Comparing Cyclophosphamide and Abatacept With Standard of Care Treatment Following Stem Cell Transplantation

Dimitrios Tzachanis, MD PhD

Status and phase: Active, not recruiting; Phase 2

Conditions: Hematologic Neoplasms; GVHD

Treatments: Drug: Cyclophosphamide; Drug: Methotrexate; Drug: abatacept; Drug: Tacrolimus

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT03680092

180383

Details and patient eligibility

About

The purpose of this study is to investigate whether the combination of cyclophosphamide and abatacept versus the treatment used in standard of care will reduce the incidence of moderate and severe chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. GVHD occurs when the cells from your donor (the graft) see your body's cells (the host) as different and attack them.

Full description

The experimental GVHD prophylaxis arm consists of cyclophosphamide and abatacept. Cyclophosphamide induces apoptosis of activated T cells and abatacept (CTLA4Ig) blocks activation of T cells by inhibiting the co-stimulatory signal.

Compared to the standard-of-care control arm, the experimental arm is much more convenient and expected to be associated with fewer toxicities.

In addition there is a great theoretical potential for immunological synergy between cyclophosphamide and abatacept for inducing post-transplant immunologic tolerance that clinically might translate into less GVHD without increase in relapse Patients will be randomized 1:1 to the experimental vs the standard of care arm. Randomization will be done prior to the use of any conditional therapy.

The two arms will be stratified by disease (acute leukemia vs others) and donor type (MRD vs MUD/MUD vs Haplo) in an effort to keep them balanced.

The conditioning regimen for both arms will be mainly Busulfan/Fludarabine (A Total Body Irradiation based conditioning regimen will be allowed for diseases such as ALL)

The GVHD prophylaxis regimen on the experimental arm will consist of high dose Cyclophosphamide on Days +3 and +4 followed by abatacept for 6 months.

The GVHD prophylaxis regimen on the standard of care arm will consist of methotrexate on Days +1,+3, +6 and +11 and tacrolimus for patients with a 10/10 matched related or unrelated donor and of high dose cyclophosphamide on Days +3 and +4 followed by tacrolimus and mycophenolate for patients with a haploidentical donor.

Enrollment: 43 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• High risk hematologic malignancy justifying the need for an allogeneic hematopoetic stem cell transplantation: AML, ALL, CML in accelerated or blast phase, MDS/MPN, NHL, Hodgkin lymphoma, and multiple myeloma
• Creatinine clearance > 40
• Adequate hepatic function
• Normal cardiac function (EF > 50%)

Exclusion criteria

• Patients with hematologic malignancies for which transplant is not the only curative option, such as AML with good or intermediate cytogenetics or molecular markers in CR1 or CML in chronic phase
• Inability to identify an 10/10 HLA-Matched Donor (related or unrelated) or a haploidentical donor
• Active malignant disease relapse
• Active, uncontrolled infection, uncontrolled cardiac angina, symptomatic congestive heart failure
• Life expectancy <3 months
• Pregnancy or lactation
• Patients may not be receiving any other investigational agents in the last 28 days
• Patients with chronic myeloid leukemia in first chronic phase

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

43 participants in 2 patient groups

Cyclophosphamide and abatacept

Experimental group

Description:

The GVHD prophylaxis regimen on the experimental arm will consist of high dose Cyclophosphamide on Days +3 and +4 followed by abatacept for 6 months. Abatacept at a dose of 10mg/kg will be administered on days +5, +14 and +28, +56, +84, +112, +140, +168

Treatment:

Drug: abatacept

Drug: Cyclophosphamide

methotrexate and tacrolimus

Active Comparator group

Description:

The GVHD prophylaxis regimen on the standard of care arm will consist of methotrexate on Days +1,+3, +6 and +11 and tacrolimus

Treatment:

Drug: Tacrolimus

Drug: Methotrexate