Brentuximab Vedotin for Systemic Sclerosis

NCT03222492 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: DAIT ITN075AIUM1AI109565NIAID CRMS ID#: 38418
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 8

Brief Summary

There is significant unmet need for effective treatment options for Diffuse Cutaneous Systemic Sclerosis (dcSSc). The present study will be a dose-escalation safety trial of brentuximab vedotin, a drug-antibody conjugate approved for the treatment of lymphoma and targeted to the protein CD30 molecule expressed on activated immune cells There is evidence for CD30 involvement in SSc. This study represents the first step in determining safety and tolerability of brentuximab vedotin in SSc.

Conditions

Diffuse Cutaneous Systemic Sclerosis; Scleroderma; dcSSc

Keywords

Diffuse Cutaneous Systemic Sclerosis (dcSSc); Phase 1/2 clinical trial; dose escalation randomized trial; Brentuximab vedotin

Outcome Measures

Primary Outcomes (2)

• Proportion of Participants That Experience at Least One Grade 3 or Higher Adverse Event at or Before Week 48.

  Adverse events were graded using the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, except for the grading of liver chemistry abnormalities. The scale ranges from grade 1 through 5, with grade 1 being the least severe and grade 5 being the most severe. Liver chemistry abnormalities were graded, from 1 through 4 (with 1 being least severe and 4 being most severe) relative to the upper limit of normal (ULN) with different grades depending on whether there was an increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), or blood bilirubin.

  Baseline through end of study (48 weeks for participants who complete the study)

• Proportion of Participants That Experience at Least One Grade 3 or Higher Adverse Event at or Before Week 48.

  Adverse events were graded using the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, except for the grading of liver chemistry abnormalities. The scale ranges from grade 1 through 5, with grade 1 being the least severe and grade 5 being the most severe. Liver chemistry abnormalities were graded, from 1 through 4 (with 1 being least severe and 4 being most severe) relative to the upper limit of normal (ULN) with different grades depending on whether there was an increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), or blood bilirubin.

  Baseline through end of study (48 weeks)

Secondary Outcomes (20)

• Proportion of Participants That Experience at Least One Grade 3 or Higher Adverse Event at or Before Weeks 12, 24, and 36.

  Baseline through Week 12 study visit or 12 weeks on study if the visit was missed. Baseline through Week 24 study visit or 24 weeks on study if the visit was missed. Baseline through Week 36 study visit or 36 weeks on study if the visit was missed

• Proportion of Participants That Experience at Least One Grade 3 or Higher Adverse Event at or Before Week12

  Baseline through Week 12 study visit or 12 weeks on study if the visit was missed.

• Proportion of Participants That Experience at Least One Grade 3 or Higher Adverse Event at or Before Weeks 24.

  Baseline through Week 24 study visit or 24 weeks on study if the visit was missed.

• Proportion of Participants That Experience at Least One Grade 3 or Higher Adverse Event at or Before Weeks 36.

  Baseline through Week 36 study visit or 36 weeks on study if the visit was missed.

• Proportion of Participants That Experience at Least One Grade 2 or Higher Adverse Event at or Before Weeks 12, 24, 36, and 48.

  Baseline thru Week 12 visit or 12 weeks on study if visit was missed/thru Week 24 visit or 24 weeks on study if visit was missed/thru Week 36 visit or 36 weeks on study if visit was missed/thru Week 48 visit or 48 weeks on study if visit was missed

Study Arms (6)

Cohort 1: 0.6 mg/kg brentuximab vedotin

EXPERIMENTAL

This is the first of three ascending dose cohorts. Participants in this cohort will receive 0.6 mg/kg brentuximab vedotin (to a maximum dose 60 mg) every 3 weeks from week 0 (initial dose) to week 21, a total of 8 treatments. Brentuximab vedotin will be administered as an intravenous infusion over 30 minutes. Cohort 1 Randomization schedule: N=6 assigned to brentuximab vedotin: N=2 assigned to placebo.

Biological: Brentuximab Vedotin

Cohort 1: placebo

PLACEBO COMPARATOR

0.6 mg/kg placebo (to a maximum dose 60 mg). Participants in this cohort will receive 0.6 mg/kg placebo every 3 weeks from week 0 (initial dose) to week 21, a total of 8 treatments. Placebo will be administered as an intravenous infusion over 30 minutes. Cohort 1 Randomization schedule: N=6 assigned to brentuximab vedotin: N=2 assigned to placebo.

Biological: Placebo

Cohort 2: 1.2 mg/kg brentuximab vedotin

EXPERIMENTAL

This is the second of three ascending dose cohorts. Participants in this cohort will receive 1.2 mg/kg brentuximab vedotin (to a maximum dose 60 mg) every 3 weeks from week 0 (initial dose) to week 21, a total of 8 treatments. Brentuximab vedotin will be administered as an intravenous infusion over 30 minutes. Cohort 2 Randomization schedule: N=6 assigned to brentuximab vedotin: N=2 assigned to placebo.

Biological: Brentuximab Vedotin

Cohort 2: placebo

PLACEBO COMPARATOR

1.2 mg/kg placebo (to a maximum dose 60 mg). Participants in this cohort will receive 1.2 mg/kg placebo every 3 weeks from week 0 (initial dose) to week 21, a total of 8 treatments. Placebo will be administered as an intravenous infusion over 30 minutes. Cohort 2 Randomization schedule: N=6 assigned to brentuximab vedotin: N=2 assigned to placebo.

Biological: Placebo

Cohort 3: 1.8 mg/kg brentuximab vedotin

EXPERIMENTAL

This is the third/last of three ascending dose cohorts. Participants in this cohort will receive 1.8 mg/kg brentuximab vedotin (to a maximum dose 60 mg) every 3 weeks from week 0 (initial dose) to week 21, a total of 8 treatments. Brentuximab vedotin will be administered as an intravenous infusion over 30 minutes. Cohort 3 Randomization schedule: N=6 assigned to brentuximab vedotin: N=2 assigned to placebo.

Biological: Brentuximab Vedotin

Cohort 3: placebo

PLACEBO COMPARATOR

1.8 mg/kg placebo (to a maximum dose 60 mg). Participants in this cohort will receive 1.8 mg/kg placebo every 3 weeks from week 0 (initial dose) to week 21, a total of 8 treatments. Placebo will be administered as an intravenous infusion over 30 minutes. Cohort 3 Randomization schedule: N=6 assigned to brentuximab vedotin: N=2 assigned to placebo.

Biological: Placebo

Interventions

Brentuximab Vedotin BIOLOGICAL

Ascending dose cohorts. All cohorts will receive intravenous administration of study medication every 3 weeks for 21 weeks, for a total of eight doses.

Also known as: Adcetris®

Cohort 1: 0.6 mg/kg brentuximab vedotin; Cohort 2: 1.2 mg/kg brentuximab vedotin; Cohort 3: 1.8 mg/kg brentuximab vedotin

Placebo BIOLOGICAL

Placebo control for blinding (masking), 0.95% normal saline.

Also known as: Placebo for brentuximab vedotin

Cohort 1: placebo; Cohort 2: placebo; Cohort 3: placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Classification of Systemic Sclerosis (SSc), as defined using the 2013 American College of Rheumatology/European Union League Against Rheumatism classification of SSc;
• Diagnosis of Diffuse Cutaneous Systemic Sclerosis (dcSSc), as defined by LeRoy and Medsger, Criteria for the classification of early systemic sclerosis. J Rheumatol, 2001. 28(7): p. 1573-6;
• Disease duration ≤ 60 months (defined as time from the first non-Raynaud phenomenon manifestation);
• Modified Rodnan Skin Score (mRSS) units ≥ 15 and ≤ 45, and both of the following:
• At least mild skin thickening (≥ 1+ mRSS) of the forearm, and
• At least moderate skin thickening (≥ 2+ mRSS) at the planned forearm skin biopsy site.
• Documentation of at least 12 weeks of ongoing immunosuppressive therapy for SSc at the time of enrollment, and at least 4 weeks at a stable dose, of one of the following:
• Methotrexate ≤ 25 mg/week, or
• Mycophenolate mofetil ≤3 grams/day or mycophenolate sodium ≤2.16 grams/day, or
• Azathioprine ≤3mg/kg/day.
• Ability to provide informed consent.

You may not qualify if:

• Rheumatic disease other than Diffuse Cutaneous Systemic Sclerosis (dcSSc); it is acceptable to include patients with osteoarthritis, fibromyalgia, sicca symptoms, and scleroderma-associated myopathy;
• Limited cutaneous Systemic Sclerosis (SSc) or sine scleroderma;
• Pulmonary disease with Forced Vital Capacity (FVC) ≤60% of predicted, or Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) (corrected for hemoglobin) ≤60% of predicted;
• Pulmonary hypertension (PH) or moderate to severe left ventricular dysfunction, defined as one of the following:
• Transthoracic echocardiography demonstrating at least one of the following (unless subsequent right heart catheterization does not demonstrate PH; or unless prior right heart catheterization within one year did not demonstrate PH and echocardiography results are not significantly changed):
• Tricuspid regurgitation jet \>2.8 m/sec or estimated right ventricular systolic pressure \> 42 mm Hg. or
• At least one of the following:
• Abnormality of right atrial size, shape, or wall thickness consistent with PH, or
• Abnormality of right ventricular size, shape, or wall thickness consistent with PH, or
• Abnormal septal wall shape consistent with PH.
• Left Ventricular Ejection Fraction (LVEF) \<50%.
• Right heart catheterization showing mean pulmonary artery pressure ≥25 mm Hg at rest;
• Current use of approved medications for PH. It is acceptable to use phosphodiesterase type 5 (PDE-5) inhibitors for Raynaud's, digital ulcers, and intermittently for erectile dysfunction.
• Active scleroderma renal crisis within the 4 months prior to enrollment;
• History of moderate-to-severe lower gastrointestinal dysmotility such as current use of parenteral nutrition and/or recent history of intestinal pseudo-obstruction within 3 months prior to enrollment;

Sponsors & Collaborators

• Immune Tolerance Network (ITN): collaborator
• Seagen Inc.: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): lead
• PPD Development, LP: collaborator
• Rho Federal Systems Division, Inc.: collaborator

Study Sites (8)

UCLA Medical Center: Division of Rheumatology

Los Angeles, California, 90095, United States

Location

Georgetown University Medical Center: Division of Rheumatology

Washington D.C., District of Columbia, 20057, United States

Location

University of Michigan Health System: Department of Internal Medicine, Division of Rheumatology

Ann Arbor, Michigan, 48109, United States

Location

Hospital for Special Surgery, New York: Division of Rheumatology

New York, New York, 10021, United States

Location

Duke University Medical Center: Division of Rheumatology and Immunology

Durham, North Carolina, 27710, United States

Location

University of Pittsburgh Medical Center: Division of Rheumatology and Clinical

Pittsburgh, Pennsylvania, 15217, United States

Location

Medical University of South Carolina: Division of Rheumatology & Immunology

Charleston, South Carolina, 29425, United States

Location

University of Texas Houston Medical School: Division of Rheumatology and Clinical Immunogenetics

Houston, Texas, 77030, United States

Location

Related Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)
• Immune Tolerance Network (ITN)

MeSH Terms

Conditions

Scleroderma, Diffuse

Interventions

Brentuximab Vedotin

Condition Hierarchy (Ancestors)

Scleroderma, Systemic; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Intervention Hierarchy (Ancestors)

Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins

Limitations and Caveats

Due to slow enrollment the study was stopped before fully enrolling cohort 2 (1.2 mg/kg) and before starting cohort 3 (1.8 mg/kg).

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Dinesh Khanna, MD, MSc

  University of Michigan Health System: Department of Internal Medicine, Division of Rheumatology

  STUDY CHAIR

• David Fox, MD

  University of Michigan Health System: Department of Internal Medicine, Division of Rheumatology

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 17, 2017
• First Posted: July 19, 2017
• Study Start: September 20, 2017
• Primary Completion: April 10, 2023
• Study Completion: April 10, 2023
• Last Updated: May 5, 2026
• Results First Posted: May 17, 2024

Record last verified: 2026-04

Locations

US (8)