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PROACTIVE: Preventing Acute/Chronic GVHD With TocIlizumab Combined With GVHD Prophylaxis Post allogEneic Transplant

Primary Purpose

Hematologic Malignancy

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Tacrolimus
Methotrexate
Tocilizumab
Sponsored by
Medical College of Wisconsin
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hematologic Malignancy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age ≥18 years.
  2. Patients with any hematologic malignancy for which alloHCT is indicated. Patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) must be in complete remission at the time of alloHCT(<5% blasts in the bone marrow, normal maturation of all cellular components in the bone marrow and absence of extramedullary disease).
  3. Myeloablative conditioning (MAC) regimen, based on Center for International Blood and Marrow Transplant Research (CIBMTR) criteria.
  4. T cell-replete peripheral blood graft.
  5. Patients must have a matched related or unrelated donor (at least 6/6 match at human leukocyte antigens (HLA) -A, -B and -C for related donors and at least 8/8 match at HLA-A, -B, -C and -DRB1 for unrelated donors).
  6. Cardiac function: Left ventricular ejection fraction ≥45% for myeloablative conditioning.
  7. Estimated creatinine clearance ≥40 mL/minute (using the Cockcroft-Gault formula and actual body weight).
  8. Pulmonary function: Diffusing capacity of the lungs for carbon monoxide (DLCO) ≥40% (adjusted for hemoglobin) and Forced Expiratory Volume (FEV1) ≥50%.
  9. Liver function: total bilirubin <3 x upper limit of normal and alanine aminotransferase (ALT) / aspartate aminotransferase (AST) <5 x upper normal limit.
  10. Signed informed consent: Voluntary written consent must be given before patient registration and performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
  11. Female patient: A negative pregnancy test will be required for women of child bearing potential. Breast-feeding or lactation is not permitted.
  12. Planned posttransplant maintenance therapy is allowed.

Exclusion Criteria:

  1. Prior allogeneic HCT.
  2. Active central nervous system (CNS) involvement with malignancy.
  3. Patients receiving cord blood or haploidentical allograft.
  4. Patients undergoing in vivo or ex vivo T cell-depleted alloHCT.
  5. Karnofsky Performance Score <60%.
  6. Patients with uncontrolled bacterial, viral or fungal infections (currently on treatment and with progression of infectious disease or no clinical improvement) at time of enrollment.
  7. Active hepatitis B or C virus infection or known human immunodeficiency virus (HIV) positive.
  8. Prior intolerance or allergy to tocilizumab.
  9. Use of rituximab, alemtuzumab, anti-thymocyte globulin (ATG) or other monoclonal antibody planned as part of conditioning regimen for GVHD prophylaxis.
  10. History of diverticulitis, Crohn's disease or ulcerative colitis.
  11. History of demyelinating disorder.
  12. Any current uncontrolled cardiovascular conditions, including uncontrolled ventricular arrhythmias, New York Heart Association (NYHA) class III or IV congestive heart failure, uncontrolled angina, or electrocardiographic evidence of active ischemia or active conduction system abnormalities.
  13. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.

Sites / Locations

  • Froedtert Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Tacrolimus/Methotrexate/Tocilizumab

Arm Description

Patients enrolled on the clinical trial will receive tacrolimus initiating at Day -1 at doses to maintain therapeutic levels per institutional preference and continued until at least Day +90 post-transplant. Methotrexate will be administered intravenously and dosed at 15 mg/m2 Day +1 and 10 mg/m2 Days +3, +6 and +11. Tocilizumab will be administered intravenously at a dose of 8 mg/kg on Day -1 and at day +100 (+/- 14 days).

Outcomes

Primary Outcome Measures

The Number of Patients With GVHD/Relapse-free (GRFS) Survival
GRFS is defined as survival without grade III-IV acute graft versus host disease (GVHD), systemic therapy requiring chronic GVHD, relapse, or death at 12 months after matched related/unrelated donor bone marrow or peripheral blood allogeneic hematopoietic cell transplantation (alloHCT) using myeloablative conditioning (MAC). Patients who are alive without GVHD will be censored at the last follow-up.

Secondary Outcome Measures

Full Information

First Posted
October 5, 2018
Last Updated
April 17, 2023
Sponsor
Medical College of Wisconsin
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT03699631
Brief Title
PROACTIVE: Preventing Acute/Chronic GVHD With TocIlizumab Combined With GVHD Prophylaxis Post allogEneic Transplant
Official Title
PROACTIVE: Prevention of Acute and Chronic GVHD Using TocIlizumab in Combination With Standard GVHD Prophylaxis After allogEneic Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Completed
Study Start Date
November 6, 2018 (Actual)
Primary Completion Date
March 2, 2022 (Actual)
Study Completion Date
April 1, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Medical College of Wisconsin
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a phase II open-label trial designed to evaluate the efficacy of tocilizumab in improving GVHD-free/relapse-free survival (GRFS) after allogeneic hematopoietic cell transplantation (alloHCT) for hematologic malignancy.
Detailed Description
The research team earlier hypothesized and demonstrated that tocilizumab could attenuate the incidence of acute GVHD (aGVHD) after myeloablative conditioning (MAC) and reduced intensity conditioning (RIC) Allogeneic hematopoietic cell transplantation (alloHCT), using matched sibling or unrelated donor. In this study, the research team hypothesizes that longer term interleukin 6 (IL-6) inhibition through treatment with tocilizumab by repeated dosing would mediate a beneficial effect not only on the risk of aGVHD, but also on chronic GVHD. This will be achieved by administering an additional dose of tocilizumab at Day +100 post-alloHCT, besides the pretransplant dose, as done in our previous clinical trial, thereby providing total prophylaxis against both acute and chronic GVHD.

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
29 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tacrolimus/Methotrexate/Tocilizumab
Arm Type
Experimental
Arm Description
Patients enrolled on the clinical trial will receive tacrolimus initiating at Day -1 at doses to maintain therapeutic levels per institutional preference and continued until at least Day +90 post-transplant. Methotrexate will be administered intravenously and dosed at 15 mg/m2 Day +1 and 10 mg/m2 Days +3, +6 and +11. Tocilizumab will be administered intravenously at a dose of 8 mg/kg on Day -1 and at day +100 (+/- 14 days).
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
Prograf
Intervention Description
Tacrolimus will be given intravenously at a dose of 0.03 mg/kg/day starting Day -3. Subsequent dosing will be based on blood levels.
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
Trexall
Intervention Description
Methotrexate will be administered at the doses of 15 mg/m2 IV bolus on Day +1, and 10 mg/m2 IV bolus on Days +3, +6 and +11 after hematopoietic cell infusion.
Intervention Type
Drug
Intervention Name(s)
Tocilizumab
Other Intervention Name(s)
Actemra
Intervention Description
Tocilizumab will be administered intravenously (IV) at a dose of 8 mg/kg (maximum dose of 800 mg) once on the Day -1 approximately 24 hours prior to the estimated time of the hematopoietic cell infusion, and subsequently, on Day +100 (+/- 14 days, i.e., Days +86 to +114) post-alloHCT. The infusion will be administered over 60 minutes through a dedicated IV line and must not be administered by IV bolus.
Primary Outcome Measure Information:
Title
The Number of Patients With GVHD/Relapse-free (GRFS) Survival
Description
GRFS is defined as survival without grade III-IV acute graft versus host disease (GVHD), systemic therapy requiring chronic GVHD, relapse, or death at 12 months after matched related/unrelated donor bone marrow or peripheral blood allogeneic hematopoietic cell transplantation (alloHCT) using myeloablative conditioning (MAC). Patients who are alive without GVHD will be censored at the last follow-up.
Time Frame
Day 365

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥18 years. Patients with any hematologic malignancy for which alloHCT is indicated. Patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) must be in complete remission at the time of alloHCT(<5% blasts in the bone marrow, normal maturation of all cellular components in the bone marrow and absence of extramedullary disease). Myeloablative conditioning (MAC) regimen, based on Center for International Blood and Marrow Transplant Research (CIBMTR) criteria. T cell-replete peripheral blood graft. Patients must have a matched related or unrelated donor (at least 6/6 match at human leukocyte antigens (HLA) -A, -B and -C for related donors and at least 8/8 match at HLA-A, -B, -C and -DRB1 for unrelated donors). Cardiac function: Left ventricular ejection fraction ≥45% for myeloablative conditioning. Estimated creatinine clearance ≥40 mL/minute (using the Cockcroft-Gault formula and actual body weight). Pulmonary function: Diffusing capacity of the lungs for carbon monoxide (DLCO) ≥40% (adjusted for hemoglobin) and Forced Expiratory Volume (FEV1) ≥50%. Liver function: total bilirubin <3 x upper limit of normal and alanine aminotransferase (ALT) / aspartate aminotransferase (AST) <5 x upper normal limit. Signed informed consent: Voluntary written consent must be given before patient registration and performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. Female patient: A negative pregnancy test will be required for women of child bearing potential. Breast-feeding or lactation is not permitted. Planned posttransplant maintenance therapy is allowed. Exclusion Criteria: Prior allogeneic HCT. Active central nervous system (CNS) involvement with malignancy. Patients receiving cord blood or haploidentical allograft. Patients undergoing in vivo or ex vivo T cell-depleted alloHCT. Karnofsky Performance Score <60%. Patients with uncontrolled bacterial, viral or fungal infections (currently on treatment and with progression of infectious disease or no clinical improvement) at time of enrollment. Active hepatitis B or C virus infection or known human immunodeficiency virus (HIV) positive. Prior intolerance or allergy to tocilizumab. Use of rituximab, alemtuzumab, anti-thymocyte globulin (ATG) or other monoclonal antibody planned as part of conditioning regimen for GVHD prophylaxis. History of diverticulitis, Crohn's disease or ulcerative colitis. History of demyelinating disorder. Any current uncontrolled cardiovascular conditions, including uncontrolled ventricular arrhythmias, New York Heart Association (NYHA) class III or IV congestive heart failure, uncontrolled angina, or electrocardiographic evidence of active ischemia or active conduction system abnormalities. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
William R Drobyski, MD
Organizational Affiliation
Medical College of Wisconsin
Official's Role
Principal Investigator
Facility Information:
Facility Name
Froedtert Hospital
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
36106394
Citation
Chhabra S, Szabo A, Clurman A, McShane K, Waters N, Eastwood D, Samanas L, Fei T, Armijo G, Abedin S, Longo W, Hari P, Hamadani M, Shah NN, Runaas L, Jerkins JH, Van den Brink M, Peled JU, Drobyski WR. Mitigation of gastrointestinal graft-versus-host disease with tocilizumab prophylaxis is accompanied by preservation of microbial diversity and attenuation of enterococcal domination. Haematologica. 2023 Jan 1;108(1):250-256. doi: 10.3324/haematol.2022.281309. No abstract available.
Results Reference
result

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PROACTIVE: Preventing Acute/Chronic GVHD With TocIlizumab Combined With GVHD Prophylaxis Post allogEneic Transplant

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