Axatilimab Plus Standard of Care Therapy for the Prevention of Graft Versus Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Hematologic Cancer, ABRAXAS Trial

Official title

Phase II Double-Blinded Placebo-Controlled Randomized Trial of CSF-1R Inhibitor, Axatilimab for Prevention of Acute and Chronic GVHD After HLA-Matched Related and Unrelated Donor Allogeneic Stem Cell Transplantation (ABRAXAS)

Overview

This phase II trial studies how well adding axatilimab to standard of care (SOC) therapy works in preventing graft versus host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (HCT) in patients with hematologic cancer. Allogeneic HCT is a procedure in which a person receives blood-forming stem cells (cells from which all blood cells develop) from a genetically similar, but not identical, donor. This is often a sister or brother, but could be an unrelated donor. Sometimes the transplanted cells from a donor can attack the body's normal cells, causing GVHD. Symptoms of GVHD can include yellowing of the skin, mucous membranes, and eyes, skin rash or blisters, dry mouth, or dry eyes. Typically, drugs such as cyclophosphamide, tacrolimus, and mycophenolate mofetil are given after the transplant to help stop GVHD from happening, but these current therapies may negatively affect patient quality of life and newer treatment strategies are needed. Axatilimab is a monoclonal antibody. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens), which may prevent GVHD from developing. Adding axatilimab to SOC therapy may be more effective in preventing GVHD following allogeneic HCT in patients with hematologic cancer.

Interventions

• Procedure Allogeneic Hematopoietic Stem Cell Transplantation
  Undergo SOC allogeneic HCT
• Biological Axatilimab
  Given IV
• Procedure Biospecimen Collection
  Undergo blood sample collection
• Procedure Bone Marrow Aspiration
  Undergo bone marrow aspiration
• Procedure Computed Tomography
  Undergo CT
• Drug Cyclophosphamide
  Given IV
• Procedure Magnetic Resonance Imaging
  Undergo MRI
• Drug Mycophenolate Mofetil
  Given IV or PO
• Drug Placebo Administration
  Given IV
• Procedure Positron Emission Tomography
  Undergo PET

Primary outcome measures

• Graft versus host disease (GVHD)-free survival [Time frame: At 1 year post-transplant]

Secondary outcome measures (11)

• Cumulative incidence of mild, moderate, and severe chronic GVHD [Time frame: Up to 1 year post-transplant]
• Cumulative incidence of systemic corticosteroid requiring chronic GVHD [Time frame: Up to 1 year post-transplant]
• Cumulative incidence of grade II-IV and III-IV acute GVHD [Time frame: At 100 days and 180 days]
• Cumulative incidence of non-relapse mortality [Time frame: Up to 1 year post-transplant]
• Incidence of primary and secondary graft failure [Time frame: At 30 days, 60 days, 100 days, 180 days, and 365 days]
• Cumulative incidence of relapse/progression of the primary hematologic malignancy [Time frame: Up to 2 years]
• Lineage specific chimerism kinetics [Time frame: At 30 days, 100 days, 180 days, and 365 days]
• Immune reconstitution [Time frame: At 30 days, 100 days, 180 days, and 365 days]
• Progression-free survival [Time frame: Up to 2 years post-transplant]
• Overall survival [Time frame: Up to 2 years post-transplant]
• Incidence of adverse events [Time frame: Up to 2 years post-transplant]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years
• Patients with a history of a hematologic malignancy with a planned myeloablative conditioning (MAC) peripheral blood allogeneic HCT

• Note: Patients with acute leukemia must be in morphologic complete remission with or without hematologic recovery with ˂ 5% blasts in the bone marrow. Patients with chronic myelomonocytic leukemia (CMML) must have a white blood cell (WBC) count ≤ 10,000 cells/µL and < 5% blasts in the marrow. Patients with ≥ 5% blasts due to a regenerating marrow must contact the protocol chairs for review. Patients with a diagnosis of myelofibrosis require sponsor approval before enrolling
• Patients must be receiving an allograft from a suitable human leukocyte antigen (HLA)-matched sibling or unrelated donor according to transplant center's guidelines (for selection of appropriate donor)
• Karnofsky performance status ≥ 60
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) or total bilirubin ≤ 3.0 x the ULN in the presence of Gilbert's syndrome (obtained ≤ 14 days prior to registration/randomization). If total bilirubin is abnormal (≥ 1.5 x ULN), assess direct bilirubin. NOTE: Patients with Gilbert syndrome and elevated baseline unconjugated (indirect) bilirubin up to 3.0 mg/dL are eligible. Gilbert syndrome should be confirmed by the presence of UGT1A1\*28 variant
• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN (obtained ≤ 14 days prior to registration/randomization)
• Calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault formula (obtained ≤ 14 days prior to registration/randomization)
• Negative serum pregnancy test done ≤ 7 days prior to registration/randomization, for persons of childbearing potential only
• Sexually active patients and their partners must use an effective method of contraception associated with a low failure rate prior to study entry and for the duration of study participation and for at least 3 months after the last dose of study drug

• Note: The following are considered effective contraceptives: oral contraceptive pill; condom plus spermicide; diaphragm plus spermicide; patient or partner surgically sterile; patient or partner more than 12 months postmenopausal; or injectable or implantable agent/device. Male patients should refrain from sperm donation and female patients should refrain from breastfeeding throughout this period
• Provide written informed consent
• Willingness to provide mandatory blood and bone marrow aspirate specimens for correlative research
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)

Exclusion criteria

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effect on the developing fetus and newborn are unknown:

• Pregnant persons
• Nursing persons
• Persons of childbearing potential, and persons able to father a child, who are unwilling to employ adequate contraception
• Any of the following current or prior therapies:

• Patients receiving a cord blood transplant
• Patients undergoing a T-cell depleted allogeneic transplantation (using ex vivo CD34 selection, or with serotherapy \[antithymocyte globulin or alemtuzumab\])
• Patients undergoing a second allogeneic transplant (after a previous allogeneic transplant)
• Pre-planned treatment with JAK1/JAK2 inhibitor after transplant
• Previous exposure to axatilimab
• Currently participating in any other interventional study
• Receiving an investigational treatment ≤ 28 days prior to registration/randomization
• Major surgery ≤ 3 weeks prior to registration/randomization
• Chemotherapy ≤ 2 weeks prior to registration/randomization unless chemotherapy is part of the pre-transplant conditioning
• Radiation therapy ≤ 2 weeks prior to registration/randomization unless radiation is part of the pre-transplant conditioning
• Planned use of donor lymphocyte infusion (DLI) therapy
• Exception: Use of maintenance regimens as routine clinical care will be permitted but must be declared prior to registration/randomization. The trial does not restrict subsequent treatment after meeting the GVHD-free survival (GFS) endpoint
• Active central nervous system (CNS) involvement by malignant cells
• Leukemia involvement in the CNS ≤ 4 weeks of registration for patients with a history of prior CNS leukemia involvement (i.e., leukemic blasts previously detected in the cerebral spinal fluid)
• History of acute or chronic pancreatitis
• History of myositis
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
• Patients with active hepatitis B or C

• Patients with a history of hepatitis B or C are allowed if hepatitis B virus (HBV) deoxyribonucleic acid (DNA) or hepatitis C virus (HCV) RNA are undetectable
• Any known infection with human immunodeficiency virus (HIV), human T-lymphotropic virus-1 (HTLV-1)
• Uncontrolled bacterial, viral, or fungal infections (currently taking medication and with progression or no clinical improvement) at the time of registration/randomization
• Psychiatric illness/social situations that would limit compliance with study requirements
• Diagnosed with another malignancy (other than malignancy for which transplant was performed) ≤ 3 years of registration/randomization, unless previously treated with curative intent and approved by principal investigator (PI) (e.g., but not limited to completely resected basal cell, squamous cell, or ductal carcinoma in situ, or low-risk prostate cancer after curative resection or on watchful waiting). In patients with transformed disease (e.g. aggressive lymphoma evolving from chronic lymphocytic leukemia \[CLL\], or acute leukemia from myelodysplastic syndrome \[MDS\]), the original hematological disorder is not considered an exclusion. Cancer treated with curative intent < 3 years previously will not be allowed unless approved by the study chairs
• History of myocardial infarction ≤ 6 months, or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Double blind

Primary purpose

Prevention

Study locations

United States · 3 centers

• Mayo Clinic in Arizona — Scottsdale
• Mayo Clinic in Florida — Jacksonville
• Mayo Clinic in Rochester — Rochester

Identifiers

NCT: NCT07349771 · MC230810 · 24-009803

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗