Glasdegib for Chronic Graft-Versus-Host Disease

A Single-Arm, Open-Label, Phase I/II Study of Glasdegib for Sclerotic Chronic Graft-Vs-Host Disease

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.

Study Overview

• Status: Terminated
• Conditions: Chronic Graft Versus Host Disease; Fasciitis
• Intervention / Treatment: Drug: Glasdegib

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute/University of Utah
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

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

Description

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

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 (glasdegib); 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.	Drug: Glasdegib; Given PO; Other Names: PF-04449913; PF 04449913; PF04449913; 1095173-27-5

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced an Adverse Event	Safety assessments will consist of monitoring and recording adverse events.	From the start of treatment through 28 days after stopping study drug (Up to 25 months total)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 partial response (PR) and return to score 0 is a complete response (CR), or (b) the photographic range of motion scale (0-25) where improvement by at least 1 point is a 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). Non-responders are those with mixed response (improvement in one regard and worsening in another), unchanged (stable), and progression.	Up to 12 months after starting glasdegib
ORR in All Chronic Graft Versus Host Disease (cGVHD) Manifestations	ORR will be calculated according to the response definitions of the NIH Consensus Conference.	Up to 12 months after the starting glasdegib
Failure-free Survival	Failure-free survival will be estimated using the Kaplan-Meier method (product limit estimator), with death, relapse, or start of another systemic immunosuppressive agent considered as events. Patients lost to follow-up or who withdraw consent will be censored.	At 12 months
Symptom Burden Assessment - Absolute Change	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. Lee Symptom Scale: minimum 0, maximum 100; higher score is worse outcome. Due to lack of adequate data at cycles 7 and 10, only Cycle 4 and End of Treatment are presented	Cycle 4 (day 85) and End of Treatment (up through 24 months) [Due to lack of adequate data at cycles 7 (day 169) and 10 (day 253), they are not presented.]
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 will be calculated based on published algorithms with absolute changes from baseline for the population as a whole and based on CR+PR versus stable disease (SD)+mixed response (MR)+progressive disease (PD), when adequate data are available for analysis. PROMIS-29 theoretical minimums and maximums are as follows: Physical Function: 22.5-57.0 Depression: 41.0-79.4 Anxiety: 40.3-81.6 Sleep Disturbance: 32.0-73.3 Fatigue: 33.7-75.8 Ability to Participate in Social Roles: 27.5-64.2 Pain Interference: 41.6-75.6 Higher score means a better outcome for Physical Function, Sleep Disturbance, and Social Roles. Higher score means a worse outcome for Anxiety, Depression, Fatigue, and Pain Interference.	Cycle 4 (day 85) and End of Treatment (up through 24 months) [Due to lack of adequate data at cycles 7 (day 169) and 10 (day 253) they are not presented.]
Biologic Impact of Hedgehog Pathway Inhibition	Banking of blood and skin biopsy material for future biologic studies of hedgehog pathway inhibition.	Up to 12 months
Symptom Burden Assessment - Clinically Meaningful Change	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. Lee Symptom Scale: minimum 0, maximum 100; higher score is worse outcome. Due to lack of adequate data at cycles 7 and 10, only Cycle 4 and End of Treatment are presented	Cycle 4 (day 85) and End of Treatment (up through 24 months) [Due to lack of adequate data at cycles 7 (day 169) and 10 (day 253), they are not presented.]
Quality of Life Assessment - Clinically Meaningful Change	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 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. PROMIS-29 minimums and maximums as follows: Physical Function: 22.5-57.0 Depression: 41.0-79.4 Anxiety: 40.3-81.6 Sleep Disturbance: 32.0-73.3 Fatigue: 33.7-75.8 Ability to Participate in Social Roles: 27.5-64.2 Pain Interference: 41.6-75.6 Higher score means a better outcome for Physical Function, Sleep, and Social Roles. Higher score means a worse outcome for Anxiety, Depression, Fatigue, and Pain.	Cycle 4 (Day 85) and End of Treatment (up through 24 months) [Due to lack of adequate data at cycles 7 (day 169) and 10 (day 253) they are not presented.]

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: Pfizer
• Investigators: Principal Investigator: Stephanie Lee, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): December 3, 2019
• Primary Completion (Actual): August 23, 2023
• Study Completion (Actual): August 23, 2023

Study Registration Dates

• First Submitted: September 26, 2019
• First Submitted That Met QC Criteria: September 30, 2019
• First Posted (Actual): October 1, 2019

Study Record Updates

• Last Update Posted (Actual): October 29, 2024
• Last Update Submitted That Met QC Criteria: October 25, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organizing Pneumonia; Musculoskeletal Diseases; Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchiolitis Obliterans Syndrome; Graft vs Host Disease; Fasciitis
• Other Study ID Numbers: RG1005365; NCI-2019-03244 (Registry Identifier: NCI / CTRP); 8771 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

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