A Rollover Study of ARRY-371797 in Patients With LMNA-Related Dilated Cardiomyopathy

An Open-label Rollover Study of ARRY-371797 in Patients With Symptomatic Genetic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation

This is a rollover study designed to investigate the safety and effectiveness of investigational study drug ARRY-371797 in patients who previously received ARRY-371797 in a study for patients with LMNA-related dilated cardiomyopathy sponsored by Array BioPharma and may, in the Investigator's opinion, derive benefit from continued treatment.

Study Overview

• Status: Completed
• Conditions: LMNA-Related Dilated Cardiomyopathy
• Intervention / Treatment: Drug: ARRY-371797, p38 inhibitor, oral

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53713
      • Meriter Wisconsin Heart

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

• Received ARRY-371797 as treatment for a genetic dilated cardiomyopathy secondary to LMNA mutations in a clinical study sponsored by Array BioPharma.
• May, in the opinion of the Investigator, benefit from continued ARRY-371797 treatment.
• Additional criteria exist.

Key Exclusion Criteria:

• Discontinued treatment in the parent study for any reason other than study completion or Sponsor termination of the study.
• Additional criteria exist.

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: ARRY-371797	Drug: ARRY-371797, p38 inhibitor, oral; multiple dose, single schedule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events between baseline up to 30 days after last dose of study drug (i.e., maximum up to 282 weeks) that were absent before treatment or that worsened relative to pre-treatment state. AEs included both serious and non-serious adverse events.	Baseline up to 30 days after last dose of study drug (i.e., maximum up to 282 weeks)
Number of Participants With Change From Baseline Value in Clinical Laboratory Hematology Test Results to Worst Value	In this outcome measure, number of participants with baseline laboratory hematology values as per National Cancer Institute Common Terminology Criteria (NCI-CTC) grade (Grade 0= within normal limits, Grade 1=Mild, Grade 2=Moderate, Grade 3= Severe, Grade 4= Life-threatening) and corresponding changes/shift to the worst CTC grades post baseline were presented. Shift data have been reported for hematology parameters: hemoglobin (g/L), platelets (10^9/L), leukocytes (10^9/L), neutrophils (10^9/L), lymphocytes (10^9/L) and eosinophils (10^9/L). Baseline was defined as last non-missing value before the initial administration of study treatment in parent study and worst post-baseline value defined as worst value between first dose of study drug up to the maximum of 282 weeks. Only those categories in which at least 1 participant had data were reported.	Baseline, Post-Baseline (anytime from first dose of study drug to maximum duration of up to 282 weeks)
Number of Participants With Change From Baseline Value in Clinical Laboratory Chemistry Test Results to Worst Value	In this outcome measure, number of participants with baseline laboratory chemistry values as per NCI-CTC grade (Grade 0= within normal limits, Grade 1=Mild, Grade 2=Moderate, Grade 3= Severe, Grade 4= Life-threatening) and corresponding changes/shift to the worst CTC grades post baseline were presented. Shift data have been reported for laboratory parameters: alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, international unit per liter (IU/L), albumin, bilirubin, urea nitrogen, calcium, creatinine, glucose, magnesium, protein and phosphate grams per deciliter (g/dL), potassium and sodium, millimol per liter (mmol/L). Baseline was defined as last non-missing value before the initial administration of study treatment in parent study and worst post-baseline value defined as worst value between first dose of study drug up to the maximum of 282 weeks. Only those categories in which at least 1 participant had data were reported.	Baseline, Post-Baseline (anytime from first dose of study drug to maximum duration of up to 282 weeks)
Number of Participants With Abnormal Physical Examination Findings	Physical examination included the assessment of skin, head, ears, eyes, nose, throat, cardiovascular system, abdomen and lungs. Abnormality in physical examination were based on investigator's discretion.	Baseline up to 30 days after last dose of study drug (i.e., maximum up to 282 weeks)
Number of Participants With Abnormalities in Vital Signs	Following vital signs parameters were analyzed using prespecified range of results for signs of clinical significance: systolic blood pressure in millimeters of mercury (mmHg): <90 mmHg and ≥160 mmHg, diastolic blood pressure: <60 mmHg and ≥100 mmHg, heart rate in beats per minute (bpm): <40bpm and >120 bpm, temperature in degree Celsius (C): <36.1 and > 37.2 degree C.	Baseline up to 30 days after last dose of study drug (i.e., maximum up to 282 weeks)
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings	Following ECG parameters were analyzed using prespecified range of results for signs of clinical significance: heart rate: <40bpm and >120 bpm; QT/QTcF (QT interval corrected using Fridericia's formula) criteria: QT interval >500 ms; QTcF interval >450 ms; or change from baseline in QTcF >30 ms.	Baseline up to 30 days after last dose of study drug (i.e., maximum up to 282 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Six Minute Walk Test (6MWT) Distance at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit	6MWT was the distance that a participant could quickly walk on a flat, hard surface in a period of 6 minutes. Participants were asked to walk a set course of 30 meters for 6 minutes (timed), and the distance walked (in meters) was recorded. Change from baseline in 6MWT distance at specified time points were reported. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study.	Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks)
Change From Baseline in Left Ventricular End Systolic Index (LVESVI) and Left Ventricular End Diastolic Volume Index (LVEDVI) at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit	LVESVI and LVEDVI were echocardiographic assessment of left ventricular remodeling. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study.	Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks)
Change From Baseline in Left Ventricular Mass (LVM) at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit	LVM is the weight of the left ventricle in grams estimated by echocardiography. For this outcome measure, Baseline is the pre-dose baseline of parent study.	Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks)
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit	LVEF was the fraction of the end-diastolic volume (EDV) that was ejected out of left ventricle with each contraction, estimated by echocardiography. EDV was the volume of blood within a ventricle immediately before a contraction. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study.	Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks)
Change From Baseline in Left Ventricular Mass (LVM) to Volume Ratio at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit	LVM divided by the end diastolic volume, estimated by echocardiography. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study.	Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks)
Change From Baseline in Right Ventricular End Diastolic Diameter at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit	The internal diameter of the right ventricle at the end of diastole, measured by echocardiography. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study.	Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks)
Change From Baseline in Right Ventricular Fractional Area at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit	Right ventricular fractional area change is a measure of global right ventricular systolic function estimated by echocardiography. For this outcome measure, Baseline is the pre-dose baseline of parent study.	Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks)
Change From Baseline in 36-Item Short-Form (SF-36) Health Survey Score at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit	The SF-36 health survey is a participant-reported survey to measure participant's health. It is a 36-item questionnaire used to measure 8 various aspects of health (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health). The score range for each of the 8 aspects was from 0 (maximum disability) to 100 (no disability), higher scores indicating good health condition. For this analysis, baseline was defined as last non-missing value before the initial administration of study treatment in parent study.	Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks)
Change From Baseline in Quality of Life by Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit	KCCQ was a 23-item heart failure specific questionnaire quantified into following 10 summary scores: physical limitation score, symptom frequency score, symptom severity score, symptom stability score, total symptoms score, quality of life score, social interference score, self-efficacy score, overall summary score and clinical summary score. These scores ranged from 0 to 100, where higher scores indicated better functioning, fewer symptoms, and better disease specific quality of life. For this analysis, baseline was defined as last non-missing value before the initial administration of study treatment in parent study.	Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks)
Mean Plasma Concentration of ARRY-371797 and Metabolites (AR00420643, AR00428028, AR00486705)	Plasma concentrations of ARRY-371797 and its metabolites (AR00420643, AR00428028 and AR00486705) was summarized on Day 1, Weeks 12 and 24 at both pre and post dose.	Pre dose and post dose on Day 1, Weeks 12 and 24

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Judge DP, Lakdawala NK, Taylor MRG, Mestroni L, Li H, Oliver C, Angeli FS, Lee PA, MacRae CA. Long-Term Efficacy and Safety of ARRY-371797 (PF-07265803) in Patients With Lamin A/C-Related Dilated Cardiomyopathy. Am J Cardiol. 2022 Nov 15;183:93-98. doi: 10.1016/j.amjcard.2022.08.001. Epub 2022 Sep 13.

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2015
• Primary Completion (Actual): December 21, 2020
• Study Completion (Actual): December 21, 2020

Study Registration Dates

• First Submitted: January 27, 2015
• First Submitted That Met QC Criteria: January 29, 2015
• First Posted (Estimate): January 30, 2015

Study Record Updates

• Last Update Posted (Actual): March 31, 2022
• Last Update Submitted That Met QC Criteria: March 3, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: ARRY-797; laminopathy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Cardiomegaly; Laminopathies; Cardiomyopathies; Cardiomyopathy, Dilated
• Other Study ID Numbers: ARRAY-797-001; C4411001 (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.