Brentuximab Vedotin in Early Diffuse Cutaneous Systemic Sclerosis

A Pilot Study of Adcetris Treatment in Active Diffuse Cutaneous Systemic Sclerosis (Diffuse Scleroderma)

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).

Study Overview

• Status: Completed
• Conditions: Diffuse Cutaneous Systemic Sclerosis
• Intervention / Treatment: Drug: 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). 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 Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 4V2
      • Rheumatology Clinic, St. Joseph's Health Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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
• 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:

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

13. Any of the following laboratory abnormalities at screening:

    • Absolute neutrophils count <2000/mm3
    • Hemoglobin <85 g/L
    • Platelet count < 100,000/mm3
    • AST/SGOT or ALT/SGPT >2.0 UNL
14. Participation in another clinical trial within six weeks before randomization in this study
15. Use of rituximab within the previous 4 months.
16. Immunization with a live/ attenuated vaccine less than 4 weeks prior to the baseline visit.
17. Previous use of brentuximab vedotin.
18. Current or history of progressive multifocal leukoencephalopathy (PML).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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: ADCETRIS, SGN-35

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in skin thickness measured by modified Rodnan Skin Score (mRSS)	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Lawson Health Research Institute
• Collaborators: Seagen Inc.
• Investigators: Principal Investigator: Janet E Pope, University of Western Ontario, Division of Rheumatology, St. Joseph's Health Care, London, Ontario, Canada

Publications and helpful links

General Publications

• 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.
• 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.
• 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, Bellamy N. Outcome measurement in scleroderma clinical trials. Semin Arthritis Rheum. 1993 Aug;23(1):22-33. doi: 10.1016/s0049-0172(05)80024-1.
• 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.
• 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. doi: 10.1074/jbc.M510026200. Epub 2006 Feb 16.

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2019
• Primary Completion (Actual): June 7, 2023
• Study Completion (Actual): August 28, 2023

Study Registration Dates

• First Submitted: June 14, 2017
• First Submitted That Met QC Criteria: June 22, 2017
• First Posted (Actual): June 26, 2017

Study Record Updates

• Last Update Posted (Actual): October 4, 2023
• Last Update Submitted That Met QC Criteria: October 3, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: skin diseases; systemic sclerosis; scleroderma; immunologic factors; connective tissue diseases; antineoplastic agents; brentuximab vedotin; antirheumatic agents; CD30-directed antibody-drug conjugate
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Connective Tissue Diseases; Sclerosis; Scleroderma, Systemic; Scleroderma, Diffuse; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Immunoconjugates; Immunotoxins; Brentuximab Vedotin
• Other Study ID Numbers: BV201708

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes