Clinical trial NCT05803382: Testing the Addition of an Anti-Cancer Drug, ZEN003694, to the Usual Chemotherapy Treatment (Capecitabine) for Metastatic or Unresectable Cancers
Official title: Phase I Trial of ZEN003694 (ZEN-3694) in Combination With Capecitabine in Patients With Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Metastatic Colorectal Carcinoma
Metastatic Malignant Solid Neoplasm
Stage IV Colorectal Cancer AJCC v8
Unresectable Colorectal Carcinoma
Unresectable Malignant Solid Neoplasm
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2023-04-07
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I trial tests the safety, side effects, and best dose of ZEN003694 in combination with the usual treatment with capecitabine in treating patients with cancer that has spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable) and that it has progressed on previous standard treatment. 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 over produce BET protein. Capecitabine is in a class of medications called antimetabolites. It is taken up by cancer cells and breaks down into fluorouracil, a substance that kills cancer cells. Giving ZEN003694 in combination with capecitabine may be safe in treating patients with metastatic or unresectable solid tumors.

Detailed description: PRIMARY OBJECTIVE:

I. To determine the safety and tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of BET bromodomain inhibitor ZEN-3694 (ZEN003694 \[ZEN-3694\]) in combination with capecitabine in patients with solid tumors.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity of ZEN003694 (ZEN-3694) in combination with capecitabine.

II. To determine the pharmacokinetics (PK) of ZEN003694 (ZEN-3694) in combination with capecitabine.

III. To determine the pharmacodynamics (PD) of ZEN003694 (ZEN-3694) in combination with capecitabine (death receptor 5 \[DR5\] dynamics and apoptosis).

IV. To identify molecular subpopulations particularly sensitized to bromodomain and extra-terminal motif inhibitor (BETi) and capecitabine.

OUTLINE: This is a dose-escalation study of ZEN003694 and capecitabine, followed by a dose-expansion study.

Patients receive ZEN003694 orally (PO) once daily (QD) and capecitabine PO twice daily (BID) 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI), positron emission tomography (PET)/CT, and collection of blood samples throughout the trial. Patients may also undergo biopsies during screening and while on the study.

After completion of study treatment, patients are followed up for safety 30 days after the last dose, and then every 3 months for 12 months.

Eligibility criteria: Inclusion Criteria:

* Dose Escalation additional criteria: Patients must have histologically confirmed cancer that is metastatic or unresectable and must have progressed on standard therapies which would have included fluorouracil (5-FU) or capecitabine
* Dose Escalation additional criteria specifically for colorectal cancer (CRC) patients: Willingness and ability to undergo a pre-treatment biopsy
* Dose Expansion additional criteria: Patients must have histologically confirmed CRC that is metastatic or unresectable and must have progressed on standard therapies which would have included 5-FU or capecitabine
* Dose Expansion additional criteria: Willingness and ability to undergo pre- and on- treatment biopsies
* Patients must have measurable disease
* Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of ZEN003694 (ZEN-3694) in combination with capecitabine in patients \< 18 years of age, children are excluded from this study
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Karnofsky \>= 60%)
* Availability of archival tumor tissue at the time of patient enrollment for molecular profiling studies
* Prior to study dosing, previous systemic therapy must have been completed for at least five half-lives or 2 weeks, whichever is shorter
* Absolute neutrophil count \>= 1,000/mcL
* Platelets \>= 100,000/mcL
* Total bilirubin =\< 1.5 institutional upper limit of normal (ULN)
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x institutional ULN
* Glomerular filtration rate (GFR) \>= 50 mL/min/1.73 m\^2
* 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
* 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
* The effects of ZEN003694 (ZEN-3694) and capecitabine on the developing human fetus are unknown. For this reason and because BET inhibitors as well as other therapeutic agents used in this trial 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 and 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 6 months after completion of ZEN003694 (ZEN-3694) and capecitabine administration
* Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

Exclusion Criteria:

* Previous treatment with BET inhibitors
* History of inability to tolerate capecitabine at the projected treatment dose on this trial
* Use of oral Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) and Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed
* Treatment for HIV, hepatitis B or hepatitis C only if this interferes with the current treatment (e.g. through drug-drug interactions)
* Gastrointestinal pathology or history that adversely impacts the ability to take or absorb oral medication
* Hepatic tumor burden \> 30% or peritoneal carcinomatosis
* Untreated/uncontrolled central nervous system (CNS) disease
* Known dihydropyrimidine dehydrogenase (DPD) deficiency
* Severe intercurrent illness or comorbidity
* Inability to comply with the protocol and/or not willing or who will not be available for follow-up assessments
* Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia and neuropathy up to and including grade 2
* Patients who are receiving any other investigational agents
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 (ZEN-3694) or other agents used in study
* Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible. Strong inhibitors of CYP3A4 must be discontinued at least 7 days, and inducers 14 days prior to the first dose of ZEN003694 and capecitabine. Substrates of CYP1A2 with narrow therapeutic window must be avoided while taking ZEN003694
* Pregnant women are excluded from this study because ZEN003694 (ZEN-3694) is an 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 (ZEN-3694), breastfeeding should be discontinued if the mother is treated with ZEN003694 (ZEN-3694). These potential risks may also apply to other agents used in this study

Primary outcomes:
measure: Incidence of adverse events
timeFrame: Up to 30 days after last dose
measure: Maximum tolerated dose (MTD)
timeFrame: Up to 30 days after last dose
measure: Recommended phase 2 dose (RP2D)
timeFrame: Up to 30 days after last dose
Secondary outcomes:
measure: Anti-tumor activity of ZEN003694 (ZEN-3694) in combination with capecitabine
timeFrame: Up to 12 months
measure: Progression free survival (PFS)
timeFrame: Up to 12 months
measure: Objective response rate (ORR)
timeFrame: Up to 12 months
measure: Pharmacokinetics (PK) of ZEN003694 (ZEN-3694) in combination with capecitabine
timeFrame: Up to 12 months
measure: Pharmacodynamics (PD) of ZEN003694 (ZEN-3694) in combination with capecitabine
timeFrame: Up to 12 months
measure: Molecular subpopulations particularly sensitized to BETi and capecitabine
timeFrame: Up to 12 months
Other outcomes:
Locations:
city: Irvine
country: United States
facility: UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
state: California
city: Orange
country: United States
facility: UC Irvine Health/Chao Family Comprehensive Cancer Center
state: California
city: Gainesville
country: United States
facility: University of Florida Health Science Center - Gainesville
state: Florida
city: Shiloh
country: United States
facility: Memorial Hospital East
state: Illinois
city: Fairway
country: United States
facility: University of Kansas Clinical Research Center
state: Kansas
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Westwood
country: United States
facility: University of Kansas Hospital-Westwood Cancer Center
state: Kansas
city: Creve Coeur
country: United States
facility: Siteman Cancer Center at West County Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center-South County
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Christian Hospital
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center at Saint Peters Hospital
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center-Einstein Campus
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center-Weiler Hospital
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: New York
country: United States
facility: NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Center-UC Medical Center
state: Ohio
city: West Chester
country: United States
facility: University of Cincinnati Cancer Center-West Chester
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center LAO
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Breast Center at One Hundred Oaks
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
Study officials:
affiliation: University of Pittsburgh Cancer Institute LAO
name: Dennis Hsu
role: PRINCIPAL_INVESTIGATOR
References: