Brentuximab Vedotin in Early Diffuse Cutaneous Systemic Sclerosis
Study Details
Study Description
Brief Summary
The purpose of this study is to assess feasibility, safety and preliminary efficacy of Brentuximab vedotin (Adcetris), a CD30-directed antibody-drug conjugate, in the treatment of active diffuse cutaneous systemic sclerosis (dcSSc).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Systemic sclerosis (SSc, Scleroderma) is a multisystem autoimmune disease characterized by widespread vascular injury and progressive fibrosis of the skin and internal organs. Internal organ involvement results in increased mortality of SSc patients. There is no effective treatment for the majority of patients with early active diffuse scleroderma (diffuse cutaneous systemic sclerosis; dcSSc). These patients early in their disease may be able to reverse their inflammation and reduce the probability of irreversible fibrosis via significant immune modulation. This is a pilot study that will treat 10 patients with early or active dcSSc who meet inclusion criteria to determine if the benefit of Brentuximab vedotin and safety are favorable in order to consider a randomized controlled trial. This is a Phase II study that is uncontrolled and patients will remain on their background immune suppressive treatment unless if contraindicated for safety or drug interactions. The trial is powered to show a mean change in mRSS of 8 over one year in an uncontrolled, unblinded study. The Health Assessment Questionnaire Disability Index (HAQ), patient and physician global scores, inflammatory markers (ESR, CRP), and combined response index in SSc (CRISS) will all be exploratory outcomes. Other outcomes such as changes in CD30-stained cells on skin biopsies with IHC from baseline to end of the trial will be explored if the study is positive.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Administration of Brentuximab vedotin Maximum duration of treatment: 48 weeks Maximum dose allowed: 0.6 mg/kg Route of administration: intravenous use |
Drug: Brentuximab Vedotin
Dose 0.6 mg/kg i.v. will be given every 3 weeks for 16 cycles (48 weeks) in addition to standard of care medications for SSc that may include cyclophosphamide, methotrexate, azathioprine, mycophenylate mofetil (MMF, cellcept) and mycophenolic acid (myfortic).
Other Names:
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Outcome Measures
Primary Outcome Measures
- Change in skin thickness measured by modified Rodnan Skin Score (mRSS) [12 months]
Secondary Outcome Measures
- Change in mRSS [3, 6 and 9 months]
- CRISS score >20% [6 months]
- Change in FVC, % [6 and 12 months]
- Change in DLCO, % [6 and 12 months]
- Change in physician-assessed disease activity, severity and damage on VASs ranked from 0 to 10 [3,6,9 and 12 months]
- Change in patient global assessment of health status (VAS 0 to 10) [3,6,9 and 12 months]
- Change in Health Transition score [3,6,9 and 12 months]
- Change in SHAQ [3,6,9 and 12 months]
Other Outcome Measures
- Change in blood levels of soluble CD30 [3,6,9 and 12 months]
- Change in serum levels of sIL-2R [3,6,9 and 12 months]
- Change in serum levels of aminoterminal propeptide of type III collagen [3,6,9 and 12 months]
- Change in myofibroblast score in skin biopsies of involved forearm skin [6 and 12 months]
- Change in CD30-positive cell count in skin biopsies of involved forearm skin [6 and 12 months]
- Change in erythrocyte sedimentation rate [3,6,9 and 12 months]
- Change in hsCRP levels [3,6,9 and 12 months]
- Number of patients with infectious complications [up to 1 month post-treatment]
- Number of patients with regimen-related toxicities [up to 12 weeks post-treatment]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
age 18 years or older
-
able to give informed consent
-
meet the ACR/EULAR classification criteria for SSc
-
early dcSSc (disease duration ≤ 5 years from first non-Raynaud's phenomenon symptom) OR active dcSSc as determined by worsening mRSS, presence of tendon friction rubs, and/or elevated inflammatory markers thought to be due to active dcSSc and not related to other issues
-
mRSS≥ 15
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a negative TB skin test at screening, or treatment with INH for 6 months or other standardized LBTI (latent TB infection) treatment in the past
Exclusion Criteria:
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Poor pulmonary function (FVC<40% and/or DLCO<30%).
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Pregnancy, breast feeding or child bearing potential without practicing reliable contraception (and partners for men in the study).
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Clinically significant pulmonary hypertension requiring drug therapy.
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Clinically significant cardiac disease.
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Chronic or ongoing active infectious disease requiring systemic treatment.
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Seropositivity for human immunodeficiency virus (HIV) at study entry.
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Active tuberculosis (TB) infection.
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Active viral infection with viral replication of hepatitis B or C virus at study entry.
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Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, pancreatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease; and cancer.
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Peripheral neuropathy at screening Grade 2 or higher.
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Known or suspected hypersensitivity to components of the treatment
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Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder)
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Any of the following laboratory abnormalities at screening:
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Absolute neutrophils count <2000/mm3
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Hemoglobin <85 g/L
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Platelet count < 100,000/mm3
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AST/SGOT or ALT/SGPT >2.0 UNL
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Participation in another clinical trial within six weeks before randomization in this study
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Use of rituximab within the previous 4 months.
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Immunization with a live/ attenuated vaccine less than 4 weeks prior to the baseline visit.
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Previous use of brentuximab vedotin.
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Current or history of progressive multifocal leukoencephalopathy (PML).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Rheumatology Clinic, St. Joseph's Health Care | London | Ontario | Canada | N6A 4V2 |
Sponsors and Collaborators
- Lawson Health Research Institute
- Seagen Inc.
Investigators
- Principal Investigator: Janet E Pope, University of Western Ontario, Division of Rheumatology, St. Joseph's Health Care, London, Ontario, Canada
Study Documents (Full-Text)
None provided.More Information
Publications
- Furst DE, Khanna D, Mattucci-Cerinic M, Silman AJ, Merkel PA, Foeldvari I; OMERACT 7 Special Interest Group. Scleroderma--developing measures of response. J Rheumatol. 2005 Dec;32(12):2477-80.
- Pope JE, Baron M, Bellamy N, Campbell J, Carette S, Chalmers I, Dales P, Hanly J, Kaminska EA, Lee P, et al. Variability of skin scores and clinical measurements in scleroderma. J Rheumatol. 1995 Jul;22(7):1271-6.
- Pope JE, Bellamy N. Outcome measurement in scleroderma clinical trials. Semin Arthritis Rheum. 1993 Aug;23(1):22-33. Review.
- Shah AA, Casciola-Rosen L, Rosen A. Review: cancer-induced autoimmunity in the rheumatic diseases. Arthritis Rheumatol. 2015 Feb;67(2):317-26. doi: 10.1002/art.38928. Review.
- Sutherland MS, Sanderson RJ, Gordon KA, Andreyka J, Cerveny CG, Yu C, Lewis TS, Meyer DL, Zabinski RF, Doronina SO, Senter PD, Law CL, Wahl AF. Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J Biol Chem. 2006 Apr 14;281(15):10540-7. Epub 2006 Feb 16.
- Young A, Khanna D. Systemic sclerosis: a systematic review on therapeutic management from 2011 to 2014. Curr Opin Rheumatol. 2015 May;27(3):241-8. doi: 10.1097/BOR.0000000000000172. Review.
- BV201708