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

NCT04116359 | Withdrawn Phase 1 DMC FDA Drug

• 3 other identifiers: NCI-2019-0667610295UM1CA186709
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Metastatic NUT Carcinoma; Unresectable NUT Carcinoma

Outcome Measures

Primary Outcomes (3)

• Incidence of adverse events (Phase I)

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

  Up to 21 days

• Maximum tolerated dose (MTD) (Phase I)

  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.

  Up to 21 days

• Overall response rate (ORR) (Phase II)

  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.

  Up to 2 years

Secondary Outcomes (5)

• Overall response rate (ORR) (Phase I, Phase II, and Non-BRD4 Exploratory Cohort)

  Up to 2 years

• Duration of response (DoR) rates (Phase I, Phase II, and Non-BRD4 Exploratory Cohort)

  From the time measurement criteria are met for CR or PR (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 I, Phase II, and Non-BRD4 Exploratory Cohort)

  From study enrollment until the identification of disease progression or death, assessed up to 2 years

• Overall survival (OS) rates (Phase I, Phase II, and Non-BRD4 Exploratory Cohort)

  Up to 2 years

• Pharmacodynamic parameters (Phase I, Phase II, and Non-Thoracic, Non-BRD4 Exploratory Cohort)

  Up to 2 years

Study Arms (2)

Non-BRD4 exploratory cohort (molibresib, cisplatin, etoposide)

EXPERIMENTAL

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.

Drug: Cisplatin; Drug: Etoposide; Drug: Etoposide Phosphate; Drug: Molibresib; Drug: Molibresib Besylate

Phase I and II cohort (molibresib, etoposide, cisplatin)

EXPERIMENTAL

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.

Drug: Cisplatin; Drug: Etoposide; Drug: Etoposide Phosphate; Drug: Molibresib; Drug: Molibresib Besylate

Interventions

Cisplatin DRUG

Given IV

Also known as: Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin

Non-BRD4 exploratory cohort (molibresib, cisplatin, etoposide); Phase I and II cohort (molibresib, etoposide, cisplatin)

Etoposide DRUG

Given IV

Also known as: Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16

Non-BRD4 exploratory cohort (molibresib, cisplatin, etoposide); Phase I and II cohort (molibresib, etoposide, cisplatin)

Etoposide Phosphate DRUG

Given IV

Also known as: Etopophos

Non-BRD4 exploratory cohort (molibresib, cisplatin, etoposide); Phase I and II cohort (molibresib, etoposide, cisplatin)

Molibresib DRUG

Given PO

Also known as: GSK-525762A, GSK525762, I-BET 762

Non-BRD4 exploratory cohort (molibresib, cisplatin, etoposide); Phase I and II cohort (molibresib, etoposide, cisplatin)

Molibresib Besylate DRUG

Given PO

Also known as: GSK525762C

Non-BRD4 exploratory cohort (molibresib, cisplatin, etoposide); Phase I and II cohort (molibresib, etoposide, cisplatin)

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• PHASE 1, PHASE 2, AND NON-THORACIC, NON-BRD4 EXPLORATORY COHORT
• Patients must have histologically or cytologically confirmed NUT carcinoma (NC) based on at least one of the following criteria:
• Ectopic expression of NUT protein (\> 50% tumor nuclei) as determined by immunohistochemistry (IHC) testing performed in a Clinical Laboratory Improvement Act (CLIA) certified laboratory
• Detection of the NUT gene translocation as determined by fluorescence in situ hybridization (FISH) performed at the Brigham and Women's Hospital (BWH) Center for Advanced Molecular Diagnostics (CAMD)
• 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 in the opinion of the treating investigator. Participants who have already undergone surgical resection are eligible
• Eastern Cooperative Oncology Group (ECOG) performance status of =\< 2 (Karnofsky \>= 60%) for patients \>= 16 years of age, Lansky \>= 50% if \< 16 years of age
• Participants must have measurable disease per RECIST version 1.1 criteria. Participants enrolling to the phase 1 or non-BRD4 exploratory cohort without measurable disease per the RECIST definition may be allowed to enroll with permission from the overall principal investigator if their disease is otherwise evaluable (e.g. bone metastases, malignant pleural effusions, malignant ascites
• Ability to swallow and retain oral medications
• Absolute neutrophil count \>= 1.5 x 10\^9/L
• Platelets \>= 100 x 10\^9/L
• Hemoglobin \>= 9.0 g/dL
• Albumin \>= 2.5 g/dL
• Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) for age
• Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional ULN for age OR
• Calculated creatinine clearance \>= 60 mL/min (via the using CKD-epi equation)

You may not qualify if:

• PHASE 1, PHASE 2, AND NON-THORACIC,NON-BRD4 EXPLORATORY COHORT.
• Participants with known untreated central nervous system (CNS) metastases. Patients with a history of CNS metastases are eligible, provided they meet the following criteria:
• 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
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to the study agent(s) (e.g., benzodiazepines for GSK525762C) the participant will be receiving once enrolled
• 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
• Any gastrointestinal (GI) disorder that may affect absorption of oral medications in the opinion of the treating investigator, such as malabsorption syndrome or major bowel or stomach resection
• Fridericia's correction formula (QTcF) \> 450 msec on screening electrocardiogram (ECG)
• Patients who are receiving any other investigational agents
• GSK525762C is primarily metabolized by CYP3A4; therefore, concomitant administration with strong inhibitors or inducers of CYP3A4 should be avoided unless medically necessary. 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
• Pregnant women are excluded from this study because GSK525762C is a 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 GSK525762C, breastfeeding should be discontinued if the mother is treated with GSK525762C. These potential risks may also apply to other agents used in this study
• Patients receiving therapeutic-dose anticoagulation (e.g., warfarin, low-molecular weight heparin \[LMWH\], or novel oral anticoagulants) are not eligible. Prophylactic anticoagulation, with low doses (per standard practice) of agents such as low molecular weight heparin (LMWH), direct thrombin inhibitors, or factor Xa inhibitors are permitted
• Patients who are known to require concurrent use of nonsteroidal antiinflammatory drugs (NSAIDS), except for cases where NSAIDS provide benefit over other analgesics or high dose aspirin (patients are allowed up to 100 mg aspirin PO daily)

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

MeSH Terms

Interventions

Cisplatin; 1,2-diaminocyclohexaneplatinum II citrate; Platinum; Etoposide; etoposide phosphate; molibresib

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Metals, Heavy; Elements; Transition Elements; Metals; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates

Study Officials

• Geoffrey I Shapiro

  Dana-Farber - Harvard Cancer Center LAO

  PRINCIPAL INVESTIGATOR

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: October 3, 2019
• First Posted: October 4, 2019
• Study Start: September 18, 2020
• Primary Completion: September 18, 2020
• Study Completion: September 18, 2020
• Last Updated: September 28, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will share