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About
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.
Full description
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.
Enrollment
Sex
Ages
Volunteers
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:
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:
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:
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:
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:
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:
Note: Purified protein derivative (PPD) tuberculin test may be substituted for QuantiFERON® - TB Gold or TB fold Plus test.
Evidence of current or prior infection with:
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:
Renal dysfunction, defined as either one of the following:
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.
Primary purpose
Allocation
Interventional model
Masking
17 participants in 6 patient groups, including a placebo group
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Data sourced from clinicaltrials.gov
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