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Patients receive ZEN003694 orally (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 for cycles 1-4 or up to 8 cycles, and cisplatin IV over 60 minutes on day 1 of cycles 1-4 or up to 8 cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may undergo radiologic evaluation (chest x-ray, CT, PET-CT, MRI, and/or FDG-PET) at the completion of every 2 cycles or 6 weeks, and then at the end of every 3 or 4 cycles after the completion of cycle 10. Patients may also undergo biopsy between cycle 1 day 4 and cycle 1 day 14.

BET Bromodomain Inhibitor ZEN-3694

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Robert Hsu

Jia Luo

Liza C. Villaruz

Sarina A. Piha-Paul

This phase I/II trial tests the safety, side effects, and best dose of a new combination of drugs, BET bromodomain inhibitor ZEN-3694 (ZEN003694), cisplatin, and etoposide in treating patients with NUT carcinoma (phase I), and identifies whether this combination therapy works to shrink tumor in these patients (phase II). 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. Chemotherapy drugs, such as etoposide and cisplatin, work by stopping or slowing the growth of cancer cells. Combination therapy with ZEN003694, etoposide and cisplatin may be effective in treating patients with NUT carcinoma.

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the addition of BET bromodomain inhibitor ZEN-3694 (ZEN003694) to etoposide and cisplatin (EP) in participants with NUT Carcinoma (NC). (Phase 1) II. Evaluate the overall objective response rate (ORR) of the addition of ZEN003694 to etoposide and cisplatin (EP) in participants with NC utilizing response evaluation criteria in solid tumors (RECIST) version 1.1 criteria (Phase 2)

SECONDARY OBJECTIVES:

I. Evaluate the preliminary progression-free survival (PFS) rate, ORR, duration of response (DoR), and overall survival (OS) of the addition of ZEN003694 to etoposide and cisplatin (EP) in participants with NC utilizing RECIST version 1.1 criteria. (Phase 1) II. Determine the pharmacokinetic (PK) profile of ZEN003694, etoposide, and cisplatin when administered in combination. (Phase 1) III. Further evaluate PFS, DoR, and OS of ZEN003694, etoposide, and cisplatin in participants with NC using RECIST version 1.1 criteria (Phase 2) IV. Confirm the safety and tolerability of the regimen in this patient population. (Phase 2) V. Confirm the recommended phase 2 dose (RP2D) from the Phase 1 portion of the trial by assessing the totality of the evidence (i.e., safety, tolerability, pharmacokinetic, pharmacodynamic and activity data) from this trial to select optimal doses for future trials with registrational intent. (Phase 2) VI. Evaluate the preliminary ORR, PFS DoR, and OS of ZEN003694 monotherapy in a small exploratory cohort of patients with non-thoracic origin, non-BRD4-NUT NC. (Phase 2) VII. To observe and record anti-tumor activity. (Phase 1, phase 2, non-thoracic, non-BRD4 exploratory cohort) VIII. Explore potential biomarker indicators of response and resistance in tumor tissue samples. (Phase 1, phase 2, non-thoracic, non-BRD4 exploratory cohort)

IX. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to, whole exome sequencing (WES) and messenger ribonucleic acid (RNA) sequencing (RNAseq), in order to:

IXa. Identify potential predictive and prognostic biomarkers beyond any genomic alteration by which treatment may be assigned; (Phase 1, phase 2, non-thoracic, non-BRD4 exploratory cohort) IXb. Identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and RNA-based assessment platforms. (Phase 1, phase 2, non-thoracic, non-BRD4 exploratory cohort) X. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research; specimens will be annotated with key clinical data, including presentation, diagnosis, staging, summary treatment, and if possible, outcome. (Phase 1, phase 2, non-thoracic, non-BRD4 exploratory cohort) XI. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA analysis), and nucleic acids obtained from patients at the National Cancer Institute (NCI) Early-Phase and Experimental Clinical Trials Biospecimen Bank (EET Biobank) at Nationwide Children's Hospital. (Phase 1, phase 2, non-thoracic, non-BRD4 exploratory cohort)

OUTLINE: This is a phase I dose escalation study of ZEN003694 with fixed dose etoposide and cisplatin followed by a phase 2 study.

Patients receive ZEN003694 orally (PO) once or twice daily on days 1-14 or days 1-21 of each cycle depending upon dosage assignment. Patients also receive etoposide intravenously (IV) over 60 minutes on days 1-3 for cycles 1-4 or up to 8 cycles, and cisplatin IV over 60 minutes on day 1 of cycles 1-4 or up to 8 cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may undergo radiologic evaluation (chest x-ray, computed tomography \[CT\], positron emission tomography \[PET\]-CT, magnetic resonance imaging \[MRI\], and/or fludeoxyglucose \[FDG\]-PET) at the completion of every 2 cycles or 6 weeks, and then at the end of every 3 or 4 cycles after the completion of cycle 10. Patients may also undergo biopsy between cycle 1 day 4 and cycle 1 day 14.

After completion of study treatment, patients are followed for 30 days after the last dose and then every 4 weeks for a maximum of 2 years.

Testing the Safety and Efficacy of the Addition of A New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment (Etoposide and Cisplatin) for Adult and Pediatric Patients (12-17 Years) With NUT Carcinoma

A Phase 1/2 Study of the Bromodomain Inhibitor ZEN003694 in Combination With Etoposide/Platinum in Patients With NUT Carcinoma

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

MTD is the highest dose level at which \< 33% of the cohort experience a dose limiting toxicity in the first cycle.

The ORR is examined using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria in patients following treatment with the triplet combination.

Examined using the RECIST version 1.1 criteria. Point estimates and exact binomial 90% confidence intervals are provided.

Examined using the RECIST version 1.1 criteria. Kaplan and Meier method is used to estimate overall survival in all patients.

Examined using the RECIST version 1.1 criteria.

Assessing the totality of the evidence (i.e., safety, tolerability, pharmacokinetic, pharmacodynamic, and activity data) from this trial to select an optimal dosage(s) for future trials with registrational intent.

On-treatment or at time-of- progression parameters will be compared to those in pre-treatment biopsies using paired statistics such as the Wilcoxon signed-rank test.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Testing the Safety and Efficacy of the Addition of A New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment (Etoposide and Cisplatin) for Adult and Pediatric Patients (12-17 Years) With NUT Carcinoma	NCT05019716	Advanced NUT Ca... Metastatic NUT ... Unresectable NU...	BET Bromodomain... Biopsy Chest Radiograp... Cisplatin Computed Tomogr... Etoposide FDG-Positron Em... Magnetic Resona... Positron Emissi...	12 Years -	National Cancer Institute (NCI)
Testing the Safety and Efficacy of the Addition of A New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment (Etoposide and Cisplatin) for Adult and Pediatric Patients (12-17 Years) With NUT Carcinoma	NCT05019716	Advanced NUT Ca... Metastatic NUT ... Unresectable NU...	BET Bromodomain... Biopsy Chest Radiograp... Cisplatin Computed Tomogr... Etoposide FDG-Positron Em... Magnetic Resona... Positron Emissi...	12 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for advanced nut carcinoma