Glasdegib for Chronic Graft-Versus-Host Disease

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.

• Chronic Graft Versus Host Disease
• Fasciitis

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
• 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

• National Cancer Institute (NCI)
• Pfizer