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

• ClinicalTrials.gov Identifier: NCT02841995
• Recruitment Status: Completed
• First Posted: July 22, 2016
• Last Update Posted: March 22, 2023
• Sponsor: Kadmon, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Kadmon, a Sanofi Company )

Study Description

Brief Summary:

This study is being conducted to evaluate the safety, tolerability, and activity of belumosudil (formerly known as KD025) in adult subjects with chronic Graft versus Host Disease (cGVHD).

Condition or disease	Intervention/treatment	Phase
Graft vs Host Disease	Drug: Belumosudil (KD025)	Phase 2

Detailed Description:

Approximately 48 subjects will be enrolled to receive orally administered belumosudil 200 mg QD (once daily), belumosudil 200 mg BID (twice daily), or belumosudil 400 mg QD. Once a recommended dose is chosen, approximately 40 additional subjects will be enrolled into the study at that dose.

Study drug will be administered in 28-day cycles until disease progression or unacceptable toxicity. Subjects may receive study drug in the inpatient or outpatient setting.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 54 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: September 15, 2016
• Actual Primary Completion Date: May 12, 2022
• Actual Study Completion Date: May 12, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: belumosudil 200 mg QD; Two 100 mg capsules or one 200 mg tablet (200 mg) of belumosudil once daily. Subjects should take 2 capsules or 1 tablet with their morning meal or within 5 minutes of completing a meal.	Drug: Belumosudil (KD025); Pharmaceutical form: Capsules or Tablets Route of administration: Oral; Other Names: SLx-2119; REZUROCK
Experimental: belumosudil 200 mg BID; Two 100 mg capsules or one 200 mg tablet (200 mg) of belumosudil twice daily. Subjects should take 2 capsules or 1 tablet with their morning meal or within 5 minutes of completing a meal and 2 capsules or 1 tablet with their evening meal or within 5 minutes of completing a meal.	Drug: Belumosudil (KD025); Pharmaceutical form: Capsules or Tablets Route of administration: Oral; Other Names: SLx-2119; REZUROCK
Experimental: belumosudil 400 mg QD; Four 100 mg capsules or two 200 mg tablets (400 mg) of belumosudil once daily. Subjects should take 4 capsules or 2 tablets with their morning meal or within 5 minutes of completing a meal.	Drug: Belumosudil (KD025); Pharmaceutical form: Capsules or Tablets Route of administration: Oral; Other Names: SLx-2119; REZUROCK

Outcome Measures

Primary Outcome Measures :

1. Overall response criteria (PR + CR) [ Time Frame: Response assessment is measured at Day 1 of every cycle starting at Cycle 2 (ex: Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day 1, etc.). Cycle length is 28 days. ]
   To evaluate the overall response of belumosudil 200 mg QD, belumosudil 200 mg BID, or belumosudil 400 mg QD in subjects with cGVHD. The overall response will be evaluated through the NIH Consensus Development Project on Clinical Trials in cGVHD.
2. Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability [ Time Frame: From patient consent to 28 days post last belumosudil dose. ]
   To evaluate the safety and tolerability of belumosudil 200 mg QD, belumosudil 200 mg BID, or belumosudil 400 mg QD when administered to subjects with cGVHD

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Adult male and female subjects at least 18 years of age who have had allogenic bone marrow transplant (BMT) or hematopoietic stem cell transplantation (HSCT).
• Receiving glucocorticoid therapy and calcineurin therapy or glucocorticoid therapy alone for cGVHD at study entry. Subjects on calcineurin therapy only, without glucocorticoid therapy, are not eligible. Subjects also receiving other therapies thought not to be immunosuppressive (such as extracorporeal photopheresis; ECP), will be considered for enrollment in this study on a case-by-case basis.
• Have 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 > 40.

• Adequate organ and bone marrow functions evaluated during the 14 days prior to enrollment as follows:

  • Absolute neutrophil count ≥ 1.5 × 109/L (without myeloid growth factors within 1 week of study entry)
  • Platelet count ≥ 50 × 109/L (without transfusion or thrombopoietin or thrombopoietin analogues within 2 weeks of study entry)

• Adequate safety laboratory values:

  • Total bilirubin ≤ 1.5 × upper limit of normal (ULN)
  • ALT and AST ≤ 3 × ULN
  • Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 using the MDRD-4 variable formula
• Female subjects of childbearing potential have a negative pregnancy test at screening. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti estrogens, or ovarian suppression.
• Women of childbearing potential (i.e., menstruating women) must have a negative urine pregnancy test (positive urine tests are 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:

  • IUD 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 patients who are sexually active and who are 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 subject who is pregnant or breastfeeding.
• Receiving an investigational GVHD treatment within 28 days of study entry.
• Has acute GVHD.
• Taking any medication known to be a moderate or strong inhibitor of the 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 subject, 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 g 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.
• Has had previous exposure to belumosudil or known allergy/sensitivity to belumosudil or any other ROCK-2 inhibitor.
• Taking other immunosuppressant drugs for GVHD, including mTor inhibitors (Note: Only steroids, calcineurin inhibitors, and ECP are acceptable).
• QTcF > 450 msec.1) Female subject who is pregnant or breastfeeding.

Contacts and Locations

Locations

United States, California

City of Hope National Medical Center

Duarte, California, United States, 91010

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

United States, Ohio

Oncology Hematology Care

Cincinnati, Ohio, United States, 45242

United States, Tennessee

Sarah Cannon Research Institute at Tennessee Oncology

Nashville, Tennessee, United States, 37203

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

United States, Texas

Texas Transplant Institute

San Antonio, Texas, United States, 78229

United States, Washington

Fred Hutchinson Cancer Center

Seattle, Washington, United States, 98109

Sponsors and Collaborators

Kadmon, a Sanofi Company

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lee SJ, Cutler C, Blazar BR, Tu A, Yang Z, Pavletic SZ. Correlation of Patient-Reported Outcomes with Clinical Organ Responses: Data from the Belumosudil Chronic Graft-versus-Host Disease Studies. Transplant Cell Ther. 2022 Oct;28(10):700.e1-700.e6. doi: 10.1016/j.jtct.2022.06.020. Epub 2022 Jul 1.

Jagasia M, Lazaryan A, Bachier CR, Salhotra A, Weisdorf DJ, Zoghi B, Essell J, Green L, Schueller O, Patel J, Zanin-Zhorov A, Weiss JM, Yang Z, Eiznhamer D, Aggarwal SK, Blazar BR, Lee SJ. ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease. J Clin Oncol. 2021 Jun 10;39(17):1888-1898. doi: 10.1200/JCO.20.02754. Epub 2021 Apr 20.

• Responsible Party: Kadmon, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT02841995
• Other Study ID Numbers: ACT17631; KD025-208 ( Other Identifier: Kadmon )
• First Posted: July 22, 2016
• Last Update Posted: March 22, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sanofi ( Kadmon, a Sanofi Company ):

cGVHD; Allogeneic hematopoietic stem cell transplantation; Immune System Diseases; Steroid refractory chronic graft vs host disease (cGVHD); Bone Marrow Transplantation; Anti-Inflammatory Agents; Glucocorticoids; Corticosteroids

Additional relevant MeSH terms:

Bronchiolitis Obliterans Syndrome; Graft vs Host Disease; Immune System Diseases; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Belumosudil; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action