Glasdegib for Chronic Graft-Versus-Host Disease

Study Overview
=================
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.

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

Conditions
-----------------
Fasciitis, Chronic Graft Versus Host Disease

Intervention / Treatment
-----------------
* Drug: Glasdegib


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (glasdegib)<br>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<br>* Given PO<br>* Other names: PF04449913;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | 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 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). | Up to 12 months after the 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. ORR both including and excluding skin sclerotic features will be reported. | Up to 12 months after the starting glasdegib | 
| 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. | At 12 months | 
| 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. | At 12 months | 
| 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. | At 12 months | 
| 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. | Up to 12 months |