Novel BET Inhibitor PLX51107 for Steroid-Refractory Acute GVHD

A Single Arm, Open Label, Phase 1b/2 Study of Novel BET Inhibitor PLX51107 for Steroid-Refractory Acute GVHD

This phase Ib/II trial studies the side effects of PLX51107 in treating steroid-refractory acute graft versus host disease (GVHD). PLX51107 is a novel, potent non-benzodiazepine structured small molecule BET inhibitor with a unique binding mode selective for BRD4 inhibition and a more tolerable side effect profile. PLX51107 may work better in treating steroid-refractory acute GVHD.

Study Overview

• Status: Terminated
• Conditions: Acute Graft Versus Host Disease; Steroid Refractory Graft Versus Host Disease
• Intervention / Treatment: Drug: BRD4 Inhibitor PLX51107

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of BRD4 inhibitor PLX51107 (PLX51107) as a single agent for allogeneic transplant recipients with steroid-refractory acute graft versus host disease (GVHD).

II. To assess the pharmacokinetic (PK) and pharmacodynamic (PD) of orally administered PLX51107 in steroid-refractory acute GVHD patients.

SECONDARY OBJECTIVE:

I. To evaluate the preliminary efficacy of PLX51107 in steroid-refractory acute GVHD patients.

OUTLINE:

Patients receive BRD4 inhibitor PLX51107 orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then up to 6 months.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Rachel Dalton; Email: Rachel.Dalton@osumc.edu
• Study Contact Backup: Name: The Ohio State University Comprehensive Cancer Center; Phone Number: 800-293-5066; Email: OSUCCCClinicaltrials@osumc.edu

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age >= 18 years at the time of signing informed consent
• Steroid-refractory acute GVHD as defined as progression of acute (a)GvHD within 3-5 days of therapy onset with >= 2 mg/kg/day of prednisone equivalent OR failure to improve within 5-7 days of treatment initiation with > 1-2 mg/kg/day of prednisone equivalent OR incomplete response after more than 28 days of immunosuppressive treatment including steroids
• Recipients of ablative and reduced-intensity conditioning regimens
• Recipients of human leukocyte antigen (HLA)-matched related and unrelated, 1-allele mismatched, haploidentical, or umbilical cord blood donor grafts
• Prior lines of therapy for treatment of steroid-refractory acute GVHD are allowed. However, exposure to investigational therapies for the treatment of GVHD must be > 14 days or 5 half-lives (whichever is shorter) of first administration of study drug. For patients treated with ruxolitinib for the treatment of acute GVHD, ruxolitinib must be discontinued by at least one day prior to initiation of PLX51107
• Eastern Cooperative Oncology Group (ECOG) performance status =< 3
• Absolute neutrophil count >= 1.0 x 10^9/L for 3 consecutive days). Use of growth factor support is allowed
• Platelet count >= 50 x 10^9/L without transfusion support for 2 consecutive days
• Women of child-bearing potential must have a negative serum pregnancy test at Screening and must agree to use an effective form of contraception from the time of the negative pregnancy test up to 6 months after the last dose of study drug. Effective forms of contraception include abstinence, hormonal contraceptive in conjunction with a barrier method, or a double barrier method. Women of non-child-bearing potential may be included if they are either surgically sterile or have been postmenopausal for >= 1 year
• Fertile men must agree to use an effective method of birth control during the study and for up to 6 months after the last dose of study drug

Exclusion Criteria:

• Prior exposure to a bromodomain inhibitor
• Evidence of chronic GVHD
• Evidence of active relapse of disease
• Exposure to other investigational or anti-cancer therapies (not for GVHD) within 28 days or 5 half-lives (whichever is shorter) of first administration of study drug
• Active, uncontrolled bacterial, fungal, or viral infection
• Known or suspected allergy to the study drug

• Clinically significant cardiac disease, defined as:

  • Clinically significant cardiac arrhythmias, including bradyarrhythmia, and/or a need for anti-arrhythmic therapy (excluding beta blockers or digoxin). Individuals with controlled atrial fibrillation are not excluded
  • Fridericia-corrected QT interval (QTcF) >= 450 ms (male) or >= 470 ms (female) at screening
  • History of clinically significant cardiac disease or congestive heart failure greater than New York Heart Association Class II. Subjects must not have unstable angina (angina symptoms at rest) or experienced either new-onset angina within the last 3 months or myocardial infarction (MI) within the last 6 months unless it was due to the underlying disease and there has been appropriate revascularization. Individuals with ambiguous troponin levels that are not diagnostic of an MI should be discussed with the principal investigator (PI) prior to enrollment
  • Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within the 6 months before start of study medication (except for catheter-related venous thrombosis
• Inability to take oral medication or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the Investigator, would preclude adequate absorption
• Active thrombotic microangiopathy (TMA)
• Women who are either pregnant or breast feeding
• Measured or calculated (Cockcroft-Gault formula) creatinine clearance (CrCl) < 45 mL/min
• Prothrombin time or international normalized ratio > 1.5 x upper limit of normal (ULN)
• Activated partial thromboplastin time > 1.5 x ULN
• Requiring mechanical ventilation or vasopressor support
• Subject is participating in any other therapeutic clinical study (observational or registry studies are allowed)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment for aGVHD (BRD4 inhibitor PLX51107); Patients receive BRD4 inhibitor PLX51107 PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: BRD4 Inhibitor PLX51107; Given PO; Other Names: PLX 51107; PLX-51107; PLX51107

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD)		Up to 28 days
Incidence of adverse event	Adverse events by grade will be summarized. The occurrence of grade 3+ adverse events according to Common Terminology Criteria for Adverse Events will be summarized as well. Adverse events will initially be reviewed regardless of attribution, but also according to whether adverse events are possibly, probably, or definitely related to treatment.	Up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response (CR)	The proportion of CR with a 95% confidence interval will be reported, assuming a binomial distribution.	At day 28
Overall response rate	The overall response rate (ORR) will include CR and partial response (PR), while mixed response (MR) and no response (NR) will be classified as no response. The ORR will be similarly analyzed as CR.	At day 28
Non-relapse mortality (NRM)	The cumulative incidence curve accounting for competing risks will be generated to estimate the cumulative incidence of NRM rate at 6 months. The comparison in NRM between patient subgroups may be explored graphically.	From the date of starting PLX51107 to date of death with the competing risk as death due to disease, assessed at 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK) analysis	Pharmacokinetics (PK) for target exposure of AUC0-24 8300 ng•hr/mL	Up to 6 months

Collaborators and Investigators

• Sponsor: Hannah Choe, MD
• Collaborators: National Cancer Institute (NCI); Plexxikon
• Investigators: Principal Investigator: Hannah Choe, MD, Ohio State University Comprehensive Cancer Center

Publications and helpful links

Helpful Links

• The Jamesline

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2022
• Primary Completion (Actual): September 28, 2023
• Study Completion (Actual): September 28, 2023

Study Registration Dates

• First Submitted: April 24, 2021
• First Submitted That Met QC Criteria: May 28, 2021
• First Posted (Actual): June 2, 2021

Study Record Updates

• Last Update Posted (Estimated): April 25, 2024
• Last Update Submitted That Met QC Criteria: April 23, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: OSU-20273; NCI-2021-02282 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); R01CA252469 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No