoagulation (e.g., low-molecular weight heparin, low-dose
warfarin, fondaparinux) are allowed. Patients receiving any medications or substances
that are strong inhibitors or inducers of CYP3A4 are ineligible. Strong inhibitors or
inducers of CYP3A4 must be discontinued at least 7 days prior to the first dose of
ZEN003694. Because the lists of these agents are constantly changing, it is important
to regularly consult a frequently updated medical reference
(https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-a…
ctions-table-substrates-inhibitors-and-inducers). 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
should avoid medications that prolong the QT

- Patients with uncontrolled intercurrent illness

- Patients with psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because ZEN003694 (ZEN-3694) and
binimetinib are a BETi and MEK inhibitor agent, respectively, with the potential for
teratogenic or abortifacient effects. Because there is an unknown but potential risk
for AEs in nursing infants secondary to treatment of the mother with ZEN003694
(ZEN-3694) and binimetinib, breastfeeding should be discontinued if the mother is
treated with ZEN003694 (ZEN-3694) and binimetinib

- Patient has a history of cerebrovascular accident, myocardial infarction, or unstable
angina within the previous 6 months prior to study treatment initiation

- Patients with any medical condition or diagnosis that would likely impair absorption
of an orally administered drug (e.g., gastrectomy, ileal bypass, chronic diarrhea,
gastroparesis) are excluded

- Patient has a history of retinal vein occlusion

- Patient has a history of pneumonitis or interstitial lung disease