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

Phase II Open-Label Trial of Tacrolimus/Methotrexate and Tocilizumab for the Prevention of Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation

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.

Study Overview

• Status: Completed
• Conditions: Hematopoietic Stem Cell Transplantation
• Intervention / Treatment: Drug: Tacrolimus; Drug: Methotrexate; Drug: Tocilizumab

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.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Hospital and the Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

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

Description

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

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

Patients in the control arm will be identified from patients reported to the CIBMTR from U.S centers. Control patients will be required to satisfy similar eligibility requirements as patients being enrolled in the clinical trial. Patients will need to fulfill the same inclusion criteria for the clinical trial according to Section 2.4.1, plus the following:

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 for the controls:

1. Karnofsky Performance Score < 70%

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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

Drug: 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.; Other Names: FK506; fujimycin; Drug: Methotrexate; Methotrexate will be dosed at 15 mg/m2 Day +1 and 10mg/m^2 Days +3, +6 and +11.; Other Names: Trexall; Drug: Tocilizumab; Tocilizumab will be administered intravenously at a dose of 8 mg/kg at Day -1.; Other Names: Actemra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects Not Experiencing Grade II-IV Acute Graph Versus Host Disease (aGVHD)	This measure is the number of subjects who did not experience grade II-IV aGVHD at or before day 180 comparing recipients of tacrolimus (Tac), methotrexate (MTX), and tocilizumab (Toc) to a contemporary control population abstracted from a database maintained by the Center for International Blood and Marrow Transplant Research (CIBMTR). The staging of aGVHD was according to the criteria of Przepiorka, et al., 1995 which assigns a score to the clinical status of multiple organ systems aggregated to determine the clinical stage. A higher stage indicates more severe aGVHD symptoms and poorer clinical outcome.	Day 180

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Score of Depressive Symptoms Using General Depressive Subscale of the Inventory of Depression and Anxiety Symptoms (IDAS) Instrument	The measure of depressive symptoms will be determined from the Inventory of Depression and Anxiety Symptoms (IDAS) instrument. The IDAS contains 10 specific symptom scales: Suicidality, Lassitude, Insomnia, Appetite Loss, Appetite Gain, Ill Temper, Well-Being, Panic, Social Anxiety, and Traumatic Intrusions (see Watson, 2007). The General Depression subscale of the IDAS and includes a subset of 20 five-item Likert-style questions (1= "Not at All" to 5-= "Extremely") with a scoring range of 20-100. Higher scores indicate more severe symptoms.	Baseline, Day 28, Day 100 and Day 180
Score of Anxiety Symptoms Using the Inventory of Depression and Anxiety Symptoms (IDAS) Instrument	Levels of anxiety symptoms will be measured using the Inventory of Depression and Anxiety Symptoms (IDAS) instrument. (see Watson, 2007). Anxiety will be assessed combining two domain categories of the IDAS (panic and traumatic intrusions). There are seven 5-item, Likert-style questions responding symptom severity "during the past 2 weeks, including today ..." ranging from 'Not at all' to 'Extremely.' Scores range from 0 to 28 with higher scores indicating worse symptoms.	Baseline, Day 28, Day 100 and Day 180
Score of Fatigue Symptoms Using the Fatigue Symptom Inventory (FSI) Instrument	Levels of fatigue symptoms will be measured using the Fatigue Symptom Inventory instrument. The FSI comprises 13 eleven-item Likert-style questions ranging from 0 = "Not at all fatigued" to 10 -"Extreme fatigue". The FSI score is the average of the individual question scores. The range of scores is 0 to 10 with higher scores indicate greater fatigue (Hann, 1998).	Baseline, Day 28, Day 100 and Day 180
Score of Sleep Symptoms Using the Pittsburgh Sleep Quality Index (PSQI) Instrument	Levels of sleep symptoms will be measured using the Pittsburgh Sleep Quality Index instrument. The PSQI contains 19 four-item Likert-style questions conducted over a 30-day period and 5 questions rated by the bed partner or roommate. Responses range from 0 = Not in the past month to 3 = Three or more times a week. The bed partner/roommate questions were not assessed. The 19 self-rated questions are grouped into seven component domains including subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. See Buysse (1989), for the scoring schema of the component domains. The PSQI score is the sum of the seven component scores and ranges from 0 to 21. Higher scores indicate poorer sleep quality.	Baseline, Day 28, Day 100 and Day 180
Score of Pain Symptoms Using the Brief Pain Inventory (BPI) Instrument (Interference)	Levels of interference in activities due to pain symptoms will be measured using the Brief Pain Inventory (BPI) instrument. The BPI Interference scale is a mean of 7 eleven-item Likert-style questions with a range of 0-10 (0 = Does not interfere to 10 = Completely interferes). Higher scores indicate greater interference in daily activities due to pain symptoms (see Cleeland 1994).	Baseline, Day 28, Day 100 and Day 180

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of depressive symptoms between allogeneic transplant recipients who received prophylactic tocilizumab and allogeneic transplant recipients who did not receive tocilizumab.	Levels of depressive symptoms will be measured using the Inventory of Depression and Anxiety Symptoms (IDAS) instrument. The IDAS contains 10 specific symptom scales: Suicidality, Lassitude, Insomnia, Appetite Loss, Appetite Gain, Ill Temper, Well-Being, Panic, Social Anxiety, and Traumatic Intrusions. Higher scores indicate worse symptoms. [Watson D, O'Hara MW, Simms LJ, Kotov R, Chmielewski M, McDade-Montez EA, Gamez W, Stuart S. Development and validation of the Inventory of Depression and Anxiety Symptoms (IDAS). Psychol Assess. 2007 Sep;19(3):253-68. doi: 10.1037/1040-3590.19.3.253. PMID: 17845118.]	Baseline, Day 28, Day 100 and Day 180
Comparison of levels of anxiety between allogeneic transplant recipients who received prophylactic tocilizumab and allogeneic transplant recipients who did not receive tocilizumab.	Levels of anxiety symptoms will be measured using the Inventory of Depression and Anxiety Symptoms (IDAS) instrument. The IDAS contains 10 specific symptom scales: Suicidality, Lassitude, Insomnia, Appetite Loss, Appetite Gain, Ill Temper, Well-Being, Panic, Social Anxiety, and Traumatic Intrusions. Higher scores indicate worse symptoms. [Watson D, O'Hara MW, Simms LJ, Kotov R, Chmielewski M, McDade-Montez EA, Gamez W, Stuart S. Development and validation of the Inventory of Depression and Anxiety Symptoms (IDAS). Psychol Assess. 2007 Sep;19(3):253-68. doi: 10.1037/1040-3590.19.3.253. PMID: 17845118.]	Baseline, Day 28, Day 100 and Day 180
Comparison of levels of fatigue between allogeneic transplant recipients who received prophylactic tocilizumab and allogeneic transplant recipients who did not receive tocilizumab.	Levels of fatigue symptoms will be measured using the Inventory of Depression and Anxiety Symptoms (IDAS) instrument. The IDAS contains 10 specific symptom scales: Suicidality, Lassitude, Insomnia, Appetite Loss, Appetite Gain, Ill Temper, Well-Being, Panic, Social Anxiety, and Traumatic Intrusions. Higher scores indicate worse symptoms. [Watson D, O'Hara MW, Simms LJ, Kotov R, Chmielewski M, McDade-Montez EA, Gamez W, Stuart S. Development and validation of the Inventory of Depression and Anxiety Symptoms (IDAS). Psychol Assess. 2007 Sep;19(3):253-68. doi: 10.1037/1040-3590.19.3.253. PMID: 17845118.]	Baseline, Day 28, Day 100 and Day 180
Comparison of sleep between allogeneic transplant recipients who received prophylactic tocilizumab and allogeneic transplant recipients who did not receive tocilizumab.	Levels of sleep symptoms will be measured using the Inventory of Depression and Anxiety Symptoms (IDAS) instrument. The IDAS contains 10 specific symptom scales: Suicidality, Lassitude, Insomnia, Appetite Loss, Appetite Gain, Ill Temper, Well-Being, Panic, Social Anxiety, and Traumatic Intrusions. Higher scores indicate worse symptoms. [Watson D, O'Hara MW, Simms LJ, Kotov R, Chmielewski M, McDade-Montez EA, Gamez W, Stuart S. Development and validation of the Inventory of Depression and Anxiety Symptoms (IDAS). Psychol Assess. 2007 Sep;19(3):253-68. doi: 10.1037/1040-3590.19.3.253. PMID: 17845118.]	Baseline, Day 28, Day 100 and Day 180
Comparison of levels of pain between allogeneic transplant recipients who received prophylactic tocilizumab and allogeneic transplant recipients who did not receive tocilizumab.	Levels of pain symptoms will be measured using the Inventory of Depression and Anxiety Symptoms (IDAS) instrument. The IDAS contains 10 specific symptom scales: Suicidality, Lassitude, Insomnia, Appetite Loss, Appetite Gain, Ill Temper, Well-Being, Panic, Social Anxiety, and Traumatic Intrusions. Higher scores indicate worse symptoms. [Watson D, O'Hara MW, Simms LJ, Kotov R, Chmielewski M, McDade-Montez EA, Gamez W, Stuart S. Development and validation of the Inventory of Depression and Anxiety Symptoms (IDAS). Psychol Assess. 2007 Sep;19(3):253-68. doi: 10.1037/1040-3590.19.3.253. PMID: 17845118.]	Baseline, Day 28, Day 100 and Day 180

Collaborators and Investigators

• Sponsor: William R. Drobyski, MD
• Investigators: Principal Investigator: William Drobyski, MD, Medical College of Wisconsin; Principal Investigator: Marcelo Pasquini, MD, Medical College of Wisconsin

Publications and helpful links

General Publications

• 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.
• Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994 Mar;23(2):129-38.
• 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.
• Watson D, O'Hara MW, Simms LJ, Kotov R, Chmielewski M, McDade-Montez EA, Gamez W, Stuart S. Development and validation of the Inventory of Depression and Anxiety Symptoms (IDAS). Psychol Assess. 2007 Sep;19(3):253-68. doi: 10.1037/1040-3590.19.3.253.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2014
• Primary Completion (Actual): September 1, 2018
• Study Completion (Actual): September 1, 2018

Study Registration Dates

• First Submitted: July 30, 2014
• First Submitted That Met QC Criteria: July 31, 2014
• First Posted (Estimate): August 1, 2014

Study Record Updates

• Last Update Posted (Estimate): March 9, 2023
• Last Update Submitted That Met QC Criteria: February 10, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Methotrexate; Tacrolimus
• Other Study ID Numbers: PRO00023000

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No