Evaluation of Fostamatinib in Patients With cGVHD After Allogeneic Stem Cell Transplant
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02611063|
Recruitment Status : Recruiting
First Posted : November 20, 2015
Last Update Posted : March 14, 2019
|Condition or disease||Intervention/treatment||Phase|
|Hematological Malignancies||Drug: fostamatinib||Phase 1|
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.
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 :||Interventional (Clinical Trial)|
|Estimated Enrollment :||18 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Trial of Fostamatinib and Chronic Graft vs. Host Disease Development After Allogeneic Stem Cell Transplantation|
|Study Start Date :||January 2016|
|Estimated Primary Completion Date :||January 2020|
|Estimated Study Completion Date :||January 2021|
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.
100mg qd, 150mg qd, or 100mg bid
- 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
- Grade > or = II aGVHD of the gut or liver or Grade III aGVHD of the skin lasting > 7 days and related to the agent
- Grade 3 toxicity from the agent in the cardiac, dermatologic, gastrointestinal, hepatic, pulmonary, renal/genitourinary or neurologic categories that lasts > 5 days
- fostamatinib related mortality (TRM)
- absolute neutrophil count (ANC) of Grade 3 or 4 plus fever attributable to the agent
- ANC<0.5 x 10e9/L for >5 days and attributable to the agent
- platelet < 25 x 10e 9/L and attributable to the agent
- Incidence of chronic graft vs host disease (cGVHD) [ Time Frame: 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 ]
- B-cell activation rate [ Time Frame: two years ]B-cell activation rate before and after fostamatinib administration
- B-cell death rate [ Time Frame: two years ]B-cell death rate before and after fostamatinib administration
- Number of B-cells [ Time Frame: two years ]Immune recovery as measured by the number of B-cells before and after fostamatinib administration
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): NCT02611063
|Contact: Krista Rowe, RNfirstname.lastname@example.org|
|Contact: Matthew Williamson, RNemail@example.com|
|Principal Investigator:||Stefanie Sarantopoulos, MD, PhD||Duke University|