Addition of Cord Blood Tissue-Derived Mesenchymal Stromal Cells to Ruxolitinib for the Treatment of Steroid-Refractory Acute Graft Versus Host Disease

• ClinicalTrials.gov Identifier: NCT04744116
• Recruitment Status: Recruiting
• First Posted: February 8, 2021
• Last Update Posted: February 15, 2023
• Sponsor: M.D. Anderson Cancer Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): M.D. Anderson Cancer Center

Study Description

Brief Summary:

This early phase I trial is to find out the effect of adding cord blood tissue-derived mesenchymal stromal cells (cb-MSCs) to ruxolitinib in treating patients with acute graft versus host disease that does not respond to steroid therapy (steroid-refractory). Ruxolitinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. cb-MSCs are a type of tissue helper cell that can be removed from donated umbilical cord blood tissue and grown into many different cell types that can be used to treat cancer and other disease, such as graft versus host disease. This trial aims to learn if adding cb-MSCs to ruxolitinib may help control steroid-refractory acute graft versus host disease.

Condition or disease	Intervention/treatment	Phase
Hematopoietic and Lymphoid Cell Neoplasm; Steroid Refractory Graft Versus Host Disease	Other: Cellular Therapy; Drug: Ruxolitinib	Early Phase 1

Detailed Description:

PRIMARY OBJECTIVE:

I. To estimate between-arm differences (Arm 3 versus [vs] Arm 1, and Arm 2 vs Arm 1) for each of the 28-day co-primary outcome probabilities.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM 1: Patients receive ruxolitinib orally (PO) twice daily (BID) for at least 3 days and may consider tapering after 6 months of therapy if response occurs and therapeutic corticosteroid doses have been discontinued.

ARM 2: Patients receive ruxolitinib PO BID as in Arm 1. Patients also receive lower dose of cb-MSCs intravenously (IV) for up to 60 minutes twice weekly (at least 3 days apart) over 4 consecutive weeks for 8 total doses.

ARM 3: Patients receive ruxolitinib PO BID as in Arm 1. Patients also receive higher dose of cb-MSCs IV for up to 60 minutes twice weekly (at least 3 days apart) over 4 consecutive weeks for 8 total doses.

After completion of study treatment, patients are followed up on day 28 and then for up to 6 months.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Controlled Pilot Study of Two Doses of Cord Blood Tissue-Derived Mesenchymal Stromal Cells Combined With Ruxolitinib Versus Ruxolitinib Alone for Therapy of Steroid-Refractory Acute Graft Versus Host Disease
• Actual Study Start Date: February 17, 2021
• Estimated Primary Completion Date: March 15, 2024
• Estimated Study Completion Date: March 15, 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Arm 1 (ruxolitinib); Patients receive ruxolitinib PO BID for at least 3 days and may consider tapering after 6 months of therapy if response occurs and therapeutic corticosteroid doses have been discontinued.	Drug: Ruxolitinib; Given PO; Other Names: INCB-18424; INCB18424; Jakafi; Oral JAK Inhibitor INCB18424
Experimental: Arm 2 (ruxolitinib, lower dose ds-MSCs); Patients receive ruxolitinib PO BID as in Arm 1. Patients also receive lower dose of cb-MSCs IV for up to 60 minutes twice weekly (at least 3 days apart) over 4 consecutive weeks for 8 total doses.	Other: Cellular Therapy; Given ds-MSCs IV; Other Name: Cell Therapy; Drug: Ruxolitinib; Given PO; Other Names: INCB-18424; INCB18424; Jakafi; Oral JAK Inhibitor INCB18424
Experimental: Arm 3 (ruxolitinib, higher dose ds-MSCs); Patients receive ruxolitinib PO BID as in Arm 1. Patients also receive higher dose of cb-MSCs IV for up to 60 minutes twice weekly (at least 3 days apart) over 4 consecutive weeks for 8 total doses.	Other: Cellular Therapy; Given ds-MSCs IV; Other Name: Cell Therapy; Drug: Ruxolitinib; Given PO; Other Names: INCB-18424; INCB18424; Jakafi; Oral JAK Inhibitor INCB18424

Outcome Measures

Primary Outcome Measures :

1. Death from any cause [ Time Frame: Within 28 days from the start of active study treatment ]
2. Response [ Time Frame: At day 28 from start of therapy on study ]
   Will compare the patient's 28-day graft versus host disease (GVHD) status to the patient's baseline GVHD status when steroid refractory acute GVHD was diagnosed.
3. Incidence of adverse events [ Time Frame: Within 28 days from the start of active study treatment ]

Secondary Outcome Measures :

1. Graft versus host disease status [ Time Frame: At days 7, 14, 21 and 28 post treatment ]
   Will assess complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD), and progressive disease (PD).
2. Proportion of response [ Time Frame: At days 7, 14, 21 and 28 post treatment ]
   Will assess proportion of patients with CR, PR, VGPR, and no-response (NR). The event NR is defined as stable disease, mixed response, disease progression, OR initiation of additional systemic (second-line) GVHD therapies.
3. Time to complete response [ Time Frame: Up to 6 months ]
   Will be estimated by the method of Kaplan and Meier.
4. Time to very good partial response [ Time Frame: Up to 6 months ]
   Will be estimated by the method of Kaplan and Meier.
5. Time to partial response [ Time Frame: Up to 6 months ]
   Will be estimated by the method of Kaplan and Meier.
6. Incidence of complete response for each organ [ Time Frame: Up to 6 months ]
7. Incidence of very good partial response for each organ [ Time Frame: Up to 6 months ]
8. Incidence of partial response for each organ [ Time Frame: Up to 6 months ]
9. Durability of organ response [ Time Frame: Up to 6 months ]
10. Cumulative incidence of non-relapse mortality (NRM) [ Time Frame: At 6 months post treatment ]
11. Cumulative incidence of relapse/progression of the primary disease [ Time Frame: At 6 months ]
12. Overall survival [ Time Frame: From enrollment to death from any cause, assessed at 6 months ]
13. Disease-free survival [ Time Frame: From enrollment to death from any cause or relapse/progression of the primary disease, assessed at 6 months ]
14. Graft versus host disease-free survival [ Time Frame: At 6 months ]
    Patients alive, free of active acute or chronic GVHD, and without other systemic agents (or escalation of steroids to >= 2.5 mg/kg/day of prednisone [or methylprednisolone equivalent of 2 mg/kg/day]) added for treatment of GVHD will be considered successes for this endpoint
15. Incidence of chronic graft versus host disease [ Time Frame: At 6 months after first mesenchymal stromal cells (MSC) infusion ]
    Chronic GVHD is defined per National Institutes of Health Consensus Criteria. Diagnosis of chronic GVHD of any severity (mild, moderate, or severe) is considered an event for this endpoint. Organ involvement and maximum severity will also be described at six months.
16. Incidence of systemic infections [ Time Frame: 28 days after last study drug ]
    The incidence of grade 2 to 3 systemic infections occurring from study treatment until 28 days after last study drug will be described using standard Common Terminology Criteria for Adverse Events (CTCAE) criteria. Infections will be recorded by site of disease, date of onset, and severity.
17. Incidence of toxicities [ Time Frame: Up to 28 days after completing last MSC infusion study drug ]
    The incidence of grade 3-5 treatment-emergent adverse events (per CTCAE version 5.0) that occur through 28 days after completing last MSC infusion study drug will be described.
18. Incidence of any grade cytokine release [ Time Frame: Up to 28 days after completing last MSC infusion study drug ]
19. Incidence of any infusional toxicity [ Time Frame: Within 24 hours of each cord blood-MSC infusion ]

Other Outcome Measures:

1. Cytokine biomarker analysis (optional) [ Time Frame: Up to 6 months ]
   Will use cytokine biomarker assays to predict response to therapy.
2. Fecal samples analysis (optional) [ Time Frame: Up to 6 months ]
   Will use fecal samples to assess microbiome and potential predictor for response to therapy.

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 80 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patients between the ages of 12 years and 80 years (inclusive).
2. Steroid refractory grades II-IV acute GVHD of the Lower GI tract or Liver (including those developing these manifestations after previous acute GVHD of skin) secondary to allogeneic HCT or donor lymphocyte infusion. (Grading, see Appendix I) GVHD with: No improvement after treatment with methylprednisolone at ≥ 2.0 mg/kg/day or equivalent for minimum 7 days, or progressive symptoms after minimum 3 days, or a flare in acute GVHD while on systemic steroids. Patients must have had a biopsy that suggests GVHD; a repeat biopsy to enroll on the study is not necessary.
3. Estimated creatinine clearance ≥ 30 mL/min
4. Karnofsky/Lansky Performance score of at least 30 at the time of study entry.
5. Patients who are women of childbearing potential, must be non-pregnant, not breast-feeding, and use adequate contraception. Male patients must use adequate contraception
6. Patient (or legal representative where appropriate) must be capable of providing written informed consent, and assent if indicated.

Exclusion Criteria:

1. De novo chronic GVHD
2. Isolated acute GVHD of skin
3. Secondary systemic therapy for acute GVHD ruxolitinib greater than 96 hours before initiation of therapy.
4. Primary treatment with agents other than alpha-1 antitrypsin (AAT) glucocorticoids and ruxolitinib.
5. Patients with uncontrolled infections will be excluded. Infections are considered controlled if appropriate therapy has been instituted and, at the time of enrollment, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
6. Patient with significant supplemental oxygen requirement defined as >6 L oxygen by nasal cannula.
7. Patient with known allergy to bovine or porcine products.

Contacts and Locations

Contacts

Contact: Partow Kebriaei, MD; 713-745-0663; pkebriae@mdanderson.org

Locations

United States, Texas

M D Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Partow Kebriaei, MD 713-745-0663 pkebriae@mdanderson.org

Principal Investigator: Partow Kebriaei, MD

Sponsors and Collaborators

M.D. Anderson Cancer Center

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Partow Kebriaei, MD; M.D. Anderson Cancer Center

More Information

Additional Information:

M D Anderson Cancer Center 

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT04744116
• Other Study ID Numbers: 2019-1122; NCI-2020-13889 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2019-1122 ( Other Identifier: M D Anderson Cancer Center ); P01CA148600 ( U.S. NIH Grant/Contract )
• First Posted: February 8, 2021
• Last Update Posted: February 15, 2023
• Last Verified: February 2023

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

Additional relevant MeSH terms:

Graft vs Host Disease; Immune System Diseases; Janus Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action