Ruxolitinib Plus Fostamatinib for Steroid Refractory cGvHD

Chronic Graft Versus Host Disease Clinical Trial

Official title:

Phase I Trial of Ruxolitinib Plus Fostamatinib for the Treatment of Steroid Refractory Chronic Graft Versus Host Disease

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06233110
• Other study ID #: Pro00113327
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: June 1, 2024
• Est. completion date: July 1, 2029

Study information

• Verified date: January 2024
• Source: Duke University
• Contact: Chenyu Lin, MD
• Phone: 919-684-8964
• Email: chenyu.lin[@]duke.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an open-label phase I study of fostamatinib in combination with ruxolitinib for the treatment of chronic GvHD with a suboptimal response to corticosteroids. The primary objective is to identify a minimum safe and biologically effective dose of fostamatinib when combined with standard of care ruxolitinib for the treatment of steroid refractory and steroid dependent cGVHD. The secondary objective is to estimate the efficacy of the combination of ruxolitinib and fostamatinib for the treatment of steroid refractory and steroid dependent cGVHD. The target enrollment is 24-30 subjects. The study will begin with an initial dose escalation cohort employing a modified 3+3 design to investigate up to three doses of fostamatinib. Using safety, efficacy, pharmacodynamic (PD), and pharmacokinetic data (PK), an interim assessment will be performed to determine two candidate doses of the biologically optimal dose to investigate further. A safety expansion cohort will be opened to backfill these two candidate doses up to a total 12 patients per dose, including those in the dose escalation cohort who received the candidate doses. Patients will then be randomized to one of these two candidate doses in te expansion. A final analysis of safety, efficacy, and PK/PD data in patients who received the two candidate doses will be conducted to determine a minimum safety and biologically effective dose, which will be the recommended phase II dose (RP2D). The primary hypothesis is that Fostamatinib combined with ruxolitinib is a safe therapy for and has synergistic activity in cGvHD. The recommended phase II dose will be determined by the study investigators in collaboration with the sponsors. The decision to select the recommended phase II dose will occur only after all patients in the part 1 have completed at least 28 days of therapy. The decision will be based on the valuation of all relevant, available data, and not solely on dose-limiting toxicities.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 30
• Est. completion date: July 1, 2029
• Est. primary completion date: January 1, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Patient is able and willing to provide written informed consent prior to any study related screening procedures are performed.

2. Age = 18 years old at the time of informed consent

3. Have undergone allogeneic hematopoietic cell transplantation (HCT) from any donor source (matched unrelated donor, sibling, haploidentical) using bone marrow, peripheral blood, or cord blood stem cells.

4. Adequate bone marrow function defined as:

4.1. Absolute neutrophil count (ANC) = 750 /mm3 4.2. Platelet count = 40,000 /mm3 4.3. Hemoglobin = 8.0 g/dL without transfusion support Note: Use of growth factor supplementation (myeloid, erythroid or megakaryocytic) is permitted to meet eligibility criteria.

5. Patients with clinically diagnosed cGvHD staging of mild to severe according to NIH Consensus Criteria4 prior to Cycle 1 Day 1 and with confirmed steroid refractoriness or steroid dependence irrespective of the concomitant use of a calcineurin inhibitor, as follows: 5.1. Disease progression after administration of a minimum dose of 1.0 mg/kg/day or equivalent for at least 1 week at any time following diagnosis of cGvHD OR 5.2. Disease persistence despite continued treatment with prednisone > 0.5mg/kg/d or equivalent for at least 4 weeks OR 5.3. Increase to prednisone > 0.25 mg/kg/d after 1 unsuccessful attempt to taper the dose. 5.4. Recurrence of chronic GVHD after attaining a complete response 5.5. Progression of chronic GVHD after attaining a partial response

6. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

Exclusion Criteria:

1. Prior or ongoing treatment with ruxolitinib for treatment of cGvHD for longer than 3 weeks prior to anticipated C1D1.

2. Prior treatment with fostamatinib or another SYK inhibitor for the treatment of acute or chronic GVHD. Prior use of fostamatinib for immune thrombocytopenic purpura is permitted.

3. Ongoing systemic therapy for cGvHD other than corticosteroids, calcineurin inhibitor, or mycophenolate mofetil, aside from fewer than 3 weeks of ruxolitinib. Prior ruxolitinib use for the indication of acute GVHD is permitted.

4. Patients with relapsed primary malignancy, or who have been treated for relapse after the allogeneic HCT was performed

5. SR-cGvHD occurring after a non-scheduled donor lymphocyte infusion (DLI) administered for pre-emptive treatment of malignancy recurrence. Patients who have received a scheduled DLI as part of their transplant procedure and not for management of malignancy relapse are eligible.

6. History of progressive multifocal leuko-encephalopathy (PML)

7. Active uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of infection progression are present.

8. Evidence of active and clinically significant viral disease including HIV, CMV, HHV-6, HBV, HCV, or BK virus.

9. Patients on mechanical ventilation or have a resting O2 saturation < 90% by pulse oximetry

10. Clinically significant and uncontrolled cardiovascular disease, including unstable angina, acute myocardial infarction, or stroke within 3 months, or NYHA Class III or IV congestive heart failure.

11. Uncontrolled hypertension with systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.

12. Creatinine clearance by Cockroft-Gault of < 15 mL/min and not on dialysis

13. Total bilirubin > 3 times ULN, ALT > 5 times ULN, or AST > 5 times ULN

14. QTc = 470 ms as calculated by the Fridericia Formula

15. Active pregnancy or breast feeding, or currently seeking active pregnancy

16. Any patient who, in the opinion of the investigator, may not be able to comply with study procedures

Related Conditions & MeSH terms

• Bronchiolitis Obliterans Syndrome
• Chronic Graft Versus Host Disease
• Graft vs Host Disease

Intervention

Drug:
• Fostamatinib
Fostamatinib will be administered as part of the initial dose escalation cohort and then two candidate doses will be identified to be administered for the safety expansion cohort.
• Ruxolitinib
Ruxolitinib 10mg BID will be administered in combination with Fostamatinib in each of the study arms.

Locations

Country	Name	City	State
United States	Duke	Durham	North Carolina

Sponsors (4)

Lead Sponsor	Collaborator
Stefanie Sarantopoulos, MD, PhD.	Incyte Corporation, National Institutes of Health (NIH), Rigel Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Minimum safe and biologically effective dose as determined by dose-limiting toxicities	Dose limiting toxicities are defined as the adverse events detailed below occurring in the first 28 days of therapy which were felt by the investigator to be possibly, probably, or definitely related to the study drugs (either ruxolitinib or fostamatinib). However, grade 4 (life-threatening consequences, per NCI CTCAE version 5 criteria) non-hematologic adverse events will be considered DLTs regardless of attribution.	6 months
Primary	Minimum safe and biologically effective dose as determined by 6-month overall response rate	Overall response rate, as defined by achievement of a complete response (CR) or partial response (PR), using the 2014 NIH Consensus criterion, during the first 6 months of therapy	6 months
Primary	Minimum safe and biologically effective dose as determined by pharmacokinetic results	Plasma concentration of R406 (fostamatinib metabolite) will be measured using a validated liquid chromatography with tandem mass spectrometry (LC-MS-MS) method, prior to the first dose and at pre-specified time points after treatment initiation.	6 months
Primary	Minimum safe and biologically effective dose as determined by pharmacodynamic results	Frequency of circulating plasmablast-like B cells will be assessed using flow cytometry as a pharmacodynamic marker.	6 months
Secondary	Overall response rate	Overall response rate, as defined by achievement of a complete response (CR) or partial response (PR), using the 2014 NIH Consensus criterion, during the first 6 months of therapy.	6 months
Secondary	Duration of Response	The length of time that a patient's response to treatment lasts.	1 year
Secondary	1-year cGvHD-free survival	The cGVHD-free survival is a composite endpoint that measures survival free from the diagnosis of chronic GVHD at any stage. cGvHD activity assessment includes medical history, physical exam, and laboratory studies per the 2014 NIH Consensus Response Criteria.	1 year
Secondary	Overall survival	The length of time that a patient lives following treatment.	1 year