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.
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.
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
Parallel
BET Bromodomain Inhibitor ZEN-3694
DrugGiven PO
Biopsy Procedure
Procedure/SurgeryUndergo biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Carboplatin
DrugGiven IV
Cisplatin
DrugGiven IV
Etoposide
DrugGiven IV
Imaging Procedure
Procedure/SurgeryUndergo imaging scans
Paclitaxel
DrugGiven IV
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.
Objective response rate (phase 1 and non-thoracic, non-BRD4 exploratory cohort)
Examined using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Point estimates and exact binomial 90% confidence intervals are provided.
Duration of response (phase 1 and non-thoracic, non-BRD4 exploratory cohort)
Examined using the RECIST version 1.1 criteria. Kaplan and Meier method is used to estimate overall survival in all patients.
Progression-free survival (phase 1 and non-thoracic, non-BRD4 exploratory cohort)
Examined using the RECIST version 1.1 criteria.
Overall survival (phase 1 and non-thoracic, non-BRD4 exploratory cohort)
Examined using the RECIST version 1.1 criteria. Kaplan and Meier method is used to estimate overall survival in all patients.
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