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

Sponsor

Dartmouth-Hitchcock Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT03480360

Collaborator

(none)

Enrollment

Location

Arm

57.1

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

N/A

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 :

Mar 28, 2018

Anticipated Primary Completion Date :

Dec 31, 2021

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Other: 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

Arm

Intervention/Treatment

Other: 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

Outcome Measures

Primary Outcome Measures

100-Day Survival [100 days post date of peripheral blood transplant]
Define 100-day survival of subjects

Secondary Outcome Measures

Immune Checkpoint Regulators - Incidence [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.
Myeloid-derived suppressor cells (MDSCs) after Graft vs. Host Disease (GVHD) diagnosis - checkpoint regulator expression [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
MDSCs after GVHD diagnosis - peripheral blood mononuclear cells [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.
MDSCs after GVHD diagnosis - myeloid subsets using flow cytometry [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.
MDSCs after GVHD diagnosis - frequency [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.
Immune Checkpoint Regulators - Prevalence [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.
Immune Checkpoint Regulators - Function [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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