Glasdegib for Chronic Graft-Versus-Host Disease

Phase 1

Terminated

Conditions: Chronic Graft Versus Host Disease
Fasciitis

Interventions: Drug: Glasdegib

Registration Number: NCT04111497

Lead Sponsor: 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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 15

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (glasdegib)	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR) in Sclerotic Manifestations	Up to 12 months after 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 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.
ORR in All Chronic Graft Versus Host Disease (cGVHD) Manifestations	Up to 12 months after the starting glasdegib	ORR will be calculated according to the response definitions of the NIH Consensus Conference.
Failure-free Survival	At 12 months	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.
Symptom Burden Assessment - Absolute Change	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.]	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
Quality of Life Assessment	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.]	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.
Biologic Impact of Hedgehog Pathway Inhibition	Up to 12 months	Banking of blood and skin biopsy material for future biologic studies of hedgehog pathway inhibition.
Symptom Burden Assessment - Clinically Meaningful Change	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.]	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
Quality of Life Assessment - Clinically Meaningful Change	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.]	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.

Trial Locations

Locations (3): Fred Hutch/University of Washington Cancer Consortium
🇺🇸
Seattle, Washington, United States
Huntsman Cancer Institute/University of Utah
🇺🇸
Salt Lake City, Utah, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States