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

• ClinicalTrials.gov Identifier: NCT03680092
• Recruitment Status: Active, not recruiting
• First Posted: September 21, 2018
• Last Update Posted: February 13, 2023
• Sponsor: Dimitrios Tzachanis, MD PhD
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Dimitrios Tzachanis, MD PhD, University of California, San Diego

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
GVHD; Hematologic Neoplasms	Drug: Cyclophosphamide; Drug: abatacept; Drug: Methotrexate; Drug: Tacrolimus	Phase 2

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 43 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Trial Comparing a Calcineurin Inhibitor-free Graft-versus-host Disease Prophylaxis Regimen With Post-transplantation Cyclophosphamide and Abatacept to Standard of Care
• Actual Study Start Date: November 26, 2019
• Estimated Primary Completion Date: December 2027
• Estimated Study Completion Date: December 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cyclophosphamide and abatacept; 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	Drug: Cyclophosphamide; Day 3 and day 4 following transplant. Dosing will be based on patients' actual weight up to 120% of ideal body weight, above which it will be based on adjusted ideal body weight (ideal weight plus 50% of the difference between ideal and actual weight).; Other Names: cytophosphane; Cytoxan; Neosar; Drug: abatacept; Abatacept at a dose of 10mg/kg will be administered on days +5, +14 and +28, +56, +84, +112, +140, +168; Other Name: ORENCIA
Active Comparator: methotrexate and tacrolimus; The GVHD prophylaxis regimen on the standard of care arm will consist of methotrexate on Days +1,+3, +6 and +11 and tacrolimus	Drug: Methotrexate; standard of care Methotrexate 5 mg/m2 on Days 1, 3, 6 and 11; Other Name: Trexall; Drug: Tacrolimus; Tacrolimus per institutional guidelines; Other Names: Prograf; Astagraf XL; Envarsus XR

Outcome Measures

Primary Outcome Measures :

1. occurrence of moderate and severe chronic GVHD at one year post transplant [ Time Frame: through study completion, an average of 1 year ]
   The occurrence of moderate and severe chronic GVHD at one year post Chronic GVHD will be diagnosed and staged according to the previously published and widely accepted National Institutes of Health consensus criteria

Secondary Outcome Measures :

1. GVHD- and relapse- free survival by one year post transplant [ Time Frame: through study completion, an average of 1 year ]
   GVHD- and relapse- free survival will be defined as the absence of acute GVHD Grade III or IV or moderate or severe chronic GVHD or relapse or non-relapse mortality by one year post transplant. Acute GVHD will be diagnosed and graded according to Glucksberg criteria

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

UC San Diego Moores Cancer Center

La Jolla, California, United States, 92093

Sponsors and Collaborators

Dimitrios Tzachanis, MD PhD

Bristol-Myers Squibb

Investigators

• Principal Investigator: Dimitrios Tzachanis, MD PhD; University of California, San Diego
• Principal Investigator: Divya Koura, MD; University of California, San Diego

More Information

• Responsible Party: Dimitrios Tzachanis, MD PhD, Assistant Clinical Professor of Medicine, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT03680092
• Other Study ID Numbers: 180383
• First Posted: September 21, 2018
• Last Update Posted: February 13, 2023
• Last Verified: February 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Dimitrios Tzachanis, MD PhD, University of California, San Diego:

cancer; Graft-Versus-Host Disease; Hematologic Neoplasms; Abatacept; Cyclophosphamide; GVHD prophylaxis; stem cell transplantation; High risk hematologic malignancy; hematologic malignancy; Allogeneic Hematopoetic Stem Cell Transplantation; GVHD

Additional relevant MeSH terms:

Hematologic Neoplasms; Neoplasms; Neoplasms by Site; Hematologic Diseases; Cyclophosphamide; Methotrexate; Abatacept; Tacrolimus; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Calcineurin Inhibitors; Immune Checkpoint Inhibitors; Antineoplastic Agents, Immunological