Testing the Safety and Efficacy of the Addition of a New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment (Cisplatin and Etoposide or Carboplatin and Paclitaxel) for Adult and Pediatric Patients (12-17 Years) With NUT Carcinoma
A Phase 1 Study of the Bromodomain Inhibitor ZEN003694 in Combination With Platinum-based Chemotherapy in Patients With NUT Carcinoma
3 other identifiers
interventional
36
1 country
5
Brief Summary
This phase I trial tests the safety, side effects, and best dose of ZEN003694 in combination with cisplatin and etoposide or carboplatin and paclitaxel in treating patients with NUT carcinoma. 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. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and deoxyribonucleic acid (DNA) repair and may kill tumor cells. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Paclitaxel is in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Combination therapy with ZEN003694 and etoposide and cisplatin or carboplatin and paclitaxel may be safe and effective in treating patients with NUT carcinoma.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_1
Started Jul 2022
Longer than P75 for phase_1
5 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 24, 2021
CompletedFirst Posted
Study publicly available on registry
August 25, 2021
CompletedStudy Start
First participant enrolled
July 13, 2022
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 30, 2026
ExpectedStudy Completion
Last participant's last visit for all outcomes
June 30, 2026
May 13, 2026
January 1, 2026
4 years
August 24, 2021
May 12, 2026
Conditions
Outcome Measures
Primary Outcomes (1)
Maximum tolerated dose (MTD) (phase 1)
MTD is the highest dose level at which \< 33% of the cohort experience a dose limiting toxicity in the first cycle.
Up to 21 days of each cycle
Secondary Outcomes (5)
Objective response rate (phase 1 and non-thoracic, non-BRD4 exploratory cohort)
Up to 2 years
Duration of response (phase 1 and non-thoracic, non-BRD4 exploratory cohort)
From the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 2 years
Progression-free survival (phase 1 and non-thoracic, non-BRD4 exploratory cohort)
From initiation of study treatment until the identification of disease progression or death, assessed up to 2 years
Overall survival (phase 1 and non-thoracic, non-BRD4 exploratory cohort)
From start of study treatment until death from any cause, assessed up to 2 years
Pharmacodynamic parameters (carboplatin/paclitaxel safety cohort and non-thoracic, non-BRD4 exploratory cohort)
Assessed on-treatment or at time-of-progression, up to 2 years
Study Arms (3)
Cohort I (ZEN003694, etoposide, cisplatin)
EXPERIMENTALPatients receive ZEN003694 PO once or twice daily on days 1-14 or days 1-21 of each cycle depending upon dosage assignment. Patients also receive etoposide IV over 60 minutes on days 1-3 of each cycle and cisplatin IV over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may then receive etoposide and cisplatin for an additional 4 cycles in the absence of disease progression or unacceptable toxicity, per the treating investigator's discretion. After completion of etoposide and cisplatin treatment, patients may then receive ZEN003694 PO once or twice daily on days 1-14 or 1-21 of each cycle, per the treating investigator's discretion. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo imaging scans, blood sample collection, and biopsies throughout the study.
Cohort II (ZEN003694, carboplatin, paclitaxel)
EXPERIMENTALPatients receive ZEN003694 PO once or twice daily on days 1-14 or days 1-21 of each cycle depending upon dosage assignment. Patients also receive carboplatin IV over 15-30 minutes on day 1 of each cycle and paclitaxel IV over 3 hours on day 1 of each cycle. Cycles repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may then receive carboplatin and paclitaxel for an additional 4 cycles in the absence of disease progression or unacceptable toxicity, per the treating investigator's discretion. After completion of carboplatin and paclitaxel treatment, patients may then receive ZEN003694 PO once or twice daily on days 1-14 or 1-21 of each cycle, per the treating investigator's discretion. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo imaging scans, blood sample collection, and biopsies throughout the study.
Cohort III (ZEN003694)
EXPERIMENTALPatients receive ZEN003694 PO on days 1-5, 8-12, and 15-19 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression have the option to cross-over to Cohort I and receive treatment for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Cross-over patients may then receive ZEN003694 PO on days 1-21 of each cycle in the absence of disease progression or unacceptable toxicity, per the treating investigator's discretion. Patients also undergo imaging scans, blood sample collection, and biopsies throughout the study.
Interventions
Undergo imaging scans
Given IV
Given IV
Given PO
Undergo biopsy
Undergo blood sample collection
Given IV
Given IV
Eligibility Criteria
You may qualify if:
- PHASE 1, CARBOPLATIN/PACLITAXEL SAFETY COHORT, \& 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 (World Health Organization \[WHO\], 2021) 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, CARBOPLATIN/PACLITAXEL SAFETY COHORT, \& 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.
- PHASE 1, CARBOPLATIN/PACLITAXEL SAFETY COHORT, \& 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, CARBOPLATIN/PACLITAXEL SAFETY COHORT, \& 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, CARBOPLATIN/PACLITAXEL SAFETY COHORT, \& 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, CARBOPLATIN/PACLITAXEL SAFETY COHORT, \& NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Ability to swallow and retain oral medications.
- PHASE 1, CARBOPLATIN/PACLITAXEL SAFETY COHORT, \& NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Absolute neutrophil count \>= 1.5 x 10\^9/L.
- PHASE 1, CARBOPLATIN/PACLITAXEL SAFETY COHORT, \& NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Platelets \>= 125 x 10\^9/L.
- PHASE 1, CARBOPLATIN/PACLITAXEL SAFETY COHORT, \& NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Hemoglobin \>= 9.0 g/dL.
- PHASE 1, CARBOPLATIN/PACLITAXEL SAFETY COHORT, \& NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Albumin \>= 2.5 g/dL.
- PHASE 1, CARBOPLATIN/PACLITAXEL SAFETY COHORT, \& NON-THORACIC, NON-BRD4 EXPLORATORY COHORT: Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) for age.
- PHASE 1, CARBOPLATIN/PACLITAXEL SAFETY COHORT, \& 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.
- +20 more criteria
You may not qualify if:
- PHASE 1, NON-THORACIC, NON-BRD4 EXPLORATORY COHORT, \& CARBOPLATIN/PACLITAXEL SAFETY 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, NON-THORACIC, NON-BRD4 EXPLORATORY COHORT, \& CARBOPLATIN/PACLITAXEL SAFETY COHORT: History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 or other agents used in study.
- PHASE 1, NON-THORACIC, NON-BRD4 EXPLORATORY COHORT, \& CARBOPLATIN/PACLITAXEL SAFETY 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, NON-THORACIC, NON-BRD4 EXPLORATORY COHORT, \& CARBOPLATIN/PACLITAXEL SAFETY 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, NON-THORACIC, NON-BRD4 EXPLORATORY COHORT, \& CARBOPLATIN/PACLITAXEL SAFETY COHORT: Patients who are receiving any other investigational agents.
- PHASE 1, NON-THORACIC, NON-BRD4 EXPLORATORY COHORT, \& CARBOPLATIN/PACLITAXEL SAFETY 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, NON-THORACIC, NON-BRD4 EXPLORATORY COHORT, \& CARBOPLATIN/PACLITAXEL SAFETY 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, NON-THORACIC, NON-BRD4 EXPLORATORY COHORT, \& CARBOPLATIN/PACLITAXEL SAFETY 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, NON-THORACIC, NON-BRD4 EXPLORATORY COHORT, \& CARBOPLATIN/PACLITAXEL SAFETY COHORT: Patients with radiation to \> 25% of the bone marrow.
- PHASE 1, NON-THORACIC, NON-BRD4 EXPLORATORY COHORT, \& CARBOPLATIN/PACLITAXEL SAFETY COHORT: Cardiac abnormalities as evidenced by any of the following:
- +11 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (5)
Los Angeles General Medical Center
Los Angeles, California, 90033, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, 90033, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232, United States
M D Anderson Cancer Center
Houston, Texas, 77030, United States
Related Publications (1)
Roden AC. Molecularly Defined Thoracic Neoplasms. Adv Anat Pathol. 2024 Sep 1;31(5):303-317. doi: 10.1097/PAP.0000000000000439. Epub 2024 Mar 19.
PMID: 38501690DERIVED
MeSH Terms
Interventions
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Jia Luo
Dana-Farber - Harvard Cancer Center LAO
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
August 24, 2021
First Posted
August 25, 2021
Study Start
July 13, 2022
Primary Completion (Estimated)
June 30, 2026
Study Completion (Estimated)
June 30, 2026
Last Updated
May 13, 2026
Record last verified: 2026-01
Data Sharing
- IPD Sharing
- Will share
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