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

Primary Purpose

Hematopoietic and Lymphoid Cell Neoplasm, Steroid Refractory Graft Versus Host Disease

Status

Recruiting

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

Cellular Therapy

Ruxolitinib

About this trial

This is an interventional treatment trial for Hematopoietic and Lymphoid Cell Neoplasm

Eligibility Criteria

12 Years - 80 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients between the ages of 12 years and 80 years (inclusive).
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.
Estimated creatinine clearance ≥ 30 mL/min
Karnofsky/Lansky Performance score of at least 30 at the time of study entry.
Patients who are women of childbearing potential, must be non-pregnant, not breast-feeding, and use adequate contraception. Male patients must use adequate contraception
Patient (or legal representative where appropriate) must be capable of providing written informed consent, and assent if indicated.

Exclusion Criteria:

De novo chronic GVHD
Isolated acute GVHD of skin
Secondary systemic therapy for acute GVHD ruxolitinib greater than 96 hours before initiation of therapy.
Primary treatment with agents other than alpha-1 antitrypsin (AAT) glucocorticoids and ruxolitinib.
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.
Patient with significant supplemental oxygen requirement defined as >6 L oxygen by nasal cannula.
Patient with known allergy to bovine or porcine products.

Sites / Locations

M D Anderson Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Arm Label

Arm 1 (ruxolitinib)

Arm 2 (ruxolitinib, lower dose ds-MSCs)

Arm 3 (ruxolitinib, higher dose ds-MSCs)

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Death from any cause

Response

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.

Incidence of adverse events

Secondary Outcome Measures

Graft versus host disease status

Will assess complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD), and progressive disease (PD).

Proportion of response

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.

Time to complete response

Will be estimated by the method of Kaplan and Meier.

Time to very good partial response

Will be estimated by the method of Kaplan and Meier.

Time to partial response

Will be estimated by the method of Kaplan and Meier.

Incidence of complete response for each organ

Incidence of very good partial response for each organ

Incidence of partial response for each organ

Durability of organ response

Cumulative incidence of non-relapse mortality (NRM)

Cumulative incidence of relapse/progression of the primary disease

Overall survival

Disease-free survival

Graft versus host disease-free survival

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

Incidence of chronic graft versus host disease

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.

Incidence of systemic infections

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.

Incidence of toxicities

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.

Incidence of any grade cytokine release

Incidence of any infusional toxicity

Full Information

NCT ID

NCT04744116

First Posted

February 3, 2021

Last Updated

October 18, 2023

Sponsor

M.D. Anderson Cancer Center

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT04744116

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

February 17, 2021 (Actual)

Primary Completion Date

March 15, 2024 (Anticipated)

Study Completion Date

March 15, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

M.D. Anderson Cancer Center

Collaborators

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hematopoietic and Lymphoid Cell Neoplasm, Steroid Refractory Graft Versus Host Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Early Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm 1 (ruxolitinib)

Arm Type

Active Comparator

Arm Description

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.

Arm Title

Arm 2 (ruxolitinib, lower dose ds-MSCs)

Arm Type

Experimental

Arm Description

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.

Arm Title

Arm 3 (ruxolitinib, higher dose ds-MSCs)

Arm Type

Experimental

Arm Description

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.

Intervention Type

Other

Intervention Name(s)

Cellular Therapy

Other Intervention Name(s)

Cell Therapy

Intervention Description

Given ds-MSCs IV

Intervention Type

Drug

Intervention Name(s)

Ruxolitinib

Other Intervention Name(s)

INCB-18424, INCB18424, Jakafi, Oral JAK Inhibitor INCB18424

Intervention Description

Given PO

Primary Outcome Measure Information:

Title

Death from any cause

Time Frame

Within 28 days from the start of active study treatment

Title

Response

Description

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.

Time Frame

At day 28 from start of therapy on study

Title

Incidence of adverse events

Time Frame

Within 28 days from the start of active study treatment

Secondary Outcome Measure Information:

Title

Graft versus host disease status

Description

Will assess complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD), and progressive disease (PD).

Time Frame

At days 7, 14, 21 and 28 post treatment

Title

Proportion of response

Description

Time Frame

At days 7, 14, 21 and 28 post treatment

Title

Time to complete response

Description

Will be estimated by the method of Kaplan and Meier.

Time Frame

Up to 6 months

Title

Time to very good partial response

Description

Will be estimated by the method of Kaplan and Meier.

Time Frame

Up to 6 months

Title

Time to partial response

Description

Will be estimated by the method of Kaplan and Meier.

Time Frame

Up to 6 months

Title

Incidence of complete response for each organ

Time Frame

Up to 6 months

Title

Incidence of very good partial response for each organ

Time Frame

Up to 6 months

Title

Incidence of partial response for each organ

Time Frame

Up to 6 months

Title

Durability of organ response

Time Frame

Up to 6 months

Title

Cumulative incidence of non-relapse mortality (NRM)

Time Frame

At 6 months post treatment

Title

Cumulative incidence of relapse/progression of the primary disease

Time Frame

At 6 months

Title

Overall survival

Time Frame

From enrollment to death from any cause, assessed at 6 months

Title

Disease-free survival

Time Frame

From enrollment to death from any cause or relapse/progression of the primary disease, assessed at 6 months

Title

Graft versus host disease-free survival

Description

Time Frame

At 6 months

Title

Incidence of chronic graft versus host disease

Description

Time Frame

At 6 months after first mesenchymal stromal cells (MSC) infusion

Title

Incidence of systemic infections

Description

Time Frame

28 days after last study drug

Title

Incidence of toxicities

Description

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.

Time Frame

Up to 28 days after completing last MSC infusion study drug

Title

Incidence of any grade cytokine release

Time Frame

Up to 28 days after completing last MSC infusion study drug

Title

Incidence of any infusional toxicity

Time Frame

Within 24 hours of each cord blood-MSC infusion

Other Pre-specified Outcome Measures:

Title

Cytokine biomarker analysis (optional)

Description

Will use cytokine biomarker assays to predict response to therapy.

Time Frame

Up to 6 months

Title

Fecal samples analysis (optional)

Description

Will use fecal samples to assess microbiome and potential predictor for response to therapy.

Time Frame

Up to 6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

12 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients between the ages of 12 years and 80 years (inclusive). 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. Estimated creatinine clearance ≥ 30 mL/min Karnofsky/Lansky Performance score of at least 30 at the time of study entry. Patients who are women of childbearing potential, must be non-pregnant, not breast-feeding, and use adequate contraception. Male patients must use adequate contraception Patient (or legal representative where appropriate) must be capable of providing written informed consent, and assent if indicated. Exclusion Criteria: De novo chronic GVHD Isolated acute GVHD of skin Secondary systemic therapy for acute GVHD ruxolitinib greater than 96 hours before initiation of therapy. Primary treatment with agents other than alpha-1 antitrypsin (AAT) glucocorticoids and ruxolitinib. 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. Patient with significant supplemental oxygen requirement defined as >6 L oxygen by nasal cannula. Patient with known allergy to bovine or porcine products.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Partow Kebriaei, MD

Phone

713-745-0663

pkebriae@mdanderson.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Partow Kebriaei, MD

Organizational Affiliation

M.D. Anderson Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

M D Anderson Cancer Center

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Partow Kebriaei, MD

Phone

713-745-0663

pkebriae@mdanderson.org

First Name & Middle Initial & Last Name & Degree

Partow Kebriaei, MD

12. IPD Sharing Statement

Links:

URL

http://www.mdanderson.org

Description

M D Anderson Cancer Center

Learn more about this trial

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

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