A Study to Evaluate the Safety, Tolerability, and Activity of KD025 in Subjects With Chronic Graft Versus Host Disease

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

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).

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.

Inclusion Criteria:

• 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 (>) 40.

• 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.

Exclusion Criteria:

• 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.