Hematologic Malignancies
Conditions
Keywords
Graft-versus-host disease
Brief summary
This is a phase 2 open-label trial designed to evaluate the efficacy of tildrakizumab in improving graft-versus-host disease (GVHD)-free relapse-free survival after myeloablative allogeneic hematopoietic cell transplantation (alloHCT) for hematologic malignancy.
Detailed description
Study Rationale: GVHD remains a major cause of morbidity and mortality following myeloablative conditioning (MAC) alloHCT. Proinflammatory cytokines play a central role in initiation and development of acute GVHD and as such, inhibition of these cytokines has been examined for both prevention and treatment of GVHD. Interleukin (IL)-23 is a proinflammatory cytokine which the investigators' lab has shown to have a unique and selective role in induction of colonic inflammation during acute GVHD and that this cytokine serves as a critical mediator linking conditioning regimen-induced mucosal injury and endotoxin lipopolysaccharide (LPS) translocation to subsequent proinflammatory cytokine production and GVHD-associated pathological damage. Moreover, additional studies have demonstrated that blocking the IL-23 signaling pathway has not abrogated the graft-versus-tumor effect. Tildrakizumab is a commercially available anti-IL-23 antibody FDA approved for the treatment of moderate to severe psoriasis with good tolerance. The investigators hypothesize that blocking IL-23, with tildrakizumab, will reduce GVHD rates for patients undergoing MAC alloHCT without having an impact on relapse rates, thus improving GVHD-free relapse-free survival (GRFS).
Interventions
DRUGTildrakizumab
100 mg will be injected subcutaneously on Day -1, Day 28 ± 3, Day 112 ± 7, Day 196 ± 14, and Day 280 ± 14.
Sponsors
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). Patients with myelodysplastic syndrome (MDS) must have \<10% blasts in the bone marrow, no circulating blasts. 3. Myeloablative conditioning (MAC) regimen, based on Center for International Blood and Marrow Transplant Research (CIBMTR) criteria (total body irradiation (TBI) ≥5 Gy single dose or ≥8 Gy fractionated or busulfan \[Bu\] dose \>8 mg/kg oral or \>6.4 mg/kg intravenous). 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 antigen (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 in 1 second (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. Female subjects must meet one of the following: Postmenopausal for at least one year before enrollment, OR 1. Surgically sterile (i.e. undergone a hysterectomy or bilateral oophorectomy), OR 2. If subject is of childbearing potential (defined as not satisfying either of the above two criteria), she must agree to practice two acceptable methods of contraception (combination methods require use of two of the following: diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge, male or female condom, hormonal contraceptive) from the time of signing of the informed consent form through 90 days after the last dose of study agent, OR 3. Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post ovulation methods\] and withdrawal are not acceptable contraception methods.) 11. Male subjects, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following: 1. Practice effective barrier contraception during the entire study period and through 60 calendar days after the last dose of study agent, OR 2. Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post ovulation methods\] and withdrawal are not acceptable methods of contraception.) 12. 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. 13. Planned post-transplant maintenance therapy is allowed. 14. Prior autologous transplant is allowed.
Exclusion criteria
1. Prior allogeneic hematopoietic cell transplant (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% or Eastern Cooperative Oncology Group (ECOG) \> or = 2. 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. Use of rituximab, alemtuzumab, anti-thymocyte globulin (ATG) or other monoclonal antibody planned as part of conditioning regimen for GVHD prophylaxis. 9. Participation in another GVHD prophylaxis clinical trial. 10. 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. 11. 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 |
|---|---|---|
| GVHD-free Relapse-Free Survival | 1 year | Number of subjects experiencing any of grade III-IV acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death at 12 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Acute GVHD | Day +100 and Day +180 | Number of subjects experiencing grades II-IV and III-IV acute GVHD will be determined at Day +100 and Day +180 post-HCT. Acute GVHD will be graded according to NIH Consensus criteria. |
| Incidence of Acute GI GVHD | Day +100 and Day +180 | Number of subjects experiencing grades II-IV and III-IV acute GI GVHD will be determined at Day +100 and Day +180 post-HCT. This will be graded according to NIH Consensus criteria. |
| Primary Graft Failure. | Day 28 | Number of subjects experiencing no neutrophil recovery to \> 500 cells/μL by Day 28 post-HCT. |
| Secondary Graft Failure | Up to Day 365 | Number of subjects experiencing initial neutrophil engraftment followed by subsequent decline in absolute neutrophil counts \<500 cells/μL, unresponsive to growth factor therapy, but cannot be explained by disease relapse or drugs. |
| Hematopoietic Recovery According to Neutrophil Count Recovery | Day +28 | This measure is the number of subjects with the event. The number of days to hematopoietic recovery will be assessed according to neutrophil count recovery after hematopoietic stem cell transplant (HSCT). Neutrophil recovery or engraftment is defined as achieving an absolute neutrophil count (ANC) ≥500/mm\^3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil engraftment. |
| Incidence of Chronic GVHD | Day +180 | Number of subjects experiencing chronic GVHD defined by NIH Consensus criteria. |
| Non-relapsed Mortality. | Day +100 and 1 year | Number of subjects who die after alloHCT without experiencing a relapse. |
| Disease Relapse or Progression | Day +100 and 1 year | The number of subjects who experience relapse. Relapse is defined by either morphological, cytogenetic or radiologic evidence of the pretransplant hematologic malignancy. |
| The Number of Subjects With Progression-free Survival. | Day +100 and 1 year | This will be measured in months. The event for this endpoint is relapse/progression or death. Patients who are alive and disease-free will be censored at last follow-up. |
| The Number of Subjects With Overall Survival. | Day +100 and 1 year | The time in months from the date of transplant to date of death from any cause or for surviving patients, to last follow-up. Patients who are alive and disease-free will be censored at last follow-up. |
| Incidence of Infections | Day +28, Day +100 and 1 year | Number of subjects experiencing a grade ≥3 (CTCAE v5) viral, fungal and/or bacterial infections. |
| Hematopoietic Recovery According to Platelet Count Recovery | Day +28 | This measure is the number of subjects with the event. The number of days to hematopoietic recovery will be assessed according to platelet count recovery after HSCT. Platelet recovery is defined by either the first day of a sustained platelet count \>20,000/mm\^3 for three days with no platelet transfusion in the preceding seven days. The first day of sustained platelet count above these thresholds will be designated the day of platelet engraftment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tildrakizumab Tildrakizumab (IluymaTM) is a humanized monoclonal antibody that specifically binds to the IL-23p19 subunit of IL-23 to neutralize its function.
Tildrakizumab: 100 mg will be injected subcutaneously on Day -1, Day 28 ± 3, Day 112 ± 7, Day 196 ± 14, and Day 280 ± 14. | 51 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Only 50 pts are evaluable as 1 pt withdrew before treatment. | 1 |
Baseline characteristics
| Characteristic | Tildrakizumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 51 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 1 Participants |
| Race (NIH/OMB) White | 47 Participants |
| Region of Enrollment United States | 51 participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 10 / 50 |
| other Total, other adverse events | 50 / 50 |
| serious Total, serious adverse events | 11 / 50 |
Outcome results
Primary
GVHD-free Relapse-Free Survival
Number of subjects experiencing any of grade III-IV acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death at 12 months
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tildrakizumab | GVHD-free Relapse-Free Survival | 19.3 percentage of subjects |
Secondary
Disease Relapse or Progression
The number of subjects who experience relapse. Relapse is defined by either morphological, cytogenetic or radiologic evidence of the pretransplant hematologic malignancy.
Time frame: Day +100 and 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tildrakizumab | Disease Relapse or Progression | Day +100 | 14 percentage of subjects |
| Tildrakizumab | Disease Relapse or Progression | 1 year | 14 percentage of subjects |
Secondary
Hematopoietic Recovery According to Neutrophil Count Recovery
This measure is the number of subjects with the event. The number of days to hematopoietic recovery will be assessed according to neutrophil count recovery after hematopoietic stem cell transplant (HSCT). Neutrophil recovery or engraftment is defined as achieving an absolute neutrophil count (ANC) ≥500/mm\^3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil engraftment.
Time frame: Day +28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tildrakizumab | Hematopoietic Recovery According to Neutrophil Count Recovery | 50 Participants |
Secondary
Hematopoietic Recovery According to Platelet Count Recovery
This measure is the number of subjects with the event. The number of days to hematopoietic recovery will be assessed according to platelet count recovery after HSCT. Platelet recovery is defined by either the first day of a sustained platelet count \>20,000/mm\^3 for three days with no platelet transfusion in the preceding seven days. The first day of sustained platelet count above these thresholds will be designated the day of platelet engraftment.
Time frame: Day +28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tildrakizumab | Hematopoietic Recovery According to Platelet Count Recovery | 47 Participants |
Secondary
Incidence of Acute GI GVHD
Number of subjects experiencing grades II-IV and III-IV acute GI GVHD will be determined at Day +100 and Day +180 post-HCT. This will be graded according to NIH Consensus criteria.
Time frame: Day +100 and Day +180
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tildrakizumab | Incidence of Acute GI GVHD | Grade III-IV; Day +180 | 4 percentage of subjects |
| Tildrakizumab | Incidence of Acute GI GVHD | Grade II-IV; Day +100 | 6 percentage of subjects |
| Tildrakizumab | Incidence of Acute GI GVHD | Grade II-IV; Day +180 | 10.3 percentage of subjects |
| Tildrakizumab | Incidence of Acute GI GVHD | Grade III-IV; Day +100 | 4 percentage of subjects |
Secondary
Incidence of Acute GVHD
Number of subjects experiencing grades II-IV and III-IV acute GVHD will be determined at Day +100 and Day +180 post-HCT. Acute GVHD will be graded according to NIH Consensus criteria.
Time frame: Day +100 and Day +180
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tildrakizumab | Incidence of Acute GVHD | Grade II-IV; Day +100 | 14 percentage of subjects |
| Tildrakizumab | Incidence of Acute GVHD | Grade II-IV; Day +180 | 18 percentage of subjects |
| Tildrakizumab | Incidence of Acute GVHD | Grade III-IV; Day +100 | 4 percentage of subjects |
| Tildrakizumab | Incidence of Acute GVHD | Grade III-IV; Day +180 | 4 percentage of subjects |
Secondary
Incidence of Chronic GVHD
Number of subjects experiencing chronic GVHD defined by NIH Consensus criteria.
Time frame: Day +180
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tildrakizumab | Incidence of Chronic GVHD | 18 percentage of subjects |
Secondary
Incidence of Chronic GVHD
Number of subjects experiencing chronic GVHD defined by NIH Consensus criteria.
Time frame: Day +365
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tildrakizumab | Incidence of Chronic GVHD | 53.7 percentage of subjects |
Secondary
Incidence of Infections
Number of subjects experiencing a grade ≥3 (CTCAE v5) viral, fungal and/or bacterial infections.
Time frame: Day +28, Day +100 and 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tildrakizumab | Incidence of Infections | Day +28 | 14 percentage of subjects |
| Tildrakizumab | Incidence of Infections | Day +100 | 16 percentage of subjects |
| Tildrakizumab | Incidence of Infections | 1 Year | 20.3 percentage of subjects |
Secondary
Non-relapsed Mortality.
Number of subjects who die after alloHCT without experiencing a relapse.
Time frame: Day +100 and 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tildrakizumab | Non-relapsed Mortality. | Day +100 | 2 percentage of subjects |
| Tildrakizumab | Non-relapsed Mortality. | 1 year | 8 percentage of subjects |
Secondary
Primary Graft Failure.
Number of subjects experiencing no neutrophil recovery to \> 500 cells/μL by Day 28 post-HCT.
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tildrakizumab | Primary Graft Failure. | 0 Participants |
Secondary
Secondary Graft Failure
Number of subjects experiencing initial neutrophil engraftment followed by subsequent decline in absolute neutrophil counts \<500 cells/μL, unresponsive to growth factor therapy, but cannot be explained by disease relapse or drugs.
Time frame: Up to Day 365
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tildrakizumab | Secondary Graft Failure | 0 Participants |
Secondary
The Number of Subjects With Overall Survival.
The time in months from the date of transplant to date of death from any cause or for surviving patients, to last follow-up. Patients who are alive and disease-free will be censored at last follow-up.
Time frame: Day +100 and 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tildrakizumab | The Number of Subjects With Overall Survival. | 1 year | 80 percentage of subjects |
| Tildrakizumab | The Number of Subjects With Overall Survival. | Day +100 | 98 percentage of subjects |
Secondary
The Number of Subjects With Progression-free Survival.
This will be measured in months. The event for this endpoint is relapse/progression or death. Patients who are alive and disease-free will be censored at last follow-up.
Time frame: Day +100 and 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tildrakizumab | The Number of Subjects With Progression-free Survival. | Day +100 | 84 percentage of subjects |
| Tildrakizumab | The Number of Subjects With Progression-free Survival. | 1 year | 78 percentage of subjects |