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Comparing Cyclophosphamide and Abatacept With Standard of Care Treatment Following Stem Cell Transplantation in Patients With Hematologic Malignancy

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ClinicalTrials.gov Identifier: NCT03680092
Recruitment Status : Not yet recruiting
First Posted : September 21, 2018
Last Update Posted : September 26, 2019
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Dimitrios Tzachanis, MD PhD, University of California, San Diego

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 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
Estimated Study Start Date : November 2019
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2021


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




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



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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03680092


Contacts
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Contact: Dimitrios Tzachanis, MD PhD 858-534-2185 dtzachanis@ucsd.edu
Contact: Elaine Eng e1eng@ucsd.edu

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

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Responsible Party: Dimitrios Tzachanis, MD PhD, Assistant Clinical Professor of Medicine, University of California, San Diego
ClinicalTrials.gov Identifier: NCT03680092     History of Changes
Other Study ID Numbers: 180383
First Posted: September 21, 2018    Key Record Dates
Last Update Posted: September 26, 2019
Last Verified: September 2019

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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:
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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