Brentuximab Vedotin for Systemic Sclerosis

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years - 70 Years
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

  • - 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.

Exclusion Criteria:

  • - 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: 1.
Abnormality of right atrial size, shape, or wall thickness consistent with PH, or. 2. Abnormality of right ventricular size, shape, or wall thickness consistent with PH, or. 3. 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; - The following medications: - Oral corticosteroids >10 mg/day of prednisone or equivalent within 2 weeks prior to enrollment; - Treatment with Intravenous Immunoglobulin (IVIG) within 12 weeks prior to enrollment; - Treatment with cyclophosphamide within 6 months prior to enrollment; - Use of investigational biologic or non-biologic medication within the past 90 days, or 5 half-lives prior to enrollment, whichever is greater; - Use of anti-TNF medication or other biologic medications within the past 90 days, or 5 half-lives prior to enrollment, whichever is greater; - Prior treatment with anti-CD20 if either of the following are true: - B cells ≤ lower limit of normal (LLN), or.
  • - Treatment with anti-CD20 has been within 12 months prior to enrollment.
  • - Any prior treatment with cell-depleting therapies other than anti-CD20, including investigational agents, including but not limited to, CAMPATH(R), anti- CD4, anti-CD5, anti-CD3, anti-CD19; or.
  • - Any prior treatment with chlorambucil, bone marrow transplantation, or total lymphoid irradiation.
  • - Receipt of a live-attenuated vaccine within 3 months of study enrollment; - Concomitant malignancies or a history of malignancy, with the exception of adequately treated basal and squamous cell carcinoma of the skin, or carcinoma in situ of the cervix; - Major surgery (including joint surgery) within 8 weeks prior to enrollment; - History of solid organ or hematopoietic stem cell transplantation; - History of primary immunodeficiency; - Comorbidities requiring systemic corticosteroid therapy, including those which have required three or more courses of systemic corticosteroids within the 12 months prior to enrollment; - Current substance abuse or history of substance abuse within 12 months prior to enrollment; - History of severe depression or severe psychiatric condition; - Lack of peripheral venous access; - Known hypersensitivity to brentuximab vedotin, a component thereof, or the excipient contained in the drug formulation; - Severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, or neurological disease (or, in the investigator's opinion, any other concomitant medical condition that places the participant at risk by participating in this study), including but not limited to: - Uncompensated congestive heart failure (New York Heart Association Class III or VI); - Clinically significant active coronary artery disease (e.g., unstable angina or acute myocardial infarction within 6 months prior to enrollment); - Recently active cerebrovascular disease (e.g., stroke or transient ischemic attack within 6 months prior to enrollment); - Uncontrolled systemic hypertension; - Confirmed diagnosis of diabetes mellitus; - Pancreatitis within 30 days prior to enrollment; or.
  • - History or presence of peripheral neuropathy, such as mononeuritis multiplex, acute or chronic inflammatory demyelinating polyneuropathy, axonal sensorimotor neuropathies, or drug related neuropathy or neuritis.
  • - Evidence of infection: - Any infected ulcer at enrollment; - Active bacterial, viral, fungal, or opportunistic infections requiring systemic anti-infective therapy; - Evidence of current or prior infection with tuberculosis: - Positive QuantiFERON® - TB Gold or TB Gold Plus test results.
  • - Note: Purified protein derivative (PPD) tuberculin test may be substituted for QuantiFERON® - TB Gold or TB fold Plus test.
  • - Indeterminant QuantiFERON® - TB Gold test results, unless followed by a subsequent negative PPD or negative QuantiFERON® and clearance by local Infectious Disease department.
  • - Evidence of current or prior infection with: - Human Immunodeficiency Virus (HIV), or.
  • - Hepatitis B Virus (as assessed by hepatitis B surface antigen, HBsAg and antibody to hepatitis B core antigen, anti-HBc), or.
  • - Hepatitis C Virus (HCV), with the exception of adequately treated HCV with documentation of sustained virologic response, defined as undetectable HCV RNA at least 12 weeks after the end of treatment.
  • - History of progressive multifocal leukoencephalopathy (PML); - Hospitalization for treatment of infections, or parenteral (intravenous or intramuscular) antibacterials, antivirals, anti-fungals, or anti-parasitic agents within the past 60 days prior to enrollment; - Chronic infection that is currently being treated with systemic suppressive antibiotic or antiviral therapy, including but not limited to tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, and atypical mycobacteria.
  • - History of significant infection or recurrent infection that, in the investigator's opinion, places the participant at risk by participating in this study.
  • - Positive polymerase chain reaction (PCR) test for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) within 14 days prior to enrollment.
  • - The following laboratory abnormalities: - Neutropenia (absolute neutrophil count <1500/mm^3); - Thrombocytopenia (platelets <100,000/mm^3); - Moderately severe anemia (hemoglobin, Hgb < 10 g/dL); - Liver function test (aspartate aminotransferase [AST], alanine aminotransferase [ALT], or alkaline phosphatase) results that are ≥ 1.5 times the upper limit of normal; - Serum total bilirubin > 1.5 times the upper limit of normal, or > 3 times the upper limit of normal in the presence of Gilbert's syndrome; or.
  • - Serum amylase and serum lipase > 1.5 times the upper limit of normal.
  • - Renal dysfunction, defined as either one of the following: - Serum creatinine > 1.5 times the upper limit of normal; or.
  • - Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m^2.
  • - Pregnancy; - Breastfeeding; - Unwillingness to use two forms of medically acceptable contraception methods by participants and their partners (if of reproductive potential) during the study and for at least 6 months after last dose of study drug; or.
  • - Inability to comply with study and follow-up procedures.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT03222492
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1/Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

National Institute of Allergy and Infectious Diseases (NIAID)
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Dinesh Khanna, MD, MScDavid Fox, MD
Principal Investigator Affiliation University of Michigan Health System: Department of Internal Medicine, Division of RheumatologyUniversity of Michigan Health System: Department of Internal Medicine, Division of Rheumatology
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

NIH, Other, Industry
Overall Status Recruiting
Countries Canada, United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Diffuse Cutaneous Systemic Sclerosis, Scleroderma, dcSSc
Study Website: View Trial Website
Additional Details

This is a multicenter prospective double blind placebo controlled dose escalation safety clinical trial with brentuximab vedotin and stable background immunosuppressive therapy in adult individuals with Diffuse Cutaneous Systemic Sclerosis (dcSSc). Adult male and female participants with dcSSc will be recruited by a collaborative group of clinical sites in the United States. Participants who meet the eligibility criteria will be enrolled without regard to gender, race, or ethnicity. Eligible participants will be randomly assigned to study treatment, either brentuximab vedotin or placebo equivalent in a 6:2 ratio favoring brentuximab vedotin. Three dose cohorts are planned with 8 participants in each cohort, for a total of 24 participants who receive sufficient doses of the investigational medication to assess safety. The doses planned for each ascending dose cohort include 0.6mg/kg, 1.2 mg/kg, and 1.8 mg/kg brentuximab vedotin or placebo equivalent. All cohorts will receive intravenous administration of study medication every 3 weeks for 21 weeks, for a total of eight doses. Following completion of treatment, participants will undergo follow-up visits at weeks 24, 28, 36 and 48.

Arms & Interventions

Arms

Experimental: Cohort 1: 0.6 mg/kg brentuximab vedotin

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.

Placebo Comparator: Cohort 1: placebo

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.

Experimental: Cohort 2: 1.2 mg/kg brentuximab vedotin

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.

Placebo Comparator: Cohort 2: placebo

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.

Experimental: Cohort 3: 1.8 mg/kg brentuximab vedotin

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.

Placebo Comparator: Cohort 3: placebo

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.

Interventions

Biological: - Brentuximab Vedotin

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

Biological: - Placebo

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

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Los Angeles, California

Status

Recruiting

Address

UCLA Medical Center: Division of Rheumatology

Los Angeles, California, 90095

Site Contact

Nashla Barroso

[email protected]

310-825-9682

Washington, District of Columbia

Status

Recruiting

Address

Georgetown University Medical Center: Division of Rheumatology

Washington, District of Columbia, 20057

Site Contact

Sabrina Elliott

[email protected]

202-444-6210

Boston, Massachusetts

Status

Withdrawn

Address

Boston University School of Medicine: Rheumatology Section, Scleroderma Clinical Centers

Boston, Massachusetts, 02118

Ann Arbor, Michigan

Status

Recruiting

Address

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

Ann Arbor, Michigan, 48109

Site Contact

Sara Jaafar

[email protected]

724-232-2119

New York, New York

Status

Recruiting

Address

Hospital for Special Surgery, New York: Division of Rheumatology

New York, New York, 10021

Site Contact

Lisa Morales

[email protected]

212-774-2561

Durham, North Carolina

Status

Recruiting

Address

Duke University Medical Center: Division of Rheumatology and Immunology

Durham, North Carolina, 27710

Site Contact

Karissa Grier

[email protected]

919-681-3230

Pittsburgh, Pennsylvania

Status

Recruiting

Address

University of Pittsburgh Medical Center: Division of Rheumatology and Clinical

Pittsburgh, Pennsylvania, 15217

Site Contact

Kristi Kong

[email protected]

412-648-7040

Charleston, South Carolina

Status

Recruiting

Address

Medical University of South Carolina: Division of Rheumatology & Immunology

Charleston, South Carolina, 29425

Site Contact

Brittany Frasier

[email protected]

843-792-6984

Houston, Texas

Status

Recruiting

Address

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

Houston, Texas, 77030

Site Contact

Patricia Gonzales

[email protected]

713-500-7118

International Sites

Toronto Mount Sinai Hospital, Toronto, Ontario, Canada

Status

Withdrawn

Address

Toronto Mount Sinai Hospital

Toronto, Ontario, ON M5G 1X5