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HIgh Dose Thymoglobulin Instead of Cyclosporine With a Low Dose of Thymoglobulin for GVHD Prophylaxis (ATG2017)

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ClinicalTrials.gov Identifier: NCT03456817
Recruitment Status : Not yet recruiting
First Posted : March 7, 2018
Last Update Posted : June 29, 2018
Sponsor:
Information provided by (Responsible Party):
AHS Cancer Control Alberta

Brief Summary:
The purpose of this study is to find out whether compared to our standard low dose ATG with CSA, the high dose ATG without CSA minimizes the chances of relapse and chronic GVHD, without increasing the chances of other transplant complications.

Condition or disease Intervention/treatment Phase
Graft-versus-host-disease Relapse Drug: Treatment Arm - high dose ATG Drug: Control Arm - standard of care Phase 2

Detailed Description:

There are a number of complications of allogeneic hematopoietic cell transplantation.

The main complications are:

  • Recurrence (relapse) of the disease for which the transplantation is done (for example, leukemia). The relapse usually leads to death.
  • Acute graft-versus-host disease (GVHD). This may lead to death.
  • Chronic GVHD. This may lead to poor quality of life long-term.

This study is being done to minimize the chances of patients getting relapse and chronic GVHD, without increasing the chances of getting acute GVHD.

At this time, the standard of care approach to treat this condition would be with:

  • Low dose thymoglobulin (ATG), given on Day -2, -1 and 0.
  • Cyclosporin (CSA), given from Day -1 through to Day 84.
  • Methotrexate, given on Days 1, 3, 6 and 11

CSA reduces the chances of getting acute GVHD, but it does not reduce the chances of getting chronic GVHD and increases the chances of getting relapse. ATG reduces both acute and chronic GVHD, and does not increase relapse.

In this study, high dose ATG will be given on days -4, -3, -2, -1 and 0 (instead of only on days -2, -1 and 0), no CSA (instead of CSA from day -1 through 84) will be given, and the routine dose of methotrexate (unchanged) will be given. We think that this may lead to better outcomes.

Patients will be followed per standard practice of the Alberta Blood and Marrow Transplant Program for the development of acute and chronic GVHD, and for relapse.

Patients will also be asked to complete a quality of life questionnaire 2 years after the transplant to assess how their treatment and illness affects their quality of life.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Graft-vs-host Disease Prophylaxis With High Dose Thymoglobulin (10 mg/kg) and Methotrexate in Comparison to Historical/Concurrent Controls Who Received Thymoglobulin (4.5 mg/kg), Methotrexate and Cyclosporine
Estimated Study Start Date : October 2018
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment Arm - high dose ATG
High dose ATG at 10 mg/kg will be infused on days -4, -3, -2, -1 and 0. Before each infusion of ATG (thymoglobulin), patient will receive medications preventing side effects from the ATG, including diphenhydramine (Benadryl), acetaminophen (Tylenol) and methylprednisolone (Solumedrol). The high dose ATG will be given into patient's vein via central venous catheter. Each infusion of ATG will take 4-8 hours. No CSA (cyclosporine A) will be given. Standard dose methotrexate will be given.
Drug: Treatment Arm - high dose ATG
Patients agreeing to 10 mg/kg ATG will be treated with 2 mg/kg daily on days -4 to 0. On days -4, -3 & -2, ATG will be infused after fludarabine & busulfan infusion. ATG will be infused over a minimum of 6 hrs on day -4 & over at least 4 hrs on days -3, -2, -1 & 0. Dose is based on actual body wt, & rounded to nearest vial-Thymoglobulin is supplied in 25 mg vials, except if rounding would result in >5% difference from calculated dose. Foothills Medical Center Unit 57 standard practice followed for ATG infusion. ATG premeds include methylprednisolone 40 mg IVPB, acetaminophen 1000 mg PO & diphenhydramine 50 mg IVPB. Acetaminophen 1000 mg PO & diphenhydramine 50 mg IVPB can be repeated in 4-6 hrs PRN for flu-like symptoms/fever/chills. Meperidine 25-50 mg IVPB given PRN every 4 hrs for rigors. MTX is given 15 mg/m2 IV on day +1 & 10 mg/m2 on days +3, +6 & +11 posttransplant. First dose of methotrexate is given on day +1, at least 24 hrs following end of infusion of stem cell product.

Control Arm - standard of care
Low dose ATG (thymoglobulin) at 4.5 mg/kg will be infused on days -2, -1 and 0, and CSA (cyclosporine A) will be given from day -1 through day 84. Standard dose methotrexate will also be given.
Drug: Control Arm - standard of care
The historical controls will have received and the concurrent controls will receive our standard GVHD prophylaxis, ie, ATG 4.5 mg/kg i.v. (0.5 mg/kg on day -2, 2.0 mg/kg on day -1 and 2.0 mg/kg on day 0), MTX (15 mg/m2 i.v. on day 1 and 10 mg/m2 i.v. on days 3, 6 and 11) and CSA (2.5 mg/kg twice a day i.v. starting from day -1, adjusting dose to target trough plasma CSA levels of 200-400 microg/L, switching to oral formulation before discharge from peritransplant hospitalization, targeting the trough plasma levels of 200-400 microg/L until day 56, and tapering to zero between day 56 and 84).




Primary Outcome Measures :
  1. moderate/severe chronic GVHD- and relapse-free survival (cGFRS) at 2 years post transplant [ Time Frame: 2 years ]
    cGRFS will be compared between the study patients and the historical/concurrent controls using a Cox proportional hazards model to determine if administering 10 mg/kg ATG + MTX and no CSA will be associated with improved cGRFS compared to historical/concurrent controls (4.5 mg/kg ATG + MTX + CSA).


Secondary Outcome Measures :
  1. quality of life [ Time Frame: approximately 2 years (21 to 27 months) post transplant ]
    each scale (domain) of the short form-36 (SF36) questionnaire will be compared between the 10 mg/kg ATG group and the control group using Mann-Whitney-Wilcoxon signed rank test to determine if quality of life (QOL) at 2 years posttransplant will be better in the 10 mg/kg ATG patients compared to the controls (due to the reduction of cGVHD).



Information from the National Library of Medicine

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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:

  • Inclusions:

    1. First allogeneic HCT, performed for a hematologic malignancy, using filgrastim-mobilized peripheral blood stem cells (PBSC).
    2. Conditioning with fludarabine 50 mg/m2 daily on day -6 to -2, busulfan approximately 3.2 mg/kg daily on day -5 to -2 with PK adjustment (target AUC of 3750 uM*min/L) and total body irradiation (TBI) 2 Gy daily on day -1 and 0 (before graft infusion), ie, our standard myeloablative conditioning.72
    3. Planned GVHD prophylaxis with our standard of ATG 4.5 mg/kg + MTX + CSA.
    4. HLA matched sibling donor, or ≥7/8 HLA allele-matched unrelated donor.
    5. Age >17 years.

Exclusion Criteria:

  1. Nonmyeloablative conditioning.
  2. Cord blood or marrow graft.
  3. Bilirubin >1.5-fold above upper normal limit (UNL), ALT or AST >2.0-fold above UNL, or alkaline phosphatase >2.5-fold above UNL.
  4. HIV positive by a serologic test that includes detection of both antibody and antigen)
  5. Increased risk of tuberculosis, defined as patient requiring an anti-tuberculosis drug peritransplant. All patients with a history of tuberculosis (active or latent) or contact with a person with active tuberculosis will be evaluated by an infectious disease specialist to determine whether treatment or prophylaxis of tuberculosis with an anti-tuberculosis drug peritransplant is needed. The infectious disease specialist will order tests (eg, Mantoux tuberculin skin test or interferon gamma release test) as needed to arrive at the decision on whether an anti-tuberculosis drug peritransplant is needed.
  6. High risk of PTLD based on donor positive AND recipient negative EBV serostatus (EBNA1 or VCA IgG)73
  7. Active viral infection on day -4, including cytomegaloviral (CMV) disease.
  8. Neutropenic fever with hypotension on day -4.
  9. Hypoxemia on day -4.
  10. Hypersensitivity to rabbit blood protein, Thymoglobulin or a Thymoglobulin excipient.
  11. Contraindication to methotrexate:

    1. Hypersensitivity to methotrexate or to any ingredient in the formulation or component of the container.
    2. Females of childbearing potential who are pregnant, breastfeeding or unwilling to use adequate contraception from the time of enrolment until at least day 100 posttransplant.

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): NCT03456817


Contacts
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Contact: Jan Storek, MD 403-210-8630 jstorek@ucalgary.ca

Sponsors and Collaborators
AHS Cancer Control Alberta
Investigators
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Principal Investigator: Jan Storek, MD Tom Baker Cancer Centre

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Responsible Party: AHS Cancer Control Alberta
ClinicalTrials.gov Identifier: NCT03456817     History of Changes
Other Study ID Numbers: ATG2017
First Posted: March 7, 2018    Key Record Dates
Last Update Posted: June 29, 2018
Last Verified: June 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Diphenhydramine
Cyclosporine
Methotrexate
Cyclosporins
Thymoglobulin
Antilymphocyte Serum
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Sensory System Agents
Peripheral Nervous System Agents
Antifungal Agents
Anti-Infective Agents
Calcineurin Inhibitors
Sleep Aids, Pharmaceutical
Hypnotics and Sedatives