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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

Biopsy

Chest Radiography

Computed Tomography

FDG-Positron Emission Tomography

Magnetic Resonance Imaging

Positron Emission Tomography

Site Public Contact

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.

National Cancer Institute (NCI)

Patients receive molibresib besylate PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression may receive molibresib besylate, etoposide phosphate and cisplatin as in Phase I and II Cohort at the discretion of the principal investigator.

Patients receive molibresib besylate PO QD on days 1-14 (may switch to days 1-21 after completion of etoposide and cisplatin cycles). Patients also receive etoposide phosphate IV over 60 minutes on days 1-3 and cisplatin IV over 60 minutes on day 1 of cycles 1-4. Treatments repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of cycle 4, patients may receive etoposide phosphate and cisplatin for up to 8 cycles total in the absence of disease progression or unacceptable toxicity at the investigator's discretion.

Etoposide Phosphate

Molibresib

Molibresib Besylate

Geoffrey I Shapiro

This phase I/II trial studies the side effects and best dose of molibresib when given together with chemotherapy (etoposide and cisplatin) and how well they work for the treatment of NUT cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Molibresib may stop the growth of tumor cells by blocking some of the proteins needed for cell growth. Drugs used in chemotherapy, such as etoposide and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding molibresib to chemotherapy (etoposide and cisplatin), may work better in treating patients with NUT cancer compared to the usual approach.

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of molibresib besylate (molibresib \[GSK525762C\]) with etoposide phosphate (etoposide) and cisplatin (EP) in patients with NUT carcinoma (NC). (Phase I) II. Evaluate the overall objective response rate (ORR) of the triplet combination in participants utilizing Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. (Phase II)

SECONDARY OBJECTIVES:

I. Evaluate the preliminary progression-free survival (PFS) rate, ORR, duration of response (DoR), and overall survival (OS) rate of the triplet combination in participants utilizing RECIST version 1.1 criteria. (Phase I) II. Determine the pharmacokinetic (PK) profile of the triplet combination. (Phase I) III. Determine the PFS, DoR, and OS rates of the triplet in participants with NC using RECIST version 1.1 criteria. (Phase II) IV. Confirm the safety and tolerability of the regimen in this patient population. (Phase II) V. Evaluate the preliminary PFS rate, ORR, DoR, and the OS rate of GSK525762C monotherapy in a small exploratory cohort of patients with non-thoracic origin, non-BRD4-NUT NC. (Phase II) VI. To observe and record anti-tumor activity. (Phase 1, phase 2, and non-thoracic, non-BRD4 exploratory cohort) VII. Explore potential biomarker indicators of response and resistance in tumor tissue samples. (Phase 1, phase 2, and non-thoracic, non-BRD4 exploratory cohort)

VIII. 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:

VIIIa. Identify potential predictive and prognostic biomarkers beyond any genomic alteration by which treatment may be assigned. (Phase 1, phase 2, and non-thoracic, non-BRD4 exploratory cohort) VIIIb. Identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and RNA-based assessment platforms. (Phase 1, phase 2, and non-thoracic, non-BRD4 exploratory cohort) IX. 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. (Phase 1, phase 2, and non-thoracic, non-BRD4 exploratory cohort) X. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital. (Phase 1, phase 2, and non-thoracic, non-BRD4 exploratory cohort)

OUTLINE: This is a phase I, dose-escalation study of molibresib besylate followed by a phase II study. Patients are assigned to 1 of 2 cohorts.

PHASE I AND II COHORT: Patients receive molibresib besylate orally (PO) once daily (QD) on days 1-14 (may switch to days 1-21 after completion of etoposide and cisplatin cycles). Patients also receive etoposide phosphate intravenously (IV) over 60 minutes on days 1-3 and cisplatin IV over 60 minutes on day 1 of cycles 1-4. Treatments repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of cycle 4, patients may receive etoposide phosphate and cisplatin for up to 8 cycles total in the absence of disease progression or unacceptable toxicity at the investigator's discretion.

Non-BRD4 EXPLORATORY COHORT: Patients receive molibresib besylate PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression may receive molibresib besylate, etoposide phosphate and cisplatin as in Phase I and II Cohort at the discretion of the principal investigator.

After completion of study treatment, patients are followed up for 30 days and then every 4 weeks for up to 2 years.

Testing of the Addition of a New Anti-cancer Drug, Molibresib, to Chemotherapy Treatment (Etoposide and Cisplatin) for Patients With NUT Carcinoma

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

Assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (V.) 5.0 criteria.

The MTD will be the highest dose level at which 0/3 or 1/6 subjects experience a dose limiting toxicity (DLT). Data will be summarized using descriptive statistics for continuous variables and frequencies, percentages for discrete variables, and presented by dose group, as appropriate.

Radiological response will be assessed by RECIST 1.1 criteria and will be graded as CR, PR, SD and PD. Point estimates and exact binomial 90% confidence intervals will be provided.

Radiological response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and will be graded as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Point estimates and exact binomial 90% confidence intervals will be provided.

The method of Kaplan and Meier will be used to estimate duration of response in those that achieve PR or CR.

The method of Kaplan and Meier will be used to estimate overall survival in all patients.

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
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)
Testing of the Addition of a New Anti-cancer Drug, Molibresib, to Chemotherapy Treatment (Etoposide and Cisplatin) for Patients With NUT Carcinoma	NCT04116359	Metastatic NUT ... Unresectable NU...	Cisplatin Etoposide Etoposide Phosp... Molibresib Molibresib Besy...	12 Years -	National Cancer Institute (NCI)

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