Hematologic Malignancy
Conditions
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.
Interventions
DRUGTacrolimus
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.
DRUGMethotrexate
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.
DRUGTocilizumab
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.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Medical College of Wisconsin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Patients With GVHD/Relapse-free (GRFS) Survival | Day 365 | 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. |
Countries
United States
Participant flow
Recruitment details
Thirty-one subjects signed consent, but two did not meet final eligibility criteria and were not enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Tacrolimus/Methotrexate/Tocilizumab 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).
Tacrolimus: 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.
Methotrexate: 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.
Tocilizumab: 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-allogeneic hematopoietic cell transplantation. The infusion will be administered over 60 minutes through a dedicated IV line and must not be administered by IV bolus. | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
Baseline characteristics
| Characteristic | Tacrolimus/Methotrexate/Tocilizumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants |
| Age, Continuous | 49.0 years STANDARD_DEVIATION 10.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 27 Participants |
| Region of Enrollment United States | 29 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 29 |
| other Total, other adverse events | 28 / 29 |
| serious Total, serious adverse events | 28 / 29 |
Outcome results
Primary
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.
Time frame: Day 365
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tacrolimus/Methotrexate/Tocilizumab | The Number of Patients With GVHD/Relapse-free (GRFS) Survival | 25 Participants |