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Haploidentical Allogeneic Peripheral Blood Transplantation: Examining Checkpoint Immune Regulators' Expression

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ClinicalTrials.gov Identifier: NCT03480360
Recruitment Status : Recruiting
First Posted : March 29, 2018
Last Update Posted : March 22, 2019
Sponsor:
Information provided by (Responsible Party):
Kenneth Meehan, Dartmouth-Hitchcock Medical Center

Brief Summary:
The standard Johns Hopkins' regimen will be used in study subjects, with the use of donor peripheral blood stem cells, rather than marrow. Clinical outcomes will be defined while focusing efforts on immune reconstitution focusing on immune checkpoint regulators after a related haploidentical stem cell transplant.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Chronic Lymphocytic Leukemia Chronic Myeloid Leukemia Myelodysplasia Myeloproliferative Disorder Myelofibrosis Lymphoma Lymphoma, Non-Hodgkin Plasma Cell Disorder Drug: Cyclophosphamide Drug: Fludarabine Radiation: Total Body Irradiation Drug: Tacrolimus Drug: cellcept Drug: g-csf Procedure: Peripheral Blood Transplant Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Haploidentical Allogeneic Peripheral Blood Transplantation: Clinical Trial and Laboratory Correlates Examining Checkpoint Immune Regulators' Expression
Actual Study Start Date : March 28, 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022


Arm Intervention/treatment
Johns Hopkins' conditioning regimen
Cyclophosphamide, fludarabine, total body irradiation, immune suppression including tacrolimus and cellcept, Granulocyte colony-stimulating factor (G-CSF), and peripheral blood transplant
Drug: Cyclophosphamide
14.5 mg/kg for 2 days (days -6, -5) and then 50 mg/kg for two days (days 3, 4)

Drug: Fludarabine
30 mg/m2 daily for 5 days

Radiation: Total Body Irradiation
200 centigray (cGy) for one day (day -1)

Drug: Tacrolimus
1 mg IV daily, (or the oral equivalent) adjusted to achieve a level between 5 and 15 ng/ml. If there is no evidence of GVHD, discontinue Tacrolimus by Day 180.

Drug: cellcept
dose at 15 mg/kg po three times per day (maximum dose of 3 grams/day). Stop Cellcept at Day 35 following transplantation.

Drug: g-csf
5 mcg/kg/d starting day 5 and continue until Absolute Neutrophil Count (ANC) > 1000/mcL for 3 days.

Procedure: Peripheral Blood Transplant
cell dose goal: < 5 x 106 Hematopoietic progenitor cell antigen CD34+ cells/kg recipient weight




Primary Outcome Measures :
  1. 100-Day Survival [ Time Frame: 100 days post date of peripheral blood transplant ]
    Define 100-day survival of subjects


Secondary Outcome Measures :
  1. Immune Checkpoint Regulators - Incidence [ Time Frame: Days 30, 60, and 90 post-transplant ]
    To characterize the incidence of immune checkpoint regulators (V-domain Ig Suppressor of T-cell Activation, cytotoxic T-lymphocyte-associated protein 4 [CTLA], Programmed cell death protein 1 [PD-1]) during early immune recovery following an allogeneic stem cell transplant.

  2. Myeloid-derived suppressor cells (MDSCs) after Graft vs. Host Disease (GVHD) diagnosis - checkpoint regulator expression [ Time Frame: Post-transplant through study completion or death, assessed up to 3 years post-transplant ]
    In those patients experiencing GVHD, the study team will define the checkpoint regulator expression on MDSCs

  3. MDSCs after GVHD diagnosis - peripheral blood mononuclear cells [ Time Frame: Post-transplant through study completion or death, assessed up to 3 years post-transplant ]
    In those patients experiencing GVHD, the study team will define the peripheral blood mononuclear cells and myeloid subsets.

  4. MDSCs after GVHD diagnosis - myeloid subsets using flow cytometry [ Time Frame: Post-transplant through study completion or death, assessed up to 3 years post-transplant ]
    In those patients experiencing GVHD, the study team will define the myeloid subsets.

  5. MDSCs after GVHD diagnosis - frequency [ Time Frame: Post-transplant through study completion or death, assessed up to 3 years post-transplant ]
    In those patients experiencing GVHD, the study team will define the MDSCs frequency.

  6. Immune Checkpoint Regulators - Prevalence [ Time Frame: Days 30, 60, and 90 post-transplant ]
    To characterize the prevalence of immune checkpoint regulators (VISTA, CTLA-4, PD-1) during early immune recovery following an allogeneic stem cell transplant.

  7. Immune Checkpoint Regulators - Function [ Time Frame: Days 30, 60, and 90 post-transplant ]
    Flow cytometry will be used to characterize the function of immune checkpoint regulators (VISTA, CTLA-4, PD-1) during early immune recovery following an allogeneic stem cell transplant.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age: less than 75 years
  • The patient must be approved for transplant by the treating transplant physician. This includes completion of their pre-transplant workup, as directed by standard Dartmouth-Hitchcock Medical Center (DHMC) Standard Operating Procedure (SOP) (DHMC SOP - Pre-transplant Evaluation of allogeneic recipient (Appendix).
  • The patient must have a disease (listed below) with treatment-responsiveness that the treating transplant physician believes will benefit from an allogeneic stem cell transplant. The diseases include:
  • Acute leukemia - Acute Myeloid Leukemia, Acute Lymphocytic Leukemia
  • Chronic leukemia - Chronic Myeloid Leukemia, Chronic Lymphocytic Leukemia
  • Myelodysplasia
  • Myeloproliferative disorder
  • Myelofibrosis
  • Lymphoma - Non-Hodgkin's Lymphoma or Hodgkin's disease
  • Plasma cell disorder, including myeloma, Waldenstrom's Macroglobulinemia
  • Donor availability- the patient must have an identified RELATED haplo-identical donor
  • No Human Immunodeficiency Virus infection or active hepatitis B or C
  • Eastern Cooperative Oncology Group performance status: 0-2
  • Diffusing capacity of carbon monoxide (DLCO) greater than or equal to 40 % predicted
  • Left ventricular ejection fraction greater than or equal to 40%
  • Serum bilirubin < 2x upper limit of normal; transaminases < 3x normal at the time of transplant
  • No active or uncontrollable infection
  • In female, a negative pregnancy test if experiencing menstrual periods
  • No major organ dysfunction precluding transplantation
  • No evidence of an active malignancy that would limit the patient's survival to less than 2 years. (If there is any question, the PI can make a decision).

Exclusion Criteria:

  • Psychiatric disorder or a mental deficiency of the patient that is sufficiently severe to make compliance with the treatment unlikely, and making informed consent impossible.
  • Major anticipated illness or organ failure incompatible with survival from bone marrow transplant.
  • History of refractory systemic infection

DONOR ELIGIBILITY

  • Human leukocyte antigen (HLA) haplo-identical matched related.
  • The donor must be healthy and must be willing to serve as a donor, based on standard National Marrow Donor Program (NMDP) guidelines and DHMC SOP - Donor Evaluation (Appendix)
  • The donor must have no significant co-morbidities that would put the donor at marked increased risk
  • There is no age restriction for the donor
  • Informed consent must be signed by donor

DONOR EXCLUSION CRITERIA

  • The NMDP guidelines for exclusion criteria will be used (Appendix). In addition, the following donors are NOT eligible:
  • Pregnant or lactating donor
  • HIV or active Hep B or C in the donor
  • Donor unfit to receive G-CSF and undergo apheresis
  • A donor with a psychiatric disorder or mental deficiency that makes compliance with the procedure unlikely and informed consent impossible

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): NCT03480360


Contacts
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Contact: Research Nurse (800) 639-6918 cancer.research.nurse@dartmouth.edu

Locations
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United States, New Hampshire
Dartmouth Hitchcock Medical Center, Norris Cotton Cancer Center Recruiting
Lebanon, New Hampshire, United States, 03756
Contact: Research Nurse    800-639-6918    cancer.research.nurse@dartmouth.edu   
Contact: Michael Sainz    603-650-5153    michael.sainz@hitchcock.org   
Sponsors and Collaborators
Dartmouth-Hitchcock Medical Center
Investigators
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Principal Investigator: Kenneth Meehan, MD Dartmouth-Hitchcock Medical Center

Publications of Results:

Other Publications:
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Responsible Party: Kenneth Meehan, Principal Investogator- Kenneth Meehan, MD Staff Physician, Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier: NCT03480360     History of Changes
Other Study ID Numbers: D17170
First Posted: March 29, 2018    Key Record Dates
Last Update Posted: March 22, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Kenneth Meehan, Dartmouth-Hitchcock Medical Center:
haploidentical
transplant
peripheral blood
allogeneic
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Leukemia, Myeloid
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lymphoma, Non-Hodgkin
Myeloproliferative Disorders
Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pathologic Processes
Leukemia, Lymphoid
Leukemia, B-Cell
Bone Marrow Diseases
Hematologic Diseases
Mycophenolic Acid
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents