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

Lymphoma Clinical Trial

Official title:

Haploidentical Allogeneic Peripheral Blood Transplantation: Clinical Trial and Laboratory Correlates Examining Checkpoint Immune Regulators' Expression

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03480360
• Other study ID #: D17170
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: March 28, 2018
• Est. completion date: September 13, 2025

Study information

• Verified date: October 2023
• Source: Dartmouth-Hitchcock Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

We propose a clinical trial to define clinical endpoints, including engraftment, 100-day survival and one year survival (Objective #1). We will characterize the incidence, prevalence and function of immune checkpoint regulators in patients' blood and bone marrow following transplantation (Objective #2). We will correlate these laboratory results with clinical outcomes and the incidence of GVHD. As an exploratory aim, in those patients experiencing GVHD and requiring treatment, we will define the frequency/expression of checkpoint regulator expression and correlate these results with the patient's response to GVHD therapy.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 20
• Est. completion date: September 13, 2025
• Est. primary completion date: March 27, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Chronic Lymphocytic Leukemia
• Chronic Myeloid Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Lymphoma
• Lymphoma, Non-Hodgkin
• Myelodysplasia
• Myelofibrosis
• Myeloproliferative Disorder
• Myeloproliferative Disorders
• Plasma Cell Disorder

Intervention

Drug:
• Cyclophosphamide
14.5 mg/kg for 2 days (days -6, -5) and then 50 mg/kg for two days (days 3, 4)
• 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.
• cellcept
dose at 15 mg/kg po three times per day (maximum dose of 3 grams/day). Stop Cellcept at Day 35 following transplantation.
• 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

Locations

Country	Name	City	State
United States	Dartmouth Hitchcock Medical Center, Norris Cotton Cancer Center	Lebanon	New Hampshire

Sponsors (1)

Lead Sponsor	Collaborator
Dartmouth-Hitchcock Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (23)

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* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	100-Day Survival	Define 100-day survival of subjects	100 days post date of peripheral blood transplant
Secondary	Immune Checkpoint Regulators - Incidence	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.	Days 30, 60, and 90 post-transplant
Secondary	Myeloid-derived suppressor cells (MDSCs) after Graft vs. Host Disease (GVHD) diagnosis - checkpoint regulator expression	In those patients experiencing GVHD, the study team will define the checkpoint regulator expression on MDSCs	Post-transplant through study completion or death, assessed up to 3 years post-transplant
Secondary	MDSCs after GVHD diagnosis - peripheral blood mononuclear cells	In those patients experiencing GVHD, the study team will define the peripheral blood mononuclear cells and myeloid subsets.	Post-transplant through study completion or death, assessed up to 3 years post-transplant
Secondary	MDSCs after GVHD diagnosis - myeloid subsets using flow cytometry	In those patients experiencing GVHD, the study team will define the myeloid subsets.	Post-transplant through study completion or death, assessed up to 3 years post-transplant
Secondary	MDSCs after GVHD diagnosis - frequency	In those patients experiencing GVHD, the study team will define the MDSCs frequency.	Post-transplant through study completion or death, assessed up to 3 years post-transplant
Secondary	Immune Checkpoint Regulators - Prevalence	To characterize the prevalence of immune checkpoint regulators (VISTA, CTLA-4, PD-1) during early immune recovery following an allogeneic stem cell transplant.	Days 30, 60, and 90 post-transplant
Secondary	Immune Checkpoint Regulators - Function	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.	Days 30, 60, and 90 post-transplant