Glasdegib in Refractory Patients With Sclerotic Chronic Graft-Versus-Host Disease

NCT03415867 | Unknown Phase 1 DMC

• 2 other identifiers: GLAS2017-000862-31
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 6

Brief Summary

This is a phase 1b/2a, open label, multi-centre, safety and efficacy study of glasdegib in patients with sclerotic cGVHD refractory to second-line treatment. The design for the current study is a standard 3+3 dose-finding scheme. A dose escalation/de-escalation design will be applied in successive patient cohorts until identification of MTD. Glasdegib will be self-administered orally once daily in the morning as monotherapy in continuous 28-day treatment cycles for a maximum of 24 cycles. Those patients enrolled in the trial that obtain objective clinical benefit under treatment with glasdegib (defined as the achievement of at least a partial response at one or more target organs), will be allowed to proceed to a slow dose withdrawal phase over a period of 6 months after the end of Cycle 24.

Conditions

Sclerodermoid Chronic Graft-Versus-Host Disease (Disorder)

Keywords

Graft-versus-host disease; Bone marrow transplantation; Hedgehog inhibitor

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose.

  To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and/or the recommended Phase 2 dose (RP2D) of glasdegib in subjects with sclerotic cGVHD.

  Up to 48 weeks.

Secondary Outcomes (12)

• Adverse events.

  Adverse events will be assessed from the date the informed consent document is signed until 28 days after the last administered dose of glasdegib.

• Overall response rate (ORR).

  Response to treatment will be evaluated on Day 1 of Cycles 1, 2, 4, 7, 10, 13, 16, 19, 22, 25, 28 (each cycle is 28 days) and end treatment.

• Immunosuppression requirements.

  Modifications to the immunosuppressive regimen will be assessed from date of study entry to study withdrawal or end of treatment (up to 48 weeks).

• Duration of clinical response.

  Response to treatment will be evaluated on Day 1 of Cycles 1, 2, 4, 7, 10, 13, 16, 19, 22, 25, 28 (each cycle is 28 days) and day 28 of Cycle 24,

• Survival outcomes: overall survival.

  Survival status of participants will be followed from inclusion to end of trial (once every recruited patient has completed 12 cycles of treatment or withdrawn from the study).

Study Arms (1)

Dose escalation sequential cohorts

EXPERIMENTAL

Glasdegib will be self-administered orally once daily in the morning as monotherapy in continuous 28-day treatment cycles for a maximum of 24 cycles. Those patients enrolled in the trial that obtain objective clinical benefit under treatment with glasdegib (defined as the achievement of at least a partial response at one or more target organs), will be allowed to proceed to a slow dose withdrawal phase over a period of 6 months after the end of Cycle 24. The dose reduction scheme is fully detailed in the protocol.

Drug: Glasdegib

Interventions

Glasdegib DRUG

A dose escalation/de-escalation design will be applied in successive patient cohorts until identification of MTD (dose range: 25-200 mg OD).

Also known as: PF-04449913

Dose escalation sequential cohorts

Eligibility Criteria

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

You may qualify if:

• Adult (≥ 18 years old) recipients of an allogeneic hematopoietic stem cell transplantation with active sclerotic cGVHD without response, in partial response or in relapse after 2 previous lines of treatment including corticosteroids and one of the following second line treatments:
• Extracorporeal photopheresis (preferably).
• A calcineurin inhibitor.
• A mammalian target of rapamycin (mTOR) inhibitor.
• Pentostatin.
• Rituximab.
• Imatinib.
• Ruxolitinib.
• Eastern Cooperative Oncology Group Performance Status 0 to 2.
• Adequate organ function as defined by the following:
• Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN).
• Total serum bilirubin ≤ 2 x ULN (except patients with documented Gilbert's syndrome).
• Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 60 mL/min as calculated using the method standard for the institution.
• Hematologic malignancy in complete remission.
• Resolved acute effects of any prior therapy to baseline severity or Grade ≤ 1 CTCAE except for adverse events not constituting a safety risk by investigator judgement.

You may not qualify if:

• Patients presenting with any of the following will not be included in the study:
• Patients with active malignancy with the exception of basal cell carcinoma, nonmelanoma skin cancer or cervical carcinoma-in-situ. Other prior or concurrent malignancies will be considered on a case-by-case basis.
• Any one of the following, currently or in the previous 6 months: myocardial infarction, congenital long QT syndrome, torsade de pointes or clinically significant ventricular arrhythmias.
• QTc interval \>470 milliseconds using the Fridericia (QTcF).
• Patients with an active, life threatening or clinically significant uncontrolled systemic infection.
• Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or active Hepatitis B or C infection.
• Known malabsorption syndrome or other condition that may impair absorption of study medication (e.g., gastrectomy or lap band).
• Major surgery or radiation within 4 weeks of starting study treatment.
• Prior treatment with:
• A hedgehog inhibitor at any time.
• An investigational agent for the treatment of cGVHD (a three-month wash-out period will be required).
• Concurrent treatment with any investigational agent.
• Concurrent administration of herbal preparations.
• Current use at time of study entry or anticipated need for drugs that are known strong CYP3A4/5 inducers.
• Current drug or alcohol abuse.

Sponsors & Collaborators

• Grupo Espanol de trasplantes hematopoyeticos y terapia celular: lead

Study Sites (6)

Hospital Clinic de Barcelona

Barcelona, Spain

Location

Hospital General Universitario Morales Meseguer

Murcia, Spain

Location

Hospital Universitario Son Espases

Palma de Mallorca, Spain

Location

Hospital Universitario de Salamanca

Salamanca, Spain

Location

Hospital Universitario Marqués de Valdecilla

Santander, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, Spain

Location

Related Publications (3)

• Inamoto Y, Storer BE, Petersdorf EW, Nelson JL, Lee SJ, Carpenter PA, Sandmaier BM, Hansen JA, Martin PJ, Flowers ME. Incidence, risk factors, and outcomes of sclerosis in patients with chronic graft-versus-host disease. Blood. 2013 Jun 20;121(25):5098-103. doi: 10.1182/blood-2012-10-464198. Epub 2013 Apr 1.

  PMID: 23547053 BACKGROUND

• Dignan FL, Amrolia P, Clark A, Cornish J, Jackson G, Mahendra P, Scarisbrick JJ, Taylor PC, Shaw BE, Potter MN; Haemato-oncology Task Force of British Committee for Standards in Haematology; British Society for Blood and Marrow Transplantation. Diagnosis and management of chronic graft-versus-host disease. Br J Haematol. 2012 Jul;158(1):46-61. doi: 10.1111/j.1365-2141.2012.09128.x. Epub 2012 Apr 26.

  PMID: 22533811 BACKGROUND

• Zerr P, Palumbo-Zerr K, Distler A, Tomcik M, Vollath S, Munoz LE, Beyer C, Dees C, Egberts F, Tinazzi I, Del Galdo F, Distler O, Schett G, Spriewald BM, Distler JH. Inhibition of hedgehog signaling for the treatment of murine sclerodermatous chronic graft-versus-host disease. Blood. 2012 Oct 4;120(14):2909-17. doi: 10.1182/blood-2012-01-403428. Epub 2012 Aug 22.

  PMID: 22915638 BACKGROUND

MeSH Terms

Conditions

Graft vs Host Disease

Interventions

glasdegib

Condition Hierarchy (Ancestors)

Immune System Diseases

Study Officials

• José Antonio Pérez-Simón, M.D. Ph.D.

  Department of Hematology, Hospital Universitario Virgen del Rocío. Spain

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2017
• First Posted: January 30, 2018
• Study Start: January 9, 2018
• Primary Completion: January 9, 2022
• Study Completion: June 9, 2022
• Last Updated: March 17, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: 6 months after data completion
• Access Criteria: Investigators participating in the study until the final publication is done

Locations

ES (6)