A Phase 2a, Dose-Escalation, Open-Label Study to Evaluate the Safety, Tolerability, and Activity of KD025 in Subjects With Chronic Graft Versus Host Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 54
- 试验地点
- 7
- 主要终点
- Percentage of Participants With Overall Response (OR)
研究概览
简要总结
This study was been conducted to evaluate the safety, tolerability, and activity of belumosudil (formerly known as KD025) in adult participants with chronic graft versus host disease (cGVHD).
详细描述
Fifty four (54) participants were enrolled to receive orally administered belumosudil 200 milligrams (mg) once daily (QD), belumosudil 200 mg twice daily (BID), or belumosudil 400 mg QD.
Study drug was administered in 28-day cycles until disease progression or occurrence of unacceptable toxicity. Participants received study drug in the inpatient or outpatient setting.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult male and female participants at least 18 years of age who had allogenic bone marrow transplant (BMT) or hematopoietic stem cell transplantation (HSCT).
- •Received glucocorticoid therapy and calcineurin therapy or glucocorticoid therapy alone for cGVHD at study entry. Participants on calcineurin therapy only, without glucocorticoid therapy, were not eligible. Participants also received other therapies thought not to be immunosuppressive (such as extracorporeal photopheresis; ECP), were considered for enrollment in this study on a case-by-case basis.
- •Had persistent active cGVHD manifestations, as defined by 2014 NIH Consensus Development Project on Criteria for Clinical trials in cGVHD, after at least 2 months of steroid therapy.
- •No more than 3 prior lines of treatment for cGVHD.
- •Karnofsky Performance Scale of greater than (>)
- •Adequate organ and bone marrow functions evaluated during the 14 days prior to enrollment as follows:
- •Absolute neutrophil count greater than or equal to (>=) 1.5*10^9/L (without myeloid growth factors within 1 week of study entry)
- •Platelet count >=50*10^9/L (without transfusion or thrombopoietin or thrombopoietin analogues within 2 weeks of study entry)
- •Adequate safety laboratory values:
- •Total bilirubin less than or equal to (<=) 1.5*upper limit of normal (ULN)
- •Alanine aminotransferase and aspartate aminotransferase <=3*ULN
- •Glomerular filtration rate (GFR) >= 30 milliliter per minute per 1.73 square meter (mL/min/1.73 m^2) using the 4-Variable Modification of Diet in Renal Disease variable formula
- •Female participants of childbearing potential have a negative pregnancy test at screening. Females of childbearing potential were defined as sexually mature women without prior hysterectomy or who had any evidence of menses in the past 12 months. However, women who had been amenorrheic for 12 or more months were still considered to be of childbearing potential if the amenorrhea was possibly due to prior chemotherapy, anti estrogens, or ovarian suppression.
- •Women of childbearing potential (i.e., menstruating women) must had a negative urine pregnancy test (positive urine tests were to be confirmed by serum test) documented within the 24-hour period prior to the first dose of study drug.
- •Sexually active women of childbearing potential enrolled in the study must agree to use two forms of accepted methods of contraception during the course of the study and for 3 months after their last dose of study drug. Effective birth control includes:
- •Intrauterine device plus one barrier method;
- •Stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method;
- •2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm); or
- •A vasectomized partner
- •For male participants who were sexually active and who were partners of premenopausal women: agreement to use two forms of contraception as in criterion 10 above during the treatment period and for at least 3 months after the last dose of study drug.
- •Able to provide written informed consent prior to the performance of any study-specific procedures.
排除标准
- •Female participant who was pregnant or breastfeeding.
- •Received an investigational GVHD treatment within 28 days of study entry.
- •Had acute GVHD.
- •Taken any medication known to be a moderate or strong inhibitor of the cytochrome (CY) CYP3A4 isozyme or any drugs that are moderate or strong CYP3A4 inducers.
- •History or other evidence of severe illness or any other conditions that would make the participant, in the opinion of the investigator, unsuitable for the study (such as poorly controlled psychiatric disease or coronary artery disease).
- •Regular and excessive use of alcohol within the 6 months prior to study entry defined as alcohol intake >14 drinks per week in a man or >7 drinks per week in a woman. Approximately 10 grams of alcohol equals one "drink" unit. One unit equals 1 ounce of distilled spirits, one 12-ounce beer, or one 4-ounce glass of wine.
- •Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV).
- •Diagnosed with another malignancy (other than malignancy for which transplant was performed) within 3 years of enrollment, with the exception of completely resected basal cell or squamous cell carcinoma of the skin, resected in situ cervical malignancy, resected breast ductal carcinoma in situ, or low-risk prostate cancer after curative resection.
- •Relapse of the underlying cancer or post-transplant lymphoproliferative disease at the time of screening.
- •Had previous exposure to belumosudil or known allergy/sensitivity to belumosudil or any other Rho-associated protein kinase-2 inhibitor.
- •Taken other immunosuppressant drugs for GVHD, including mammalian target of rapamycin inhibitors (Note: Only steroids, calcineurin inhibitors, and ECP are acceptable).
- •Corrected QT interval using Fridericia's formula >450 milliseconds.
- •Female participant who was pregnant or breastfeeding.
研究组 & 干预措施
Cohort 1: Belumosudil 200 mg QD
Participants received belumosudil 200 mg orally QD in each 28-day treatment cycle until disease progression, unacceptable toxicity, or death whichever occurred first (maximum duration: 64.2 months).
干预措施: Belumosudil (KD025) (Drug)
Cohort 2: Belumosudil 200 mg BID
Participants received belumosudil 200 mg orally BID in each 28-day treatment cycle until disease progression, unacceptable toxicity, or death whichever occurred first (maximum duration: 45.9 months).
干预措施: Belumosudil (KD025) (Drug)
Cohort 3: Belumosudil 400 mg QD
Participants received belumosudil 400 mg orally QD in each 28-day treatment cycle until disease progression, unacceptable toxicity, or death whichever occurred first (maximum duration: 49.2 months).
干预措施: Belumosudil (KD025) (Drug)
结局指标
主要结局
Percentage of Participants With Overall Response (OR)
时间窗: From the date of randomization to the date of first documentation of progression or death due to any cause or data cut-off, whichever occurred first (maximum duration: up to 64.2 months)
OR was defined as the percentage of participants with complete response (CR) or partial response (PR). The OR determination of chronic graft versus host disease (cGVHD) was based on cGVHD response assessment performed by clinicians as per the 2014 National Institutes of Health (NIH) Consensus Development Project for Clinical Trials in cGVHD criteria. CR was defined as the resolution of all manifestations in each organ or site. PR was defined as the improvement in at least 1 organ or site without progression in any other organ or site; and cGVHD progression was defined as the clinically meaningful worsening in 1 or more organs regardless of improvement in other organs.
Number of Participants With Treatment-emergent Adverse Events (TEAEs), and Treatment-emergent Serious Adverse Events (TESAEs)
时间窗: From first dose of study drug up to 28 days after the last dose of study drug (maximum duration: up to 64.2 months)
An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. Serious adverse events (SAEs) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (defined as the time from the first dose of study drug up to 28 days after the last dose of study drug). TEAEs included both SAEs and non-SAEs.
次要结局
- Number of Participants With Best Overall Response (BOR)(From the date of randomization to the date of first documentation of progression or death due to any cause or data cut-off, whichever occurred first (maximum duration: up to 64.2 months))
- Number of Participants With Maximal Improvement From Baseline in Global Severity Rating (GSR) by Clinician-reported cGVHD Assessment(From Baseline up to end of treatment (i.e., up to 64.2 months))
- Number of Participants With Maximal Improvement From Baseline in Symptom Activity by cGVHD Activity Assessment Participant Self-Report(From Baseline up to end of treatment (i.e., up to 64.2 months))
- Time-to-Response (TTR)(From first dose of study drug treatment to the time of first documentation of response or data cut-off, whichever occurred first (maximum duration: up to 64.2 months))
- Failure-free Survival (FFS)(From first dose of study drug to either start of another new systemic treatment for cGVHD, relapse of the underlying disease or death or data cut-off, whichever occurred first (maximum duration: up to 64.2 months))
- Overall Survival (OS)(From first dose of study drug to date of death from any cause or data cut-off, whichever occurred first (maximum duration: up to 64.2 months))
- Change From Baseline in Overall Score on Lee cGvHD Symptom Scale at Specified Time Points(Baseline, Day 1 of Cycles 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26, 27,28,29,30,31,32,33,34,35,36,37, 38,39,40,41,42,43,44,45,46,47,48, 49, 50,51,52,53, 54,55, 56, 57,58,59,60,61,62,63,67 and EOT (i.e., anytime up to 64.2 months))
- Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Each Specified Time Points(Baseline, Day 1 of Cycles 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27, 29,30,31,32,33,34,35,36,37,38, 39,40,41,43, 47,48,49,51,52,53, 54, 55,56, 57,58,60,61,62,63,67, EOT (i.e., anytime up to 64.2 months))
- Change From Baseline in Corticosteroids Dose(Baseline up to end of treatment (i.e., anytime up to 64.2 months))
- Number of Participants With Change From Baseline in Calcineurin Inhibitor (CNI) Usage(Baseline up to end of treatment (i.e., anytime up to 64.2 months))
- Percentage of Participants With Best Response in Each Individual Organ(From date of randomization until disease progression or data cut-off, whichever occurred first (maximum duration: up to 64.2 months))
- Time to Next Therapy (TTNT)(From time of first treatment to the time of new systemic cGVHD treatment or long term follow-up assessment, whichever occurred first (maximum duration: up to 64.2 months))
- Duration of Response (DOR)(From the date of first response until documented disease progression or death due to any cause or data cut-off, whichever occurred first (maximum duration: up to 64.2 months))
- Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Each Specified Time Points(Baseline, Day 1 of Cycles 2, 3,4, 5,6,7,8,9,10,11,12,13, 14,15,16,17,18,19,20,21,22,23,24,25,26, 27,29,30,31,32,33,34,35,36,37,38,39,40,41,43,47, 48,49, 51,52,53,54, 55, 56,57,58,60,61, 62, 63,67, EOT (i.e., anytime up to 64.2 months))
- Change From Baseline in Percent Predicted Hemoglobin (HGB) Corrected Diffusing Capacity of Lung for Carbon Monoxide (DLco) at Each Specified Time Points(Baseline, Day 1 of Cycles 2,3,4,5,6,7,8,9,10,11,12,13, 14,15,16,17,18,19,20,21,22,23,24,25,26,27, 29,31,32,33,34,35,36,37,39,40,41,43,47,49,51,53,55, 61, 62, 63, 67, EOT (i.e., anytime up to 64.2 Months))
- Change From Baseline in Percent Predicted Total Lung Capacity (TLC) at Each Specified Time Points(Baseline, Day 1 of Cycles 2,3, 4, 5,6,7, 8, 9, 10,11,12,13, 14, 15, 16, 17, 18, 19, 20,21, 22,23,24, 25, 26, 27,29, 30, 31,32, 33, 34, 35,36, 37, 38,39, 40,41,43,47, 48, 49,51,52,53, 54,55,56,57,58, 60,61,62, 63, 67, EOT (i.e., anytime up to 64.2 Months))
- Change From Baseline in Percent Predicted Residual Volume (RV) at Each Specified Time Points(Baseline, Day 1 of Cycles 2, 3, 4,5, 6,7, 8, 9, 10, 11,12, 13, 14,15, 16,17, 18, 19,20, 21,22,23, 24, 25, 26,27, 29, 30, 31, 32, 33,34, 35,36, 37,38, 39, 40,41, 43,47, 48, 49,51,52,53, 54, 55,56,57, 58,60,61,62,63,67, EOT (i.e., anytime up to 64.2 Months))
- Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Belumosudil and Its Metabolites (KD025m1 and KD025m2)(Cycles 1 and 2: pre-dose (0 hour), 1, 2, 3, 4, 5, and 6 hours post-dose on Day 1)
- Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Belumosudil and Its Metabolites (KD025m1 and KD025m2)(Cycles 1 and 2: pre-dose (0 hour), 1, 2, 3, 4, 5, and 6 hours post-dose on Day 1)
- Pharmacokinetics: The Area Under the Plasma Concentration Versus Time Curve From Time 0 to 6 Hours Post-dose (AUC0-6hr) of Belumosudil and Its Metabolites (KD025m1 and KD025m2)(Cycles 1 and 2: pre-dose (0 hour), 1, 2, 3, 4, 5, and 6 hours post-dose on Day 1)