Clinical trial NCT03198689: Brentuximab Vedotin in Early Diffuse Cutaneous Systemic Sclerosis
Official title: A Pilot Study of Adcetris Treatment in Active Diffuse Cutaneous Systemic Sclerosis (Diffuse Scleroderma)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diffuse Cutaneous Systemic Sclerosis
Keywords: systemic sclerosis
scleroderma
brentuximab vedotin
CD30-directed antibody-drug conjugate
antirheumatic agents
antineoplastic agents
connective tissue diseases
skin diseases
immunologic factors
Lead sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Sponsor class: OTHER
Collaborators: name: Seagen Inc.
First posted: 2017-06-26
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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.

Eligibility 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
* 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).

Primary outcomes:
measure: Change in skin thickness measured by modified Rodnan Skin Score (mRSS)
timeFrame: 12 months
Secondary outcomes:
measure: Change in mRSS
timeFrame: 3, 6 and 9 months
measure: CRISS score >20%
timeFrame: 6 months
measure: Change in FVC, %
timeFrame: 6 and 12 months
measure: Change in DLCO, %
timeFrame: 6 and 12 months
measure: Change in physician-assessed disease activity, severity and damage on VASs ranked from 0 to 10
timeFrame: 3,6,9 and 12 months
measure: Change in patient global assessment of health status (VAS 0 to 10)
timeFrame: 3,6,9 and 12 months
measure: Change in Health Transition score
timeFrame: 3,6,9 and 12 months
measure: Change in SHAQ
timeFrame: 3,6,9 and 12 months
Other outcomes:
measure: Change in blood levels of soluble CD30
timeFrame: 3,6,9 and 12 months
measure: Change in serum levels of sIL-2R
timeFrame: 3,6,9 and 12 months
measure: Change in serum levels of aminoterminal propeptide of type III collagen
timeFrame: 3,6,9 and 12 months
measure: Change in myofibroblast score in skin biopsies of involved forearm skin
timeFrame: 6 and 12 months
measure: Change in CD30-positive cell count in skin biopsies of involved forearm skin
timeFrame: 6 and 12 months
measure: Change in erythrocyte sedimentation rate
timeFrame: 3,6,9 and 12 months
measure: Change in hsCRP levels
timeFrame: 3,6,9 and 12 months
measure: Number of patients with infectious complications
timeFrame: up to 1 month post-treatment
measure: Number of patients with regimen-related toxicities
timeFrame: up to 12 weeks post-treatment
Locations:
city: London
country: Canada
facility: Rheumatology Clinic, St. Joseph's Health Care
state: Ontario
Study officials:
affiliation: University of Western Ontario, Division of Rheumatology, St. Joseph's Health Care, London, Ontario, Canada
name: Janet E Pope
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.