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Glasdegib for Chronic Graft-Versus-Host Disease

Primary Purpose

Chronic Graft Versus Host Disease, Fasciitis

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Glasdegib
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Graft Versus Host Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosed with moderate or severe cGVHD according to the 2014 National Institute of Health (NIH) Consensus Criteria

  • Diagnosed with cGVHD-related sclerosis or fasciitis

    • Skin feature score of at least 2 OR
    • Joints and fascia score of at least 1
  • New, stable or progressive sclerosis/fasciitis despite treatment with at least one prior line of systemic therapy for cGVHD

  • Female patients who:

    • Are documented to be postmenopausal or are surgically sterile, OR
    • If of childbearing potential, agree to use at least 1 highly effective method of contraception from the time of signing the informed consent form through 30 days after the last dose of study drug, OR agree to practice true abstinence or exclusively non-heterosexual activity when this is in line with the preferred and usual lifestyle of the subject

  • Male patients who:

    • Are surgically sterile (vasectomized) OR
    • Agree to use at least 1 highly effective method of contraception during the entire study treatment period and through 30 days after the last dose of study drug, OR agree to practice true abstinence or exclusively non-heterosexual activity when this is in line with the preferred and usual lifestyle of the subject, AND
    • Agree to use a condom to prevent potential transmission of investigational drug in seminal fluid
  • Absolute neutrophil count (ANC) > 1000/uL
  • Platelet count > 50 x 10^9/mL
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2 x upper limit of normal (ULN) unless attributed to cGVHD
  • Normal total bilirubin unless attributed to cGVHD
  • Creatinine < 2.0 mg/dl

Exclusion Criteria:

  • Hospitalization for evaluation or management of an infection within the last 8 weeks

  • Known organ dysfunction

    • Uncontrolled cardiovascular disease, including arrhythmias, congestive heart failure
    • Oxygen requirement

  • Addition of any new systemic immunosuppressive treatment within the last 2 weeks

    * Addition of new systemic immunosuppressive treatment along with glasdegib is also prohibited

  • Corrected QT (QTc) interval > 480 ms
  • Female patients who are lactating or have a positive serum pregnancy test

  • Major surgery within 14 days before enrollment

    * Does not include placement of venous access device, bone marrow biopsy, GVHD diagnostic biopsy, or other routine procedures in chronic GVHD or post-transplantation care

  • Use of any concomitant medications meds that are prohibited within the past 7 days
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
  • Known intolerance to glasdegib, sonidegib, or vismodegib

  • Non-hematologic malignancy within the past 2 years with the exception of:

    • Adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer
    • Carcinoma in situ of the cervix or breast
    • Prostate cancer of Gleason grade 6 or less with stable prostate-specific antigen levels
    • Cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study
  • Treatment with non-Food and Drug Administration (FDA) approved drug within 21 days of start of this trial
  • Evidence of recurrent or progressive underlying malignant disease
  • Karnofsky performance status < 70%
  • History of non-compliance
  • Life expectancy < 6 months
  • Grade 2 or 3 muscle cramping, or grade 1 muscle cramping that occurs at least weekly

Sites / Locations

  • Duke University Medical Center
  • Huntsman Cancer Institute/University of Utah
  • Fred Hutch/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (glasdegib)

Arm Description

Patients receive glasdegib PO QD on days 1-28. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Incidence of adverse events
Safety assessments will consist of monitoring and recording adverse events.

Secondary Outcome Measures

Overall response rate (ORR) in sclerotic manifestations
ORR will be calculated according to (1) the response definitions of the National Institute of Health (NIH) Consensus Conference for (a) skin or joint scores (0-3), where improvement by at least 1 point is a PR and return to score 0 is a complete (CR), or (b) the photographic range of motion scale (0-25) where improvement by at least 1 point is a partial response (PR) and return to score 25 is a CR; and (2) change in the 0-10 sclerotic severity scale where at least a 2 point improvement is a PR or return to 0 (CR).
ORR in all chronic graft versus host disease (cGVHD) manifestations
ORR will be calculated according to the response definitions of the NIH Consensus Conference. ORR both including and excluding skin sclerotic features will be reported.
Failure-free survival
Will be estimated with events considered death, relapse, or start of another systemic immunosuppressive agent. Patients lost to follow-up or who withdraw consent will be censored.
Symptom Burden Assessment
Subjects will provide assessments of their symptom burden using a validated instrument recommended by the NIH Consensus on Chronic GVHD (Lee Chronic GVHD Symptom Scale). These will be collected before starting glasdegib on day 1 of cycle 1, and again on day (D)1, cycles 4, 7, 10 and end of treatment. Summary scores will be calculated based on published algorithms with absolute changes from baseline and clinically meaningful changes described for the population as a whole and based on CR+PR versus (vs.) stable disease (SD)+mixed response (MR)+progressive disease (PD), when adequate data are available for analysis.
Quality of Life Assessment
Subjects will provide assessments of their quality of life using the NIH-endorsed Patient Reported Outcomes Measurement Information System (PROMIS)-29. These will be collected before starting glasdegib on day 1 of cycle 1, and again on day (D)1, cycles 4, 7, 10 and end of treatment. Scores for physical functioning will be calculated based on published algorithms with absolute changes from baseline and clinically meaningful changes described for the population as a whole and based on CR+PR versus (vs.) stable disease (SD)+mixed response (MR)+progressive disease (PD), when adequate data are available for analysis.
Biologic impact of hedgehog pathway inhibition
Aim to discern the biologic impact of Hedgehog pathway inhibition in the treatment of cGVHD and may include the following skin assays as well as others: expression of Shh, Gli1, Gli2, ptch-2, collagen, TGFb, and Smo. Immunohistochemistry may be performed for Patched, Shh, Snail, GSK3-beta, beta-catenin, or Ihh as well as other markers.

Full Information

First Posted
September 26, 2019
Last Updated
September 11, 2023
Sponsor
Fred Hutchinson Cancer Center
Collaborators
Pfizer
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1. Study Identification

Unique Protocol Identification Number
NCT04111497
Brief Title
Glasdegib for Chronic Graft-Versus-Host Disease
Official Title
A Single-Arm, Open-Label, Phase I/II Study of Glasdegib for Sclerotic Chronic Graft-Vs-Host Disease
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Terminated
Why Stopped
Study closed to accrual early due to side effects of study drug.
Study Start Date
December 3, 2019 (Actual)
Primary Completion Date
August 23, 2023 (Actual)
Study Completion Date
August 23, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
Pfizer

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I/II trial studies whether glasdegib is helpful in treating sclerosis associated with chronic graft-versus-host disease. It will also investigate the safety of glasdegib in treating patients with chronic graft-versus-host disease.
Detailed Description
OUTLINE: This is a phase I/II study. Patients receive glasdegib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Graft Versus Host Disease, Fasciitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (glasdegib)
Arm Type
Experimental
Arm Description
Patients receive glasdegib PO QD on days 1-28. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Glasdegib
Other Intervention Name(s)
1095173-27-5, PF 04449913, PF-04449913, PF04449913
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Incidence of adverse events
Description
Safety assessments will consist of monitoring and recording adverse events.
Time Frame
From the start of treatment through 28 days after stopping study drug (Up to 25 months total)
Secondary Outcome Measure Information:
Title
Overall response rate (ORR) in sclerotic manifestations
Description
ORR will be calculated according to (1) the response definitions of the National Institute of Health (NIH) Consensus Conference for (a) skin or joint scores (0-3), where improvement by at least 1 point is a PR and return to score 0 is a complete (CR), or (b) the photographic range of motion scale (0-25) where improvement by at least 1 point is a partial response (PR) and return to score 25 is a CR; and (2) change in the 0-10 sclerotic severity scale where at least a 2 point improvement is a PR or return to 0 (CR).
Time Frame
Up to 12 months after the starting glasdegib
Title
ORR in all chronic graft versus host disease (cGVHD) manifestations
Description
ORR will be calculated according to the response definitions of the NIH Consensus Conference. ORR both including and excluding skin sclerotic features will be reported.
Time Frame
Up to 12 months after the starting glasdegib
Title
Failure-free survival
Description
Will be estimated with events considered death, relapse, or start of another systemic immunosuppressive agent. Patients lost to follow-up or who withdraw consent will be censored.
Time Frame
At 12 months
Title
Symptom Burden Assessment
Description
Subjects will provide assessments of their symptom burden using a validated instrument recommended by the NIH Consensus on Chronic GVHD (Lee Chronic GVHD Symptom Scale). These will be collected before starting glasdegib on day 1 of cycle 1, and again on day (D)1, cycles 4, 7, 10 and end of treatment. Summary scores will be calculated based on published algorithms with absolute changes from baseline and clinically meaningful changes described for the population as a whole and based on CR+PR versus (vs.) stable disease (SD)+mixed response (MR)+progressive disease (PD), when adequate data are available for analysis.
Time Frame
At 12 months
Title
Quality of Life Assessment
Description
Subjects will provide assessments of their quality of life using the NIH-endorsed Patient Reported Outcomes Measurement Information System (PROMIS)-29. These will be collected before starting glasdegib on day 1 of cycle 1, and again on day (D)1, cycles 4, 7, 10 and end of treatment. Scores for physical functioning will be calculated based on published algorithms with absolute changes from baseline and clinically meaningful changes described for the population as a whole and based on CR+PR versus (vs.) stable disease (SD)+mixed response (MR)+progressive disease (PD), when adequate data are available for analysis.
Time Frame
At 12 months
Title
Biologic impact of hedgehog pathway inhibition
Description
Aim to discern the biologic impact of Hedgehog pathway inhibition in the treatment of cGVHD and may include the following skin assays as well as others: expression of Shh, Gli1, Gli2, ptch-2, collagen, TGFb, and Smo. Immunohistochemistry may be performed for Patched, Shh, Snail, GSK3-beta, beta-catenin, or Ihh as well as other markers.
Time Frame
Up to 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosed with moderate or severe cGVHD according to the 2014 National Institute of Health (NIH) Consensus Criteria Diagnosed with cGVHD-related sclerosis or fasciitis Skin feature score of at least 2 OR Joints and fascia score of at least 1 New, stable or progressive sclerosis/fasciitis despite treatment with at least one prior line of systemic therapy for cGVHD Female patients who: Are documented to be postmenopausal or are surgically sterile, OR If of childbearing potential, agree to use at least 1 highly effective method of contraception from the time of signing the informed consent form through 30 days after the last dose of study drug, OR agree to practice true abstinence or exclusively non-heterosexual activity when this is in line with the preferred and usual lifestyle of the subject Male patients who: Are surgically sterile (vasectomized) OR Agree to use at least 1 highly effective method of contraception during the entire study treatment period and through 30 days after the last dose of study drug, OR agree to practice true abstinence or exclusively non-heterosexual activity when this is in line with the preferred and usual lifestyle of the subject, AND Agree to use a condom to prevent potential transmission of investigational drug in seminal fluid Absolute neutrophil count (ANC) > 1000/uL Platelet count > 50 x 10^9/mL Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2 x upper limit of normal (ULN) unless attributed to cGVHD Normal total bilirubin unless attributed to cGVHD Creatinine < 2.0 mg/dl Exclusion Criteria: Hospitalization for evaluation or management of an infection within the last 8 weeks Known organ dysfunction Uncontrolled cardiovascular disease, including arrhythmias, congestive heart failure Oxygen requirement Addition of any new systemic immunosuppressive treatment within the last 2 weeks * Addition of new systemic immunosuppressive treatment along with glasdegib is also prohibited Corrected QT (QTc) interval > 480 ms Female patients who are lactating or have a positive serum pregnancy test Major surgery within 14 days before enrollment * Does not include placement of venous access device, bone marrow biopsy, GVHD diagnostic biopsy, or other routine procedures in chronic GVHD or post-transplantation care Use of any concomitant medications meds that are prohibited within the past 7 days Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol Known intolerance to glasdegib, sonidegib, or vismodegib Non-hematologic malignancy within the past 2 years with the exception of: Adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer Carcinoma in situ of the cervix or breast Prostate cancer of Gleason grade 6 or less with stable prostate-specific antigen levels Cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study Treatment with non-Food and Drug Administration (FDA) approved drug within 21 days of start of this trial Evidence of recurrent or progressive underlying malignant disease Karnofsky performance status < 70% History of non-compliance Life expectancy < 6 months Grade 2 or 3 muscle cramping, or grade 1 muscle cramping that occurs at least weekly
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephanie Lee
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Huntsman Cancer Institute/University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Facility Name
Fred Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Glasdegib for Chronic Graft-Versus-Host Disease

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