Trial Title:
Trial of 2 Step ATG for Acute GVHD Prevention Post Myeloablative Allogeneic Stem Cell Transplant
NCT ID:
NCT06315309
Condition:
GVHD,Acute
Acute Leukemia
Myelodysplastic Syndromes
Myeloproliferative Disorders
Conditions: Official terms:
Preleukemia
Myelodysplastic Syndromes
Myeloproliferative Disorders
Methotrexate
Tacrolimus
Conditions: Keywords:
Leukemia
Myelodysplastic Syndrome
Myeloproliferative Disorders
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
ATG Combined with Tacrolimus and Mini Methotrexate
Description:
On Day -7, subjects will be admitted to the hospital and receive a dose of prednisone at
1 mg/kg (ATG premedication). Subjects will receive a steroid injection 3 hours before
every ATG infusion. On day -6, subjects will receive a small dose of ATG as an IV
infusion. ATG will be repeated on days -5,-4 and -1. Routine transplant chemotherapy
agent fludarabine will be given on days -6 to -2 as daily IV infusions. Busulfan, a
routine transplant chemotherapy will be given on days -5 to -2 as IV infusion. Subjects
with lymphoblastic leukemia will receive an alternative regimen of cyclophosphamide, a
routine chemotherapy on days -6 and -5, followed by total body radiation on days -3 to
-1. Tacrolimus (standard immune suppression agent) starts on day -3 as continuous IV
infusion and switched to oral after engraftment. Methotrexate a standard immune
suppression medication which is given IV on day +1,+3,+6, and +11 post-transplant. Blood
draws on days -4,-1,+3,+7,+14 to measure ATG levels.
Arm group label:
phase II single arm study of 2 step ATG dosing in prevention of aGVHD.
Summary:
The purpose of this study is to test whether the combination of the drugs called
tacrolimus (Tac), methotrexate (MTX) and new dosing strategy of another drug called
(rabbit Anti-thymocyte Globulin [ATG]) will help prevent the development and/or improve
severity of acute and/or chronic GVHD.
Detailed description:
The goal is to study the effectiveness and drug levels of new dosing strategy of ATG
(GVHD preventing medicine) in preventing graft versus host disease post allogeneic stem
cell transplantation.
In an effort to reduce graft versus host disease (GVHD) and enhance graft versus leukemia
(GVL) effect post allogenic hematopoietic stem cell transplantation (AHSCT), recent
research has focused on host immune cell depletion. Frame shifting anti-thymocyte
globulin (ATG) backwards to earlier days before days 0 can result in deeper host and less
graft T-cell depletion, leading to better immune reconstitution. Preliminary data where
80% of the ATG dose is given on days -6,-5,-4 and 20% given on day -1, showed effective
prevention of severe acute GVHD, chronic GVHD and favorable early immune reconstitution.
We hypothesize that our 2 step ATG dosing platform when combined with standard tacrolimus
and mini methotrexate in a myeloablative setting can prevent grade III-IV acute GVHD and
chronic GVHD, resulting in improvement of GVHD/relapse free survival at one year post
transplant.
This study aims to:
1. Confirm the effectiveness of ATG based GVHD prevention regimen based on the
encouraging clinical outcomes observed above.
2. Examine ATG blood levels pre and post-transplant to evaluate any possible
correlation between ATG levels and its ability to protect from GVHD.
3. Examine post-transplant immune cell recovery as part of routine post-transplant
immune monitoring at UABMC.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Adult male or female, age 18-60 years
2. Patients must have a related or unrelated peripheral blood stem cell donor. Sibling
donor must be a 6/6 match for HLA-A and -B at intermediate (or higher) resolution,
and -DRB1 at high resolution using DNA-based typing, and must be willing to donate
peripheral blood stem cells and meet institutional criteria for donation. Unrelated
donor must be 8/8 match at HLA-A, -B, -C and -DRB1 at high resolution using
DNA-based typing. Unrelated donor must be willing to donate peripheral blood stem
cells and be medically eligible to donate stem cells according to NMDP criteria.
3. A candidate for Myeloablative preparative regimen, based on age ≤ 60, or HCT-CI of ≤
4, and considered by the treating physician to be a candidate for such regimen.
4. Cardiac function: Ejection fraction ≥ 45%
5. Calculated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault
formula and actual body weight).
6. Pulmonary function: DLCO ≥50% (adjusted for hemoglobin) and FEV1≥50%
7. Liver function: total bilirubin < 1.5x the upper limit of normal and ALT/AST < 2.5x
the upper normal limit. Patients who have been diagnosed with Gilbert's Disease are
allowed to exceed the defined bilirubin value up to <3mg/dl.
8. Female subjects (unless postmenopausal for at least 1 year before the screening
visit, or surgically sterilized), agree to practice two effective methods of
contraception (hormonal contraception and male partner to use condom) or agree to
complete abstain from heterosexual intercourse from the time of signing the informed
consent through 12 months post-transplant.
9. Male subjects (even if surgically sterilized), of partners of women of childbearing
potential must agree to practice effective barrier contraception or abstain from
heterosexual intercourse from the time of signing the informed consent through 12
months post-transplant.
10. Karnofsky performance status KPS ≥ 80 (Appendix B)
11. Patients must have a diagnosis of one of the following:
A-Acute myeloid leukemia (AML) in complete remission CR 1 with intermediate or high
risk for relapse as defined by ELN 2022 criteria(Dohner et al., 2022) (appendix C),
or deemed to be at high risk for relapse by treating physician, based on, therapy
related, or extra medullary presentation.
B-AML in >CR1. C-Myelodysplastic syndrome (MDS) with IPSS-M ≥
intermediate-low.(Bernard et al., 2022; Mohty et al., 2022) D- Chronic
myeloproliferative disorder (ET, PV, myelofibrosis) with bone marrow blasts > 5%
and/or other evidence of progression to acute leukemia or Int or high-risk disease
by MIPPS v2 score.(Ali et al., 2019; Guglielmelli et al., 2018) E- CMML especially
those with high-risk features based in: The CMML-specific prognostic scoring system
with molecular features (CPSS-Mol) - high risk and intermediate-2 risk, Mayo
molecular model - high risk and Intermediate-2 risk, Groupe Francophone des
Myélodysplasies (GFM) - high risk and selected patients with intermediate
risk.(Elena et al., 2016; Itzykson et al., 2013; Patnaik et al., 2014). F- Acute
lymphoblastic leukemia (ALL) in CR1 with high risk for relapse
- B-cell ALL: High white blood cell count at diagnosis (ie, >30,000/µl),
Clonalcytogenetic abnormalities - t(4;11), t(1;19), t(9;22), or BCR-ABL gene
positivity, BCR-ABL1-like (Ph-like) gene signature, progenitor-B cell
immunophenotype (eg, blasts expressing membrane CD19, CD79a, and cytoplasmic
CD22, but not CD10), Length of time from start of induction therapy to
attainment of CR greater than four weeks, and minimal residual disease (MRD)
post-remission bone marrow MRD+.(Akabane & Logan, 2020; Lafage-Pochitaloff et
al., 2017)
- T-cell ALL: Failure to achieve CR after one induction, MRD> 1X 10-4 after 2
courses of induction, Presenting WBC > 100 X 109/L, complex cytogenetics
≥5,early T-cell Precursor ALL, poor risk genetics including lack of NOTCH1
ith/FBXW7 or presence of N-RAS & K-RAS, EZH2 and age>40 years.(Marks &
Rowntree, 2017) G- ALL in >CR1
12. The subject is willing and able to sign informed consent and abide by the protocol
requirements.
Exclusion Criteria:
1. Autologous hematopoietic stem cell transplant < 3 months prior to enrollment.
2. Patients with florid residual AML with > 5% blast in the marrow or circulating blast
in the peripheral blood are not eligible for this study.
3. Previous allogeneic stem cell transplant.
4. Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or EKG suggestive
of acute ischemia or active conduction system abnormalities.
5. Known hypersensitivity to the study agent (ATG)
6. Received any investigational drugs within the 14 days prior to the first day of
transplant conditioning
7. Pregnant and/or breastfeeding
8. Evidence of HIV infection or known HIV positive serology.
9. Current uncontrolled bacterial, viral or fungal infection (currently taking
medication with evidence of progression of clinical symptoms or radiologic
findings).
10. Non-hematologic malignancy within prior three (3) years, with the exception of
squamous cell or basal cell skin carcinoma.
11. Participation in another clinical study with an investigational product during the
last 28 days.
Gender:
All
Minimum age:
18 Years
Maximum age:
60 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
University of Alabama at Birmingham
Address:
City:
Birmingham
Zip:
35294
Country:
United States
Contact:
Last name:
Zaid S Al Kadhimi, MD
Contact backup:
Last name:
Manuel Espinoza-Gutarra, MD
Contact backup:
Last name:
Omer Jamy, MD
Contact backup:
Last name:
Donna Salzman, MD
Contact backup:
Last name:
Razan Mohty, MD
Contact backup:
Last name:
Lauren Shea, MD
Start date:
November 29, 2024
Completion date:
April 2027
Lead sponsor:
Agency:
University of Alabama at Birmingham
Agency class:
Other
Source:
University of Alabama at Birmingham
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06315309
