Phase 2 Trial to determine the safety and efficacy of simultaneous treatment with ruxolitinib and extracorporeal photopheresis for patients with steroid-refractory chronic Graft-versus-Host-Disease (SR-cGvHD) - RUX-ECP

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medical Center - University Of Freiburg

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20], Diseases [C] - Neoplasms [C04]

Trial duration

19 Feb 2025 → ongoing

Decision date (initial)

2024-10-07

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Mallinckrodt Pharmaceuticals / Therakos EMEA Ltd.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The primary objective of this phase 2 trial is a first evaluation of the efficacy of
combined treatment of ruxolitinib and ECP for patients with SR-cGvHD as
assessed by Overall Response Rate (ORR) at the week 25 (Cycle 7 Day 1)
visit.

Secondary objectives 13

1. Failure-free survival (FFS), defined as time from start of treatment to the earliest recurrence of underlying disease, start of new systemic treatment for cGvHD, or death
2. Change in the modified Lee Symptom Scale score at week 25. Response defined as a ≥7-point reduction from baseline (Day 1 week 1) in total symptom score
3. Overall survival (OS)
4. Best overall response (BOR)
5. Response according to organs
6. Duration of response (DOR)
7. Non-relapse mortality (NRM)
8. Proportion of patients with ≥50% reduction in daily steroid dose at week 25
9. Proportion of patients who successfully tapered off all steroids at week 25
10. Cumulative incidence of Malignancy Relapse/Recurrence (MR)
11. Time to treatment response (TTTR)
12. Immune cell phenotype (T cells, NK cells, B cells, NKT cells, myeloid cell types) and biomarkers during treatment (Freiburg only)
13. Changes in FACT-BMT

Conditions and MedDRA coding

steroid-refractory chronic Graft-versus-Host-Disease

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Male and female patients aged ≥18 years
2. Patients have undergone alloSCT from any donor source (matched unrelated donor sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of non-myeloablative, myeloablative, and reduced intensity conditioning are eligible.
3. Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines.
4. SR-cGvHD diagnosis: Patients with clinically diagnosed moderate to severe cGvHD according to NIH Consensus Criteria (Jagasia 2015). Moderate: - at least one organ (not lung) with a score of 2-3 or more organs with score 1 or - lung score 1 Severe: - at least one organ with a score of 3 or - lung score 2
5. Patients who have received systemic glucocorticoids for the treatment of chronic graft-versus-host disease for a duration of < 6 months prior to cycle 1 day 1 and have a confirmed diagnosis of steroid refractory cGvHD defined per 2014 NIH consensus criteria (Martin 2015) irrespective of the concomitant use of a calcineurin inhibitor, as follows:  A lack of response or disease progression after administration of minimum prednisone 1 mg/kg/day for ≥1 week (or equivalent) or  Disease persistence without improvement despite continued treatment with prednisone at >0.5 mg/kg/day or 1 mg/kg/every other day for ≥4 weeks (or equivalent) or  Increase to prednisone dose to >0.25 mg/kg/day after two unsuccessful attempts to taper the dose (or equivalent)
6. Evident myeloid and platelet engraftment: absolute neutrophil count >1x109/L and platelet count >25x109/L
7. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
8. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2

Exclusion criteria 32

1. Patients that transition from active aGvHD to cGvHD without tapering off corticosteroids ± CNI and any systemic treatment (acute to chronic GvHD overlap syndrome). Patients receiving up to 30 mg by mouth once a day of hydrocortisone (i.e., physiologic replacement dose) of corticosteroids are allowed.
2. History of tuberculosis infection that developed after alloSCT.
3. Evidence of active viral disease including CMV, EBV, HHV-6, HBV, HCV, or BK virus (e.g. CMV pneumonia, not just CMV copy number increase). Patients with pre-transplant positive serology results must have negative viral load results for HBV and HCV within 28 days prior to Cycle 1 Day 1. Patients with unknown viral testing results prior to transplant must have viral load results confirming no evidence of active viral disease within 28 days prior to Cycle 1 Day 1.
4. Mechanical ventilation or patients who have resting O2 saturation <90% by pulse-oximetry.
5. History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study including any of the following:  recent myocardial infarction (within last 6 months prior to Cycle 1 Day 1)  New York Heart Association Class III or IV congestive heart failure  unstable angina (within last 6 months prior to Cycle 1 Day 1  clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker); ventricular arrhythmias  uncontrolled hypertension
6. Patients requiring vasopressors.
7. Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration and contraindications of study drug/study procedure and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data.
8. Presence of severely impaired renal function defined by serum creatinine > 2 mg/dL (> 176.8μmol/L), renal dialysis requirement, or have estimated creatinine clearance <30 ml/min measured or calculated by Cockroft Gault equation (confirmed within 48 hours prior to study treatment start).
9. Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to cGvHD and ongoing organ dysfunction) OR total bilirubin >2mg/dL not attributable to GvHD.
10. Impairment of gastrointestinal (GI) function (unrelated to GvHD) or GI disease (unrelated to GvHD) that may significantly alter the absorption of oral ruxolitinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
11. Any corticosteroid therapy for indications other than cGvHD at doses >1 mg/kg/day methylprednisolone or equivalent within 7 days of Cycle 1 Day 1.
12. Prior treatment with ruxolitinib or ECP except if the treatment was for acute GvHD.
13. Patient is receiving treatment with medications that interfere with coagulation or platelet function including, but not limited to, heparin or warfarin sodium (Coumadin®). Use of low molecular weight heparin is allowed. In patients in whom aspirin is indicated for secondary cardiovascular disease prevention, aspirin daily dose must not exceed 150 mg/day.
14. Patient is receiving fluconazole at daily doses higher than 200 mg.
15. Patient is receiving and does not agree to stop herbal preparations/medications. These herbal medications include, but are not limited to, St. John’s Wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Patients must stop using herbal medications at least 7 days prior to first dose of study treatment.
16. Known allergies, hypersensitivity, or intolerance of ruxolitinib or any of its excipients or similar compounds, methoxypsoralen or psoralen compounds
17. Photosensitive disease
18. Aphakia
19. Failed prior alloSCT within the past 6 months from Cycle 1 Day 1 (relapsed original disease).
20. Patients with relapsed primary malignancy, or who have been treated for relapse after the alloSCT was performed.
21. 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 (up to day 120) and not for management of malignancy relapse are eligible.
22. History of progressive multifocal leuko-encephalopathy (PML).
23. Active treatment in a clinical study of any investigational agent within 30 days prior to Cycle 1 Day1, or within 5 half-lives of the study treatment, whichever is longer.
24. 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. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
25. Positive result for HIV at screening.
26. Inability to tolerate extracorporeal volume loss
27. Sexually active men and female patients of child-bearing potential who are not willing to use highly effective methods of contraception during the trial and at least 5 months after the last ECP procedure
28. Pregnancy and lactation
29. Previous splenectomy
30. Coagulation disorder
31. Leucocytes > 25x109/L
32. Current Melanoma, basal cell carcinoma or squamous cell carcinoma of the skin requiring treatment

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The Overall Response Rate (ORR) at the week 25 (Cycle 7 Day 1) visit. The ORR is defined as the proportion of patients demonstrating a complete response (CR) or partial response (PR) without the requirement of additional systemic therapies for an earlier progression, mixed response or nonresponse. Scoring of response will be relative to the organ score at the time of baseline assessment.

Secondary endpoints 13

1. To evaluate failure-free survival (FFS), FFS will be used as the first key secondary; FFS is defined as time from start of treatment to the earliest recurrence of underlying disease, start of a new systemic treatment for cGvHD, or death, or the date the patient is last seen alive without event (censored observation)
2. To evaluate change in the modified Lee Symptom Scale score (Symptom control); Response defined as a ≥7-point reduction from baseline in total symptom score (evaluation at week 25).
3. To assess Overall Survival (OS); OS is defined as time from start of treatment to the date of death from any cause, or the date the patient is last seen alive (censored observation)
4. To assess the best overall response (BOR); Proportion of patients who achieved OR (CR+PR) at any time point (up Cycle 7 day 1 or the start of additional systemic therapy for cGvHD)
5. Response according to organs; Scoring of response will be relative to the organ score at the time of baseline assessment
6. To assess the duration of response (DOR), Duration of response (DOR) is assessed for responders only. DOR is defined as the time from first response until cGvHD progression, death, or the date of change/addition of systemic therapies for cGvHD, or the date the patient is last seen alive without event (censored observation)
7. To assess the non-relapse mortality (NRM); Non-relapse mortality (NRM) is defined as the time from start of treatment to date of death not preceded by underlying disease relapse/recurrence. Underlying disease relapse/ recurrence is considered as a competing event
8. To assess the proportion of patients with ≥50% reduction in daily steroid dose at week 25
9. To assess the proportion of patients who successfully tapered off all steroids at week 25
10. To assess the cumulative incidence of Malignancy Relapse/Recurrence (MR); Malignancy Relapse/Recurrence (MR) is defined as the time from start of treatment to hematologic malignancy relapse/recurrence. Calculated for patients with underlying hematologic malignant disease. NRM is considered as a competing event.
11. To assess time to treatment response (TTTR), Time to response is defined as time from treatment start to the date of first documentation of PR or CR. Death without prior response will be considered to be a competing event.
12. To assess changes in immune cell phenotype during treatment (only Freiburg), Changes in immune cell phenotype (T cells (CD3, CD4 and CD8), NK cells (CD56, CD3-, TCR-), NKT cells (CD3+ CD1d Tetramer+), monocytes (CD11bCD14); neutrophils (CD11b, CD15)) B cells (CD21low) and immune metabolism during treatment as described in section 7.6.15.
13. To evaluate changes in FACTBMT, Change in FACT-BMT from baseline to each visit where measured.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medical Center - University Of Freiburg

Sponsor organisation

Medical Center - University Of Freiburg

Address

Breisacher Strasse 153, Mooswald Mooswald

City

Freiburg Im Breisgau

Postcode

79110

Country

Germany

Scientific contact point

Organisation

Medical Center - University Of Freiburg

Contact name

Prof. Robert Zeiser

Public contact point

Organisation

Medical Center - University Of Freiburg

Contact name

ECTU

Locations

2 EU/EEA countries · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications