Evaluation of Fostamatinib in Patients With cGVHD After Allogeneic Stem Cell Transplant

March 15, 2023 updated by: Stefanie Sarantopoulos, MD, PhD.

A Phase I Trial of Fostamatinib and Chronic Graft vs. Host Disease Development After Allogeneic Stem Cell Transplantation

The purpose of this study is to evaluate whether fostamatinib, a drug that blocks activated B cells will be effective in preventing and treating chronic graft vs host disease (cGVHD) after allogeneic stem cell transplant. Activated B cells may play a role in development of cGVHD. Inhibiting the B cell activation using fostamatinib after allogeneic stem cell transplant may prevent the development of cGVHD.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Design & Procedures

All patients will undergo allogeneic stem cell transplantation (HCT) according to the program's standards. No specific conditioning regimen is mandated. The stem cell source must have been peripheral blood stem cells. Prophylaxis against acute GVHD must be with standard agents (sirolimus and/or tacrolimus and/or methotrexate and/or cyclosporine). Participation in a trial evaluating novel agents for therapy of acute GVHD is allowed, as long as the experimental agent was discontinued > 14 days prior to trial entry.

Therapy: Patients will receive 100mg daily, 150mg daily or 100 mg bid beginning 90 days after allogeneic transplantation and continue for up to 1 year from day of transplant OR beginning at time of steroid-refractory cGVHD. Dosage will be determined using the modified continual reassessment method.

Patient evaluations: Patients will be evaluated for cGVHD and other toxicity at a minimum on day 1(baseline), day 3, day 11, day 25, day 39, day 60, day 88, day 116, day 144, day 186, day 228, and day 275 from initiation of protocol therapy. While the assessment for safety is determined based on the evaluation at day 60, patients may stay on therapy for up to 1 year after transplantation (study treatment day 275). In addition, patients will be observed for one year after stopping study treatment with evaluation for toxicity and cGVHD during clinic visits at 6 and 12 months after completion of study therapy. If at any time within the first year after transplantation, a study subject is determined to have evidence of moderate or severe stage cGVHD according to NIH consensus criteria for global severity, the subject will be removed from this clinical trial and appropriate therapy for cGVHD will be administered per the treating physician's discretion. The study subject may continue to receive Fostamatinib as per the guidelines of this clinical trial in the event that mild stage cGVHD is diagnosed. If cGVHD develops during the observation period, a second course of Fostamatinib at 100% tolerated study dose may be given during the observation period.

Immunosuppressive and other medications should be tapered according to the treating physicians' discretion with careful attention to the clinical trial or treatment plan to which the participating subject is already enrolled.

Laboratory samples will be obtained according to the study schedule. The following tests are to be collected and analyzed for the study: complete blood counts, serum chemistry, liver function tests (LFTs), chimerism analysis if indicated, and immunology/correlative science studies.

This study will be open to members of all demographic groups who meet the eligibility criteria. Approximately 18 subjects will be recruited at Duke.

A total of eighteen patients will receive fostamatinib beginning at day 90 after allogeneic transplantation. The safety assessment is determined at day 60. Patients with steroid-refractory cGVHD are also eligible for this phase I study. Three dose levels are considered: 100 mg qd, 150 mg qd, 100 mg bid, and the target dose-limiting toxicity (DLT) probability is 0.33. The Bayesian model averaging continual reassessment method (BMA-CRM) will be used for this trial.[15]

The investigators will study targeted molecular mechanisms underpinning aberrant B-cell signaling in cGVHD. Corollary studies will determine whether B and T cell subsets and/or soluble B-cell activation factors are altered after Syk inhibition. The objective is to implement preemptive targeted therapies that decrease excessive immune activation in patients.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
22

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Patients who have undergone allogeneic stem cell transplantation for the treatment of any hematological malignancy are eligible. Transplant must have occurred 90 days before the start of study drug.
  2. Peripheral blood stem cells must have been used as the stem cell source.
  3. Patients must have received transplantation from adult donors (both related and unrelated) who are Human Leukocyte Antigen (HLA) matched or mismatched at 1 locus (5/6) or are mismatched at one allele (3/6). Class I and II typing is to be performed by standard methods at our institution.
  4. Complete remission of hematological malignancy prior to transplantation. All patients must have undergone appropriate staging for their malignancy prior to transplantation including bone marrow aspirate/biopsy and radiographic scanning if indicated.
  5. Patients who have undergone a non-myeloablative stem cell transplant must have > 65% donor lymphoid hematopoiesis within 30 days of study enrollment.
  6. Patient age greater than 18 years of age.
  7. ECOG performance status 0-2 or Karnofsky Performance Status (KPS) > 60.
  8. Must be able to tolerate routine oral posaconazole or voriconazole as fungal prophylaxis therapy.
  9. Written informed consent.

Exclusion Criteria:

  1. Recipients of allogeneic stem cell transplantation using a single or multiple umbilical cord blood units or using bone marrow.
  2. Participation in a clinical trial evaluating another preventative strategy for chronic GVHD or ongoing participation in a clinical trial for therapy of acute GVHD. Prior completion of experimental therapy for acute GVHD is permissible if the experimental agent was used > 14 days prior to enrollment.
  3. Evidence of relapsed hematologic malignancy based on routine restaging studies.
  4. Evidence of any active uncontrolled infection (bacterial, viral or fungal) or evidence of natural exposure to Hepatitis B, Hepatitis C or HIV without demonstration of PCR negativity for said virus. Vaccination to Hepatitis B is not an exclusion criterion.
  5. Any evidence of ongoing gastrointestinal or hepatic acute GVHD or evidence of greater than ongoing Stage I cutaneous acute GVHD at time of enrollment. Ongoing, tapering therapy for resolved acute GVHD is permissible.
  6. Patients with GVHD with chronic features diagnosed prior to day +60 or prior to enrollment are ineligible.
  7. Patients may have received no more than one Donor Lymphocyte Infusion (DLI), DLI must have been administered > 6 weeks prior to enrollment on study, and no plans for a DLI in the upcoming 30 days.
  8. Any major cardiovascular even within 6 months of study initiation, including but not limited to myocardial infarction, unstable angina, cerebrovascular accident, pulmonary embolism, heart failure uncontrolled by medications or New York Heart Association Class III or IV heart failure.
  9. Uncontrolled or poorly controlled hypertension, defined as systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg, whether or not the subject is receiving anti-hypertensive treatment. Subjects may be rescreened if the blood pressure is successfully and promptly controlled within 5 days using conventional anti-hypertensive therapy to achieve optimal blood pressure control (<140/90 mmHg).
  10. Active hemolytic anemia.
  11. History of arterial or venous thrombosis (unless a single episode of venous thrombosis > 1 year prior to study initiation).
  12. Liver function test abnormalities including ALT or AST > 3.0x ULN; total bilirubin > 1.5x ULN; alkaline phosphatase > 2.5 x ULN
  13. Neutrophil count < 1.5 x 10e9/L or platelet count < 75 x10e9/L
  14. Pregnancy or lactation.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: fostamatinib
Subjects will receive fostamatinib 100 mg qd, 150 mg qd, or 100 mg bid with dosage determined by the modified continual reassessment method. The treatment period begins at baseline 90 days after transplant and continues for up to 1 year after transplant. In patients with steroid-refractory cGVHD who are also included on this study, these subjects also receive fostamatinib 100mg qd, 150mg qd, or 100mg bid dosage determined by the modified continual reassessment method.
Drug: fostamatinib
100mg qd, 150mg qd, or 100mg bid

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Evaluate maximum tolerated dose of fostamatinib delivered following allogenic transplantation
Time Frame: day 60 after fostamatinib initiation

three dose levels are considered: 100 mg qd, 150 mg qd, 100 mg bid dose limiting toxicity is any of the following

  1. Grade > or = II aGVHD of the gut or liver or Grade III aGVHD of the skin lasting > 7 days and related to the agent
  2. Grade 3 toxicity from the agent in the cardiac, dermatologic, gastrointestinal, hepatic, pulmonary, renal/genitourinary or neurologic categories that lasts > 5 days
  3. fostamatinib related mortality (TRM)
  4. absolute neutrophil count (ANC) of Grade 3 or 4 plus fever attributable to the agent
  5. ANC<0.5 x 10e9/L for >5 days and attributable to the agent
  6. platelet < 25 x 10e 9/L and attributable to the agent
day 60 after fostamatinib initiation

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Incidence of chronic graft vs host disease (cGVHD)
Time Frame: one and two years when fostamatinib administered after allogeneic HCT
one and two years when fostamatinib administered after allogeneic HCT
Incidence of relapse of chronic graft vs host disease (cGVHD)
Time Frame: one and two years when fostamatinib administered after allogeneic HCT
one and two years when fostamatinib administered after allogeneic HCT
B-cell activation rate
Time Frame: two years
B-cell activation rate before and after fostamatinib administration
two years
B-cell death rate
Time Frame: two years
B-cell death rate before and after fostamatinib administration
two years
Number of B-cells
Time Frame: two years
Immune recovery as measured by the number of B-cells before and after fostamatinib administration
two years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Stefanie Sarantopoulos, MD, PhD.

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Stefanie Sarantopoulos, MD, PhD, Duke University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2016

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 1, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 22, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 16, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 18, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
November 20, 2015

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 17, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 15, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • Pro00064227

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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