A Study of Tacrolimus/Methotrexate and Tocilizumab to Prevent Acute Graft-Versus-Host Disease (AGVD) After Allogeneic Hematopoietic Stem Cell Transplant

NCT ID: NCT02206035

Last Updated: 2023-03-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-12-31
• Study Completion Date: 2018-09-30

Brief Summary

This is a phase II open label trial designed to evaluate the efficacy of Tac/MTX/Toc in preventing graft versus host disease (GVHD). Outcomes of patients on this clinical trial will be compared to those of contemporary controls from the CIBMTR.

Detailed Description

This is a Phase II open label trial designed to evaluate the efficacy of Tacrolimus (Tac), Methotrexate (MTX) and Tocilizumab (Toc) (combined Tac/MTX/Toc) in preventing graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation compared to a contemporary control cohort selected from the Center for International Bone Marrow Transplant Research (CIBMTR) that is treated with standard methotrexate and tacrolimus for GVHD prevention. The control group of patients will satisfy similar eligibility requirements as the patients enrolled in the clinical trial and they will be matched for relevant clinical variables (age, sex, conditioning regimen, disease, graft source, etc).

Patients enrolled in the clinical trial will receive tacrolimus per institutional guidelines at doses to maintain therapeutic levels and continued until at least Day 90 post transplant. Methotrexate will be dosed at 15 mg/m^2 Day +1 and 10mg/m^2 Days +3, +6 and +11. Tocilizumab will be administered intravenously at a dose of 8 mg/kg at Day -1.

Ancillary Study:

The ancillary study will evaluate whether tocilizumab is effective at positively impacting mood, fatigue, sleep, and pain in a group of individuals undergoing allogeneic hematopoietic stem cell transplantation as compared to individuals not receiving tocilizumab. We will also assess whether tocilizumab alters gene expression and Rap1 prenylation in a manner that may reduce further progression or relapse of cancer after transplant.

Conditions

Hematopoietic Stem Cell Transplantation

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Tacrolimus, Methotrexate and Tocilizumab (Tac/MTX/Toc)

Patients enrolled in the clinical trial will receive tacrolimus per institutional guidelines at doses to maintain therapeutic levels and continued until at least Day 90 posttransplant. Methotrexate will be dosed at 15 mg/m2 Day +1 and 10mg/m2 Days +3, +6 and +11. Tocilizumab will be administered intravenously at a dose of 8 mg/kg at Day -1

Group Type: EXPERIMENTAL

Tacrolimus

Intervention Type: DRUG

Patients enrolled in the clinical trial will receive tacrolimus per institutional guidelines at doses to maintain therapeutic levels and continued until at least Day 90 posttransplant.

Methotrexate

Intervention Type: DRUG

Methotrexate will be dosed at 15 mg/m2 Day +1 and 10mg/m\^2 Days +3, +6 and +11.

Tocilizumab

Intervention Type: DRUG

Tocilizumab will be administered intravenously at a dose of 8 mg/kg at Day -1.

Interventions

Tacrolimus

Patients enrolled in the clinical trial will receive tacrolimus per institutional guidelines at doses to maintain therapeutic levels and continued until at least Day 90 posttransplant.

Intervention Type: DRUG

Methotrexate

Methotrexate will be dosed at 15 mg/m2 Day +1 and 10mg/m\^2 Days +3, +6 and +11.

Intervention Type: DRUG

Tocilizumab

Tocilizumab will be administered intravenously at a dose of 8 mg/kg at Day -1.

Intervention Type: DRUG

Other Intervention Names

fujimycin; FK506; Trexall; Actemra

Eligibility Criteria

Inclusion Criteria

1. Age ≥18 years

2. Patients with acute leukemia, chronic myelogenous leukemia, myeloproliferative disease and myelodysplasia with less than 5% of blasts in the bone marrow

3. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, Non-Hodgkin Lymphoma or Hodgkin Disease with chemosensitive disease at time of transplant

4. Planned conditioning regimens including combination of busulfan and fludarabine or busulfan and cyclophosphamide

5. Transplantation with T-cell-replete grafts

6. Bone marrow or mobilized peripheral blood cell grafts

7. Patients must have either a sibling donor (6/6 match at human leukocyte antigens (HLA-A, -B and -DRB1) or a unrelated donor (8/8 match at HLA-A, -B, -C and -DRB1)

8. Cardiac function: Ejection fraction at rest >45% for myeloablative conditioning or >40% for reduced intensity conditioning

9. Estimated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault formula and actual body weight)

10. Pulmonary function: Diffusing Capacity of Lung for Carbon Monoxide (DLCO) ≥40% (adjusted for hemoglobin) and FEV1≥50%

11. Liver function: total bilirubin < 1.5 x the upper limit of normal and alanine aminotransferase (ALT) / aspartate aminotransferase (AST) < 2.5x the upper normal limit

12. Signed informed consent

1. Receive Tac/MTX as the sole GVHD prophylaxis approach

2. Receive the same regimens as specified in Table 2.5

3. Year of transplant from 2010 to 2013

Exclusion Criteria

1. Prior allogeneic hematopoietic cell transplant (HCT)

2. Karnofsky Performance Score <70%

3. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression of infectious disease or no clinical improvement) at time of enrollment

4. Prior intolerance or allergy to Tocilizumab

5. Use of rituximab, alemtuzumab, anti-thymocyte globulin (ATG) or other monoclonal antibody at time of conditioning regimen

6. History of diverticulitis, Crohn's disease or ulcerative colitis

7. History of demyelinating disorder

8. Pregnant and lactating women

9. Patients with a history of rheumatologic disorders who have previously received Tocilizumab

Eligibility for the Control Arm

1. Karnofsky Performance Score < 70%

Data for all eligible patients will be used to constitute the control database for this study

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

William R. Drobyski, MD

OTHER

Sponsor Role: lead

Responsible Party

William R. Drobyski, MD

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

William Drobyski, MD

Role: PRINCIPAL_INVESTIGATOR

Medical College of Wisconsin

Marcelo Pasquini, MD

Role: PRINCIPAL_INVESTIGATOR

Medical College of Wisconsin

Jennifer Knight, MD

Role: PRINCIPAL_INVESTIGATOR

Medical College of Wisconsin

Locations

Froedtert Hospital and the Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

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Reference Type: BACKGROUND

PMID: 17845118 (View on PubMed)

D'Souza A, Lee S, Zhu X, Pasquini M. Current Use and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant. 2017 Sep;23(9):1417-1421. doi: 10.1016/j.bbmt.2017.05.035. Epub 2017 Jun 9.

Reference Type: BACKGROUND

PMID: 28606646 (View on PubMed)

Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995 Jun;15(6):825-8.

Reference Type: BACKGROUND

PMID: 7581076 (View on PubMed)

Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, Palmer J, Weisdorf D, Treister NS, Cheng GS, Kerr H, Stratton P, Duarte RF, McDonald GB, Inamoto Y, Vigorito A, Arai S, Datiles MB, Jacobsohn D, Heller T, Kitko CL, Mitchell SA, Martin PJ, Shulman H, Wu RS, Cutler CS, Vogelsang GB, Lee SJ, Pavletic SZ, Flowers ME. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015 Mar;21(3):389-401.e1. doi: 10.1016/j.bbmt.2014.12.001. Epub 2014 Dec 18.

Reference Type: BACKGROUND

PMID: 25529383 (View on PubMed)

Hann DM, Jacobsen PB, Azzarello LM, Martin SC, Curran SL, Fields KK, Greenberg H, Lyman G. Measurement of fatigue in cancer patients: development and validation of the Fatigue Symptom Inventory. Qual Life Res. 1998 May;7(4):301-10. doi: 10.1023/a:1024929829627.

Reference Type: BACKGROUND

PMID: 9610214 (View on PubMed)

Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213. doi: 10.1016/0165-1781(89)90047-4.

Reference Type: BACKGROUND

PMID: 2748771 (View on PubMed)

Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994 Mar;23(2):129-38.

Reference Type: BACKGROUND

PMID: 8080219 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

PRO00023000

Identifier Type: -

Identifier Source: org_study_id