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Brentuximab Vedotin in Early Diffuse Cutaneous Systemic Sclerosis

Primary Purpose

Diffuse Cutaneous Systemic Sclerosis

Status

Completed

Phase

Phase 2

Locations

Canada

Study Type

Interventional

Intervention

Brentuximab Vedotin

About this trial

This is an interventional treatment trial for Diffuse Cutaneous Systemic Sclerosis focused on measuring systemic sclerosis, scleroderma, brentuximab vedotin, CD30-directed antibody-drug conjugate, antirheumatic agents, antineoplastic agents, connective tissue diseases, skin diseases, immunologic factors

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

Poor pulmonary function (FVC<40% and/or DLCO<30%).
Pregnancy, breast feeding or child bearing potential without practicing reliable 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) at study entry.
Active tuberculosis (TB) infection.
Active viral infection with viral replication of hepatitis B or C virus at study entry.
Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, pancreatic, haematological, 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 <2000/mm3
- Hemoglobin <85 g/L
- Platelet count < 100,000/mm3
- AST/SGOT or ALT/SGPT >2.0 UNL
Participation in another clinical trial within six weeks before randomization in this study
Use of rituximab within the previous 4 months.
Immunization with a live/ attenuated vaccine less than 4 weeks prior to the baseline visit.
Previous use of brentuximab vedotin.
Current or history of progressive multifocal leukoencephalopathy (PML).

Sites / Locations

Rheumatology Clinic, St. Joseph's Health Care

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Administration of Brentuximab vedotin

Arm Description

Maximum duration of treatment: 48 weeks Maximum dose allowed: 0.6 mg/kg Route of administration: intravenous use

Outcomes

Primary Outcome Measures

Change in skin thickness measured by modified Rodnan Skin Score (mRSS)

Secondary Outcome Measures

Change in mRSS

CRISS score >20%

Change in FVC, %

Change in DLCO, %

Change in physician-assessed disease activity, severity and damage on VASs ranked from 0 to 10

Change in patient global assessment of health status (VAS 0 to 10)

Change in Health Transition score

Change in SHAQ

Full Information

NCT ID

NCT03198689

First Posted

June 14, 2017

Last Updated

October 3, 2023

Sponsor

Lawson Health Research Institute

Collaborators

Seagen Inc.

1. Study Identification

Unique Protocol Identification Number

NCT03198689

Brief Title

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

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Completed

Study Start Date

May 7, 2019 (Actual)

Primary Completion Date

June 7, 2023 (Actual)

Study Completion Date

August 28, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Lawson Health Research Institute

Collaborators

Seagen Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

5. 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).

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Masking Description

Open Label

Allocation

N/A

Enrollment

11 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Administration of Brentuximab vedotin

Arm Type

Experimental

Arm Description

Maximum duration of treatment: 48 weeks Maximum dose allowed: 0.6 mg/kg Route of administration: intravenous use

Intervention Type

Drug

Intervention Name(s)

Brentuximab Vedotin

Other Intervention Name(s)

ADCETRIS, SGN-35

Intervention Description

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).

Primary Outcome Measure Information:

Title

Change in skin thickness measured by modified Rodnan Skin Score (mRSS)

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Change in mRSS

Time Frame

3, 6 and 9 months

Title

CRISS score >20%

Time Frame

6 months

Title

Change in FVC, %

Time Frame

6 and 12 months

Title

Change in DLCO, %

Time Frame

6 and 12 months

Title

Change in physician-assessed disease activity, severity and damage on VASs ranked from 0 to 10

Time Frame

3,6,9 and 12 months

Title

Change in patient global assessment of health status (VAS 0 to 10)

Time Frame

3,6,9 and 12 months

Title

Change in Health Transition score

Time Frame

3,6,9 and 12 months

Title

Change in SHAQ

Time Frame

3,6,9 and 12 months

Other Pre-specified Outcome Measures:

Title

Change in blood levels of soluble CD30

Time Frame

3,6,9 and 12 months

Title

Change in serum levels of sIL-2R

Time Frame

3,6,9 and 12 months

Title

Change in serum levels of aminoterminal propeptide of type III collagen

Time Frame

3,6,9 and 12 months

Title

Change in myofibroblast score in skin biopsies of involved forearm skin

Time Frame

6 and 12 months

Title

Change in CD30-positive cell count in skin biopsies of involved forearm skin

Time Frame

6 and 12 months

Title

Change in erythrocyte sedimentation rate

Time Frame

3,6,9 and 12 months

Title

Change in hsCRP levels

Time Frame

3,6,9 and 12 months

Title

Number of patients with infectious complications

Time Frame

up to 1 month post-treatment

Title

Number of patients with regimen-related toxicities

Time Frame

up to 12 weeks post-treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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: Poor pulmonary function (FVC<40% and/or DLCO<30%). Pregnancy, breast feeding or child bearing potential without practicing reliable 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) at study entry. Active tuberculosis (TB) infection. Active viral infection with viral replication of hepatitis B or C virus at study entry. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, pancreatic, haematological, 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 <2000/mm3 Hemoglobin <85 g/L Platelet count < 100,000/mm3 AST/SGOT or ALT/SGPT >2.0 UNL Participation in another clinical trial within six weeks before randomization in this study Use of rituximab within the previous 4 months. Immunization with a live/ attenuated vaccine less than 4 weeks prior to the baseline visit. Previous use of brentuximab vedotin. Current or history of progressive multifocal leukoencephalopathy (PML).

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Janet E Pope

Organizational Affiliation

University of Western Ontario, Division of Rheumatology, St. Joseph's Health Care, London, Ontario, Canada

Official's Role

Principal Investigator

Facility Information:

Facility Name

Rheumatology Clinic, St. Joseph's Health Care

City

London

State/Province

Ontario

ZIP/Postal Code

N6A 4V2

Country

Canada

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

25775190

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.

Results Reference

background

PubMed Identifier

25371098

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.

Results Reference

background

PubMed Identifier

7562757

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.

Results Reference

background

PubMed Identifier

16331791

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.

Results Reference

background

PubMed Identifier

8235663

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.

Results Reference

background

PubMed Identifier

16484228

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.

Results Reference

background

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Brentuximab Vedotin in Early Diffuse Cutaneous Systemic Sclerosis

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