Open Label Extension Study of Brentuximab Vedotin in Early dcSSc

Official title

An Open Label Extension Study of Brentuximab Vedotin Treatment in Active Diffuse Cutaneous Systemic Sclerosis (Diffuse Scleroderma)

Overview

The purpose of this study is to assess safety and efficacy of Brentuximab vedotin, a CD30-directed antibody-drug conjugate, in patients with active diffuse cutaneous systemic sclerosis (dcSSc) who relapsed after discontinuation of Brentuximab vedotin.

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). It's possible to reverse immune inflammation and reduce the probability of irreversible fibrosis early in the disease course via significant immune modulation. The preliminary results of the Phase II study of Brentuximab vedotin (Protocol BV201708) in SSc demonstrated the short-term safety and benefits of this treatment as many participants already achieved the primary endpoint at 24 weeks. This study is proposed as an extension of the ongoing protocol for up to 48 weeks to make the treatment available for SSc patients who have significantly improved on Brentuximab vedotin, but relapsed after discontinuation of the treatment. Similar to the ongoing Phase II study, the Health Assessment Questionnaire Disability Index (HAQ-DI), patient and physician global scores, inflammatory markers (ESR, CRP), and combined response index in SSc (CRISS) and changes in CD30-stained cells on skin biopsies with IHC will all be exploratory outcomes.

Interventions

• Drug Brentuximab vedotin
  Dose 0.6mg/kg 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, mycophenolate mofetil (MMF, cellcept) and mycophenolic acid (myfortic)

Primary outcome measures

• Change in skin thickness measured by modified Rodnan Skin Score [Time frame: 48 weeks]

Secondary outcome measures (11)

• Change in skin thickness over time measured by modified Rodnan Skin Score [Time frame: 12 weeks and 36 weeks]
• Change in physician global assessment of disease activity [Time frame: 12, 24, 36, and 48 weeks.]
• Change in physician global assessment of disease severity [Time frame: 12, 24, 36, and 48 weeks]
• Change in physician global assessment of disease damage [Time frame: 12, 24, 36, and 48 weeks]
• Change in patient global assessment of health status [Time frame: 12, 24, 36, and 48 weeks]
• Change in Scleroderma Health Assessment Questionnaire (SHAQ) [Time frame: 12, 24, 36, and 48 weeks]
• Change in the diffusing capacity for carbon monoxide (pulmonary function) [Time frame: 24 and 48 weeks*]
• Change in Forced Vital Capacity (pulmonary function) [Time frame: 24 and 48 weeks*]
• Combined Response Index in diffuse cutaneous systemic sclerosis score (CRISS) [Time frame: Baseline (week 0), and at 24, 48 weeks]
• Change in serum concentrations C-Reactive Protein [Time frame: 12, 24, 36, and 48 weeks]
• Change in serum concentrations of Erythrocyte Sedimentation Rate [Time frame: 12, 24, 36, and 48 weeks]

Eligibility criteria

Inclusion criteria

• Patients with diffuse cutaneous systemic sclerosis enrolled in the Phase II Adcetris study (BV201708) at St. Joseph's Health centre, aged 18 years or older, and:
• Worsening mRSS of ≥ 4 points as compared to mRSS score at the end of treatment visit (week 48) in the initial study (BV201708).
• Able to give informed consent.

Exclusion criteria

• Poor pulmonary function (FVC<40% and/or DLCO<30%).
• Pregnancy, breast feeding or child bearing potential without practicing highly effective contraception (and partners for men in the study).
• Clinically significant pulmonary hypertension requiring drug therapy.
• Clinically significant cardiac disease.
• Chronic or ongoing active infectious disease requiring systemic treatment.
• Seropositivity for human immunodeficiency virus (HIV).
• Active tuberculosis (TB) infection.
• Active viral infection with viral replication of hepatitis B or C virus.
• Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, pancreatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease; and cancer.
• Peripheral neuropathy at screening Grade 2 or higher.
• Known or suspected hypersensitivity to components of the treatment
• Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder)
• Any of the following laboratory abnormalities at screening:

• Absolute neutrophils count <2.0 x 109/L
• Hemoglobin <85 g/L
• Platelet count < 100 x 109/L
• AST/SGOT or ALT/SGPT >2.0 UNL
• Participation in another clinical trial within six weeks before randomization in this study, with the exception of continuation from the initial study BV201708.
• Use of rituximab within the previous 4 months.
• Immunization with a live/ attenuated vaccine less than 4 weeks prior to the baseline visit.
• Current or history of progressive multifocal leukoencephalopathy (PML).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 1 center

• Rheumatology Clinic, St. Joseph's Health Care — London

Publications

• Komocsi A, Vorobcsuk A, Faludi R, Pinter T, Lenkey Z, Kolto G, Czirjak L. The impact of cardiopulmonary manifestations on the mortality of SSc: a systematic review and meta-analysis of observational studies. Rheumatology (Oxford). 2012 Jun;51(6):1027-36. doi: 10.1093/rheumatology/ker357. Epub 2012 Jan 5. PMID 22223705
• 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. PMID 25775190
• 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. No abstract available. PMID 25371098
• Andras C, Ponyi A, Constantin T, Csiki Z, Szekanecz E, Szodoray P, Danko K. Dermatomyositis and polymyositis associated with malignancy: a 21-year retrospective study. J Rheumatol. 2008 Mar;35(3):438-44. Epub 2008 Jan 15. PMID 18203322
• Hasegawa M, Sato S, Sakai H, Ohashi T, Takehara K. Systemic sclerosis revealing T-cell lymphoma. Dermatology. 1999;198(1):75-8. doi: 10.1159/000018070. PMID 10026408
• Juarez M, Marshall R, Denton C, Evely R. Paraneoplastic scleroderma secondary to hairy cell leukaemia successfully treated with cladribine. Rheumatology (Oxford). 2008 Nov;47(11):1734-5. doi: 10.1093/rheumatology/ken367. Epub 2008 Sep 23. No abstract available. PMID 18812428
• Khanna D, Berrocal VJ, Giannini EH, Seibold JR, Merkel PA, Mayes MD, Baron M, Clements PJ, Steen V, Assassi S, Schiopu E, Phillips K, Simms RW, Allanore Y, Denton CP, Distler O, Johnson SR, Matucci-Cerinic M, Pope JE, Proudman SM, Siegel J, Wong WK, Wells AU, Furst DE. The American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic PMID 26808827
• Valentini G, Silman AJ, Veale D. Assessment of disease activity. Clin Exp Rheumatol. 2003;21(3 Suppl 29):S39-41. PMID 12889221

Identifiers

NCT: NCT05149768 · BV202108

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗