Biomarkers in Acute Graft-Versus-Host Disease and Extraco... | NCT02322190

ID	Type	Description	Link
15-C-0039

Status Module

Description Module

Brief Summary

Background:

- Some allogeneic stem cell transplant recipients get acute graft-versus-host disease (GVHD). They always get steroids as the first treatment, but this may not work. Those people where steroids are not enough may benefit from a treatment called extracorporeal photopheresis (ECP). ECP exposes white blood cells to ultraviolet light outside the body. Researchers want to study how certain markers in the blood predict the severity and outcome of acute GVHD and how ECP treatments work for people with acute GVHD. They will also study how these markers in the blood may help predict who should get ECP and its effects on the immune system.

Objectives:

- To learn more about treatments for acute GVHD after allogeneic stem cell transplantation.

Eligibility:

- Adults with acute GVHD enrolled in an National Cancer Institute (NCI) allogeneic transplantation protocol.

Design:

Transplant physicians will confirm participant eligibility.
Participants will receive treatment with steroids for their acute GVHD as prescribed by their transplant physician. This will continue while they are enrolled on this study.
If steroids work in treating their acute GVHD, then every 28 days for 6 months, participants will have:
a physical exam.
blood tests.
If steroids do not work, participants will get additional treatments as prescribed by their transplant physician who may choose to use ECP as a part of this additional treatment. For ECP, blood is removed through an intravenous (IV) catheter. A machine separates the white blood cells from the other blood parts. Those cells are treated with methoxsalen and exposed to ultraviolet light. Then they are returned to the participant through their IV.
Participants who get ECP will over at least 6 months have:
veins researched. They may have a catheter placed in a larger vein in the chest or groin.
multiple blood tests.
multiple pregnancy tests (if needed).
multiple ECP procedures.
At the end of ECP treatment and 6 months after ECP, participants will have additional physical exams and blood tests.

Detailed Description

Background:

Acute graft versus host disease (GVHD) remains a difficult to manage complication of allogeneic hematopoietic stem cell transplantation causing significant morbidity and mortality.
Biomarkers have recently been described in acute GVHD that have the potential to better predict onset, severity, steroid failure, and non-relapse mortality.
First line treatment of acute GVHD with high dose corticosteroids will fail in approximately 30% of patients and is associated with significant steroid related complications.
No second line treatment of acute GVHD after a failure of steroids has been established as a standard approach.
Choice of second line therapy for acute GVHD is currently based primarily on physician familiarity, existing toxicities, and patient's ability to tolerate new potential toxicities.
Extracorporeal photopheresis (ECP) is an attractive therapy to combine with other therapies for steroid refractory disease due to a unique mechanism of action involving immunomodulation as well as an extremely low rate of reported side effects and complications.
Biomarkers may also prove useful in predicting the success or failure of specific treatments for steroid refractory disease, including those combined with ECP.
This study will allow for collection of biomarker data in patients undergoing allogeneic transplantation on National Cancer Institute (NCI) protocols, including those who develop acute GVHD and investigate their role in predicting outcomes in initial corticosteroid therapy as well as in currently used treatments in the management of patients with steroid refractory acute GVHD with or without the addition of ECP.

Objective:

-To study biomarkers in patients undergoing allogeneic transplantation, with acute GVHD including their ability to predict steroid refractoriness and predict outcome of investigator chosen second line therapies with and without Extracorporeal Photopheresis (ECP).

Eligibility:

- Adult patients on an NCI allogeneic transplantation protocol.

Design:

Non-randomized, single institution study.
Research blood for biomarkers will be collected on all patients enrolled.
ECP will be offered as an addition to investigator chosen treatments in patients who develop steroid refractory acute GVHD.
The study will enroll a total of up to 450 patients.

Label	Type	Description	Intervention Names
Investigator chosen second line therapy	No Intervention	Investigator chosen second line therapy
Second line therapy + Extracorporeal Photopheresis	Experimental	Second line therapy in addition to Extracorporeal Photopheresis (ECP)	Procedure: Extracorporeal Photopheresis (ECP) Drug: Methoxsalen

Name	Type	Description	Arm Group Labels	Other Names
Extracorporeal Photopheresis (ECP)	Procedure	Twice weekly for 1 month or Twice every other week for 2 months or Twice during one week per month for 4 months for a total of up to 7 months of treatment.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants With Biomarkers (Serum TIM3, IL-6, Reg-3-a, ST2, LPS-BP, Nitrate, TNFR1, IL-2Ra, CXCL10, and HGF) Present in Blood and/or Tissue Who Were Steroid Refractory After ECP Treatment	In an effort to determine steroid refractoriness after Extracorporeal Photopheresis (ECP) treatment, tissue and blood obtained from participants was examined to see if biomarkers (i.e., Serum T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), ST2, Nitrate, Interleukin-6 (IL-6), regenerating family member 3 alpha (Reg-3-a), lipopolysaccharide binging protein (LPS-BP), tumor necrosis factor receptor 1 (TNFR1), interleukin-2 receptor alpha chain (IL-2Ra), CXC motif chemokine 10 (CXCL10), hepatocyte growth factor (HGF)) were present.	14 Days
Number of Participants With Steroid Refractory Disease Who Had Improvement and/or Resolution of Graft-versus-host Disease (GVHD) Associated Symptoms	GVHD associated symptoms was assessed by the American Society for Bone Marrow Transplantation consensus statement. Complete Response (CR) is no residual organ specific symptoms or findings. Very Good Partial Response (VGPR) is Skin: An active erythematous rash involving < 25% of the body surface area; Liver: Persistent low-level hyperbilirubinemia, and/or Gut: Gastrointestinal function and water resorption in the colon are approaching normal. Partial Response (PR) is any improvement over baseline symptoms. Progressive disease (PD) is stable or worsening organ specific findings requiring change of therapy.	7 months

Secondary Outcomes

Measure	Description	Time Frame
Days to Overall Survival	Overall survival is defined as the time from study entry to end of observations/off study.	time from study entry to end of observations/off study, up to a year
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).

Eligibility Module

Eligibility Criteria

INCLUSION CRITERIA:
Age greater than or equal to18 years.
Ability of subject to understand and the willingness to sign a written informed consent document.
Subject must be also enrolled on an National Cancer Institute (NCI) allogeneic transplant protocol.
Patients must agree to practice effective contraception (both male and female subjects, if the risk of conception exists)The effects of Extracorporeal Photopheresis (ECP) on the developing human fetus are unknown. For this reason and as well as other Methoxsalen used in this trial is in a class of agents that is known to be teratogenic, men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for 4 months after the completion of study treatment. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately.

EXCLUSION CRITERIA:

Any physical or mental condition that, in the opinion of the principal Investigator (PI), would cause the risk/benefit ratio of participation to be unacceptable.
Inclusion of ECP in the treatment of any patient is contraindicated by any of the following:
Unstable hemodynamics requiring vasopressors or other support measures not amenable to or medically appropriate for continuation during the procedure.
Uncontrolled infection.
Inability to maintain acceptable venous access.
Uncontrolled or uncorrectable coagulopathy.
Pregnant women are excluded from ECP because methoxsalen, an agent utilized for the study procedure, may cause fetal harm. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with methoxsalen, breastfeeding should be discontinued if the mother is treated with methoxsalen. Pregnancy will be evaluated prior to initiation of ECP.
History of allergic or idiosyncratic/hypersensitivity reactions to 8- methoxypsoralen/psoralen compounds.
History of a light-sensitive cutaneous disease
Subjects with aphakia

Name	Affiliation	Role
Ronald E Gress, M.D.	National Cancer Institute (NCI)	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
National Institutes of Health Clinical Center, 9000 Rockville Pike		Bethesda	Maryland	20892	United States

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Investigator Chosen Second Line Therapy	Investigator chosen second line therapy is determined on an individual basis based on standard care and actual site of Graft -versus-Host Disease (GVHD). The frequency or duration of therapy is based on Principal Investigator (PI) discretion.
FG001

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Oct 2, 2018

ID	Title	Description
BG000	Investigator Chosen Second Line Therapy	Investigator chosen second line therapy is determined on an individual basis based on standard care and actual site of Graft -versus-Host Disease (GVHD). The frequency or duration of therapy is based on Principal Investigator (PI) discretion.

Units	Counts
Participants	BG0005

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Categorical

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
<=18 years	BG0000
Between 18 and 65 years	BG0005
>=65 years	BG000

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00044.62± 11.65

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG0003
Male	BG0002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG0004
Not Hispanic or Latino	BG0001

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000
Asian	BG0000

Region of Enrollment

Count of Participants

Participants

Title

Denominators

Categories

United States

Title	Measurements
	BG0005

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants With Biomarkers (Serum TIM3, IL-6, Reg-3-a, ST2, LPS-BP, Nitrate, TNFR1, IL-2Ra, CXCL10, and HGF) Present in Blood and/or Tissue Who Were Steroid Refractory After ECP Treatment

In an effort to determine steroid refractoriness after Extracorporeal Photopheresis (ECP) treatment, tissue and blood obtained from participants was examined to see if biomarkers (i.e., Serum T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), ST2, Nitrate, Interleukin-6 (IL-6), regenerating family member 3 alpha (Reg-3-a), lipopolysaccharide binging protein (LPS-BP), tumor necrosis factor receptor 1 (TNFR1), interleukin-2 receptor alpha chain (IL-2Ra), CXC motif chemokine 10 (CXCL10), hepatocyte growth factor (HGF)) were present.

No data was collected for this outcome measure and it not done because biomarker studies require large patient numbers to analyze data. Only five participants were enrolled in this study. With early termination, there are no biomarker data to report.

Posted

14 Days

ID	Title	Description
OG000	Investigator Chosen Second Line Therapy	Investigator chosen second line therapy is determined on an individual basis based on standard care and actual site of Graft -versus-Host Disease (GVHD). The frequency or duration of therapy is based on Principal Investigator (PI) discretion.

Units	Counts
Participants	OG0000

Primary

Number of Participants With Steroid Refractory Disease Who Had Improvement and/or Resolution of Graft-versus-host Disease (GVHD) Associated Symptoms

GVHD associated symptoms was assessed by the American Society for Bone Marrow Transplantation consensus statement. Complete Response (CR) is no residual organ specific symptoms or findings. Very Good Partial Response (VGPR) is Skin: An active erythematous rash involving < 25% of the body surface area; Liver: Persistent low-level hyperbilirubinemia, and/or Gut: Gastrointestinal function and water resorption in the colon are approaching normal. Partial Response (PR) is any improvement over baseline symptoms. Progressive disease (PD) is stable or worsening organ specific findings requiring change of therapy.

Posted

Count of Participants

Participants

7 months

ID	Title	Description
OG000	Investigator Chosen Second Line Therapy	Investigator chosen second line therapy is determined on an individual basis based on standard care and actual site of Graft -versus-Host Disease (GVHD). The frequency or duration of therapy is based on Principal Investigator (PI) discretion.

Units	Counts
Participants	OG000

Secondary

Days to Overall Survival

Overall survival is defined as the time from study entry to end of observations/off study.

Posted

Median

Full Range

Days

time from study entry to end of observations/off study, up to a year

ID	Title	Description
OG000	Investigator Chosen Second Line Therapy	Investigator chosen second line therapy is determined on an individual basis based on standard care and actual site of Graft -versus-Host Disease (GVHD). The frequency or duration of therapy is based on Principal Investigator (PI) discretion.

Units	Counts
Participants	OG0005

Secondary

Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Posted

Count of Participants

Participants

Date treatment consent signed to date off study, approximately 8 months and 6 days

ID	Title	Description
OG000	Investigator Chosen Second Line Therapy	Investigator chosen second line therapy is determined on an individual basis based on standard care and actual site of Graft -versus-Host Disease (GVHD). The frequency or duration of therapy is based on Principal Investigator (PI) discretion.

Units	Counts
Participants

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Investigator Chosen Second Line Therapy	Investigator chosen second line therapy is determined on an individual basis based on standard care and actual site of Graft -versus-Host Disease (GVHD). The frequency or duration of therapy is based on Principal Investigator (PI) discretion.	1	5	1	5	0	5
EG001	Second Line Therapy + Extracorporeal Photopheresis	Second line therapy in addition to Extracorporeal Photopheresis (ECP) Extracorporeal Photopheresis (ECP): Twice weekly for 1 month or Twice every other week for 2 months or Twice during one week per month for 4 months for a total of up to 7 months of treatment Methoxsalen: Used in conjunction with photopheresis procedure	0	0	0	0	0	0

ID	Term
D011701	PUVA Therapy
D014467	Ultraviolet Therapy
D010789	Phototherapy
D013812	Therapeutics
D005112	Extracorporeal Circulation
D013514	Surgical Procedures, Operative
D011564	Furocoumarins
D003374	Coumarins
D001578	Benzopyrans
D011714	Pyrans
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006575	Heterocyclic Compounds, 3-Ring