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 and Other Solid Tumors

Study Overview
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Brief Summary
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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 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 or other solid tumors.

Detailed Description
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PRIMARY OBJECTIVE: I. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of BET bromodomain inhibitor ZEN-3694 (ZEN003694) and abemaciclib. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. Determine the preliminary rates of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), time to response (TTR) and duration of response (DoR) for the combination of ZEN003694 and abemaciclib in participants utilizing Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. III. Evaluate the pharmacokinetic (PK) profile of the combination. EXPLORATORY OBJECTIVE: I. Explore potential biomarker indicators of response and resistance in tumor tissue and blood samples. OUTLINE: This is a dose-escalation study of BET bromodomain inhibitor ZEN-3694 followed by a dose expansion study. Patients receive ZEN003694 orally (PO) once daily (QD) on days 1-28 or 5 days on and 2 days off, and abemaciclib PO twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo imaging evaluation, blood sample collection and tumor biopsy throughout the study. After completion of study treatment, patients are followed up for 30 days, every 3 months for 2 years, and then every 6 months for 3 years.

Official Title
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A Phase 1 Study of BET Bromodomain Inhibitor ZEN003694 in Combination With the CDK4/6 Inhibitor Abemaciclib in Patients With NUT Carcinoma and Other Solid Tumors

Conditions
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Malignant Solid Neoplasm, NUT Carcinoma

Intervention / Treatment
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* Drug: Abemaciclib
* Drug: BET Bromodomain Inhibitor ZEN-3694
* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Diagnostic Imaging


Participation Criteria
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Eligibility Criteria
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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 (> 50% tumor nuclei) as determined by immunohistochemistry (IHC) testing, OR Detection of the NUT gene translocation as determined by fluorescence in situ hybridization (FISH) testing 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 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]) =< 3 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 Schwartz formula for participants 12 - 17 years old) 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 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 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

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ZEN003694, abemaciclib)<br>Patients receive ZEN003694 PO QD on days 1-28 or 5 days on and 2 days off, and abemaciclib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo imaging evaluation, blood sample collection and tumor biopsy throughout the study. | Drug: Abemaciclib<br>* Given PO<br>* Other names: Verzenio;Drug: BET Bromodomain Inhibitor ZEN-3694<br>* Given PO<br>* Other names: ZEN003694;Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Diagnostic Imaging<br>* Undergo imaging evaluation<br>* Other names: Medical Imaging;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose or recommended phase 2 dose (Phase I dose escalation) | The toxicity of the combination will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v). 5.0 criteria. | During the first cycle of therapy (28 days) | 
| Incidence of adverse events (Phase I dose expansion) | Safety will be reported with descriptive statistics. Toxicity will be graded according to National Cancer Institute CTCAE, v5.0. Toxicities will be summarized by maximum grade and by treatment arm. Incidence rate of each toxicity will be reported with 95% exact confidence intervals. | Up to 5 years | 
| Overall response rate (Phase I dose expansion) | Will be graded as complete response (CR), partial response (PR), stable disease (SD) and progressive disease. | Up to 5 years | 
| Clinical benefit rate (CBR) (Phase I dose expansion) | Clinical benefit is defined as CR, PR or SD >= 24 weeks according to Response Evaluation Criteria in Solid Tumors 1.1. CBR will be reported with 90% exact confidence intervals. | Up to 5 years | 
| Duration of response (DoR) (Phase I dose expansion) | Median DOR will be reported with ranges. | From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 5 years | 
| Time to response (TTR) (Phase I dose expansion) | Median DOR will be reported with ranges. | From the time initiation of therapy to the time measurement criteria are met for CR or PR (whichever is first recorded), assessed up to 5 years | 
| Overall survival (Phase I dose expansion) |  | From study enrollment until death due to any cause, assessed up to 5 years | 
| Progression free survival (Phase I dose expansion) |  | From study enrollment until the identification of disease progression or death, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) | Designed the PK sampling to enable simultaneous estimation of individual pharmacokinetic parameters of abemaciclib, ZEN003694, and their respective metabolites using nonlinear mixed effects modeling. Will compare the ratio of observed/historical 90% confidence interval of abemaciclib exposure. | Up to 5 years | 
| Thymidine kinase (TK) | Will compare exposures of abemaciclib and abemaciclib metabolites to TK activity at cycle 1 day 15 and beyond and also change in TK activity versus clinical outcomes. | Up to 5 years |