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Glasdegib for Chronic Graft-Versus-Host Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04111497
Recruitment Status : Active, not recruiting
First Posted : October 1, 2019
Last Update Posted : June 15, 2022
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Fred Hutchinson Cancer Center

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.

Condition or disease Intervention/treatment Phase
Chronic Graft Versus Host Disease Fasciitis Drug: Glasdegib Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single-Arm, Open-Label, Phase I/II Study of Glasdegib for Sclerotic Chronic Graft-Vs-Host Disease
Actual Study Start Date : December 3, 2019
Estimated Primary Completion Date : October 2023
Estimated Study Completion Date : October 2023


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:
  • 1095173-27-5
  • PF 04449913
  • PF-04449913
  • PF04449913




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 12 months ]
    Safety assessments will consist of monitoring and recording adverse events.


Secondary Outcome Measures :
  1. Overall response rate (ORR) in sclerotic manifestations [ Time Frame: Up to 12 months after the starting glasdegib ]
    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).

  2. ORR in all chronic graft versus host disease (cGVHD) manifestations [ Time Frame: Up to 12 months after the starting glasdegib ]
    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.

  3. Failure-free survival [ Time Frame: At 12 months ]
    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.

  4. Symptom Burden Assessment [ Time Frame: At 12 months ]
    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.

  5. Quality of Life Assessment [ Time Frame: At 12 months ]
    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.

  6. Biologic impact of hedgehog pathway inhibition [ Time Frame: Up to 12 months ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04111497


Locations
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United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Utah
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, United States, 84112
United States, Washington
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Center
Pfizer
Investigators
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Principal Investigator: Stephanie Lee Fred Hutch/University of Washington Cancer Consortium
  Study Documents (Full-Text)

Documents provided by Fred Hutchinson Cancer Center:
Informed Consent Form  [PDF] July 9, 2020

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Responsible Party: Fred Hutchinson Cancer Center
ClinicalTrials.gov Identifier: NCT04111497    
Other Study ID Numbers: RG1005365
NCI-2019-03244 ( Registry Identifier: NCI / CTRP )
8771 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
First Posted: October 1, 2019    Key Record Dates
Last Update Posted: June 15, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Fasciitis
Graft vs Host Disease
Immune System Diseases
Musculoskeletal Diseases