BRAVOS: Brentuximab Vedotin for Systemic Sclerosis

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Recruiting

CT.gov ID

NCT03222492

Collaborator

Immune Tolerance Network (ITN) (Other), Seagen Inc. (Industry), PPD (Industry), Rho Federal Systems Division, Inc. (Industry)

Enrollment

Locations

Arms

72.3

Anticipated Duration (Months)

2.4

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Cutaneous Systemic Sclerosis Scleroderma dcSSc	Biological: Brentuximab Vedotin Biological: Placebo	Phase 1/Phase 2

Detailed 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

24 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

Evaluation of Brentuximab Vedotin for Diffuse Cutaneous Systemic Sclerosis BRAVOS: A Phase 1/2 Multicenter Randomized, Double Blinded, Safety Study (ITN075AI)

Actual Study Start Date :

Sep 20, 2017

Anticipated Primary Completion Date :

Oct 1, 2023

Anticipated Study Completion Date :

Oct 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
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.	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. Other Names: Adcetris®
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.	Biological: Placebo Placebo control for blinding (masking), 0.95% normal saline. Other Names: Placebo for brentuximab vedotin
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.	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. Other Names: Adcetris®
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.	Biological: Placebo Placebo control for blinding (masking), 0.95% normal saline. Other Names: Placebo for brentuximab vedotin
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.	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. Other Names: Adcetris®
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.	Biological: Placebo Placebo control for blinding (masking), 0.95% normal saline. Other Names: Placebo for brentuximab vedotin

Outcome Measures

Primary Outcome Measures

Proportion of participants who experience at least one Grade 3 or higher adverse event [From week 0 (≥first dose of assigned treatment) to week 48 post-randomization]
Severity will be reported using NCI-CTCAE grading criteria. Reference: the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (November 27,2017): http://ctep.cancer.gov/reporting/ctc.html.

Secondary Outcome Measures

Proportion of participants who experience at least one Grade 3 or higher adverse event [From week 0 (≥first dose of assigned treatment) to week 12, week 24, and week 36 post-randomization]
Severity will be reported using NCI-CTCAE grading criteria. Reference: the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (November 27,2017): http://ctep.cancer.gov/reporting/ctc.html.
Proportion of participants who experience at least one Grade 2 or higher adverse event [From week 0 (≥first dose of assigned treatment) to week 12, week 24, week 36, and week 48 post-randomization]
Severity will be reported using NCI-CTCAE grading criteria. Reference: the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (November 27,2017): http://ctep.cancer.gov/reporting/ctc.html.
Proportion of participants with Grade 2 or higher peripheral neuropathy [From week 0 (≥first dose of assigned treatment) to week 12, week 24, week 36, and week 48 post-randomization]
Severity will be reported using NCI-CTCAE grading criteria. Reference: the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (November 27,2017): http://ctep.cancer.gov/reporting/ctc.html.
Proportion of participants with Grade 3 or higher neutropenia [From week 0 (≥first dose of assigned treatment) to week 12, week 24, week 36, and week 48 post-randomization]
Severity will be reported using NCI-CTCAE grading criteria. Reference: the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (November 27,2017): http://ctep.cancer.gov/reporting/ctc.html.
Proportion of participants with any of the following Grade 3 or higher adverse events by week 48: peripheral neuropathy, neutropenia, infectious, infusion reactions and/or progressive multifocal leukoencephalopathy [From week 0 (≥first dose of assigned treatment) to week 48 post-randomization]
Severity will be reported using NCI-CTCAE grading criteria. Reference: the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (November 27,2017): http://ctep.cancer.gov/reporting/ctc.html.
Proportion of participants with infectious adverse events Grade 3 or higher [From week 0 (≥first dose of assigned treatment) to week 48 post-randomization]
Severity will be reported using NCI-CTCAE grading criteria. Reference: the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (November 27,2017): http://ctep.cancer.gov/reporting/ctc.html.

Other Outcome Measures

EXPLORATORY: Change from Baseline in Modified Rodnan Skin Score [From Baseline (prior to assigned treatment administration) to week 12, week 24, and week 48 post-randomization]
The Modified Rodnan Skin Score (mRSS) is a measure of skin thickness. MRSS is a measurement of the degree of skin disease in systemic sclerosis where 17 areas of skin are rated by the examiner.
EXPLORATORY: Change from Baseline in Provisional American College of Rheumatology Combined Response Index in Systemic Sclerosis (CRISS) [From Baseline (prior to assigned treatment administration) to week 24 and week 48 post-randomization]
CRISS responders and its domains of modified Rodnan skin score, forced vital capacity percent predicted, Physician Global Assessment, Patient Global Assessment, and Health Assessment Questionnaire Disability-Index.
EXPLORATORY: Change from Baseline in Predicted Forced Vital Capacity [From Baseline (prior to assigned treatment administration) to week 24 and week 48 post-randomization]
Forced Vital Capacity (FVC) is the amount of air that can be forcibly exhaled after a full breath and is a measure of lung function. Predicted FVC is based on institutional standards.
EXPLORATORY: Change from Baseline in Physician's global assessment on a Likert scale [From Baseline (prior to assigned treatment administration) to week 24 and week 48 post-randomization]
A physician self-administered questionnaire that measures disease status changes in scleroderma.
EXPLORATORY: Change from Baseline in Patient's global assessment on a Likert scale [From Baseline (prior to assigned treatment administration) to week 24 and week 48 post-randomization]
A patient self-administered questionnaire that measures disease status changes in scleroderma.
EXPLORATORY: Change from Baseline in Health-related quality of life [From Baseline (prior to assigned treatment administration) to week 24 and week 48 post-randomization]
A patient self-administered questionnaire that assesses multiple domains of well-being. Assessed by PROMIS-29 version 2.0.
EXPLORATORY: Change from Baseline in Physical function assessed by the Scleroderma Health Assessment Questionnaire-Disability Index [From Baseline (prior to assigned treatment administration) to week 24 and week 48 post-randomization]
This is a patient self-administered health assessment questionnaire. The SHAQ-DI assesses five scleroderma-specific visual analogue scale (VAS) items to explore the impact of participant's disease. These items were developed to measure the effect of scleroderma on five elements of disease that could have a great impact on a participant's daily activities. Each VAS item is rated separately (0-100 millimeters [mm]), with higher scores indicating more severe disease. The five items are: 1) intestinal disease, 2) breathing problem, 3) Raynaud syndrome, 4) finger ulcers, and 5) overall disease. The measure produces a discrete value that can change through time and in response to medication.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy 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,

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:

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;
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Medical Center: Division of Rheumatology	Los Angeles	California	United States	90095
2	Georgetown University Medical Center: Division of Rheumatology	Washington	District of Columbia	United States	20057
3	Boston University School of Medicine: Rheumatology Section, Scleroderma Clinical Centers	Boston	Massachusetts	United States	02118
4	University of Michigan Health System: Department of Internal Medicine, Division of Rheumatology	Ann Arbor	Michigan	United States	48109
5	Hospital for Special Surgery, New York: Division of Rheumatology	New York	New York	United States	10021
6	Duke University Medical Center: Division of Rheumatology and Immunology	Durham	North Carolina	United States	27710
7	University of Pittsburgh Medical Center: Division of Rheumatology and Clinical	Pittsburgh	Pennsylvania	United States	15217
8	Medical University of South Carolina: Division of Rheumatology & Immunology	Charleston	South Carolina	United States	29425
9	University of Texas Houston Medical School: Division of Rheumatology and Clinical Immunogenetics	Houston	Texas	United States	77030
10	Toronto Mount Sinai Hospital	Toronto	Ontario	Canada	ON M5G 1X5

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)
Immune Tolerance Network (ITN)
Seagen Inc.
PPD
Rho Federal Systems Division, Inc.

Investigators

Study Chair: 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