A multi-centre Phase 2 study exploring optimal dosing and scheduling of cyclophosphamide in systemic sclerosis patients undergoing haematopoietic stem cell transplantation.

Phase 2

Recruiting

• Conditions: systemic sclerosis; Inflammatory and Immune System - Autoimmune diseases

• Registration Number: ACTRN12623000292673
• Lead Sponsor: St Vincent's Hospital, Sydney

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2023-03-17
• Last Update Posted: 8 July 2024

Recruitment & Eligibility

• Status: Recruiting
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

For those patients who will receive standard dose regimens (200mg/kg cyclophosphamide):
•Able to provide informed written consent
•2013 ACR/EULAR classification criteria for SSc
•Disease duration is 5 years from first non-Raynaud’s manifestation
•Progressive interstitial lung disease [ILD] (ILD defined as typical findings on a HRCT chest as determined by a radiologist, with greater than 10% of lung involvement) – where progression is defined between two timepoints as a relative FVC decline of 10%, or a relative FVC decline of 5–9% in association with a DLCO relative decline of 15%, or radiological progression on HRCT
AND/OR
•mRSS is equal to 15 with dSSc skin pattern and progression over the previous 3-12 months of greater than 25% and 5 mRSS points
AND
•Patient has trialled 3-6 months of highly active therapy at discretion of local site (for example, but not limited to: MMF, rituximab, nintedanib, tocilizumab, cyclophosphamide, methotrexate, azathioprine)
•Age 16-49
•Karnofsky grade greater than 60%.
•Negative serology for HIV.
•If hepatitis B +ve - willing to take entacavir for 1 year
•If hepatitis C +ve - must be cleared by anti-viral therapy prior to HSCT
•Negative pregnancy test.
•Absence of severe chronic infection.
•Sperm collection or ova cryopreservation is to be offered prior to HSCT in those of child-bearing age.
•Cardiac LV Ejection Fraction greater than 50%
•Resting mean pulmonary artery pressure (mPAP) equal to 20mmHg
•mPAP less than 30mm/hg after 500mls bolus
•DLCO equal to 40%.
•Normal Cardiac MRI

For those patients who will receive a low dose conditioning with cyclophosphamide 100mg-140mg/kg with/without rituximab:

•Able to provide informed written consent
•2013 ACR/EULAR classification criteria for SSc
•Disease duration of 5 years from first non-Raynaud’s manifestation
•Progressive interstitial lung disease [ILD] (ILD defined as typical findings on a HRCT chest as determined by a radiologist, with greater than 10% of lung involvement) – where progression is defined between two timepoints as a relative FVC decline of 10%, or a relative FVC decline of 5–9% in association with a DLCO relative decline of 15%, or radiological progression on HRCT
AND/OR
•mRSS equal to 15 with dSSc skin pattern and progression over the previous 3-12 months of greater than 25% and 5 mRSS points
AND
•Patient has trialled 3-6 months of highly active therapy at discretion of local site (for example, but not limited to: MMF, rituximab, nintedanib, tocilizumab, cyclophosphamide, methotrexate, azathioprine)
•Age 50-70 or less than 50 yrs with poor Karnofsky or cardio-respiratory compromise (as per below).
•Karnofsky grade greater than 40%
•Negative serology for HIV.
•If hepatitis B +ve - willing to take entecavir for 1 year
•If hepatitis C +ve – must be cleared by anti-viral therapy prior to HSCT
•Negative pregnancy test.
•Absence of severe chronic infection.
•Sperm collection or ova cryopreservation is to be offered prior to HSCT in those of child-bearing age.
•Ineligible for 200mg/kg cyclophosphamide due to:
oCardiac LV Ejection Fraction less than 50%
oResting Pulmonary arterial systolic pressure (PASP) greater than 40mmHg or greater than 45mmHg after 500mls bolus
oResting Mean pulmonary arterial pressure (mPAP) greater than 20 mmHg or mPAP greater than 30mmHg after 500mls bolus
oDecrease or lack of augmentation of CO after fluid challenge
oP

Exclusion Criteria

All patients
•Karnofsky 30% or less
•Left ventricular ejection fraction less than 40%
•Constrictive pericarditis or cardiac tamponade
•Uncontrolled severe arrhythmia
•Unstable or severe unrevascularised coronary artery disease
•Pulmonary arterial systolic pressure (PASP) greater than 60mmHg
•Mean pulmonary arterial pressure (mPAP) greater than 40mmHg at rest or mPAP greater than 50mmHg with 500mL fluid bolus
•Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) less than 30%
•Respiratory failure as defined in the endpoints (use of continuous oxygen or partial pressure of oxygen (pO2) less than 60 mmHg or partial pressure of carbon dioxide (pCO2) greater than 50mmHg without oxygen)
•Unwilling to cease smoking permanently prior to mobilisation for at least 12 weeks
•Prior history of malignancy or other current medical condition which in the opinion of the investigators would restrict the ability of the patient to tolerate the procedure.
•Unable to provide informed consent and/or the diagnosis of mental and cognitive deficits which can interfere with the capability of providing the informed consent.
•Major bone marrow failure or condition (such as myelodysplasia) which results in significant neutropenia (less than 1000/ul) or thrombocytopenia (less than 100,000/ul).
•Severe renal disease creatinine clearance less than 40mL/min (measured or estimated)
•Severe liver disease (Bilirubin greater 50umol/l or known cirrhosis)
•Gastric antral vascular ectasia (GAVE) with active bleeding ( For inclusion, patients with GAVE must have treated disease eg with argon laser and have no active bleeding). Immediate pre-conditioning endoscopy should be considered in those with a history of GAVE or anaemia/iron deficiency.
•Gut involvement with systemic sclerosis resulting in malabsorption, chronic diarrhoea or low BMI (less than 20) which in the opinion of the investigators would restrict the ability of the patient to tolerate the procedure
•Uncontrolled infection.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
determine safety of stem cell transplant for severe scleroderma patients by measuring transplant related mortality (TRM) using medical records in standard dose cyclophosphamide arm [ reviewed at 100 days post transplant ];determine safety of stem cell transplant for severe scleroderma patients by measuring transplant related mortality (TRM) using medical records in Low dose cyclophosphamide arm[ reviewed at 100 days post transplant ]