Open Label Extension Study of Brentuximab Vedotin in Early dcSSc

Diffuse Cutaneous Systemic Sclerosis Clinical Trial

Official title:

An Open Label Extension Study of Brentuximab Vedotin Treatment in Active Diffuse Cutaneous Systemic Sclerosis (Diffuse Scleroderma)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05149768
• Other study ID #: BV202108
• Status: Recruiting
• Phase: Phase 2
• Start date: February 14, 2024
• Est. completion date: July 1, 2026

Study information

• Verified date: February 2024
• Source: Lawson Health Research Institute
• Contact: Janet E Pope, PhD
• Phone: 519-646-6332
• Email: Janet.Pope[@]sjhc.london.on.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess safety and efficacy of Brentuximab vedotin, a CD30-directed antibody-drug conjugate, in patients with active diffuse cutaneous systemic sclerosis (dcSSc) who relapsed after discontinuation of Brentuximab vedotin.

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). It's possible to reverse immune inflammation and reduce the probability of irreversible fibrosis early in the disease course via significant immune modulation. The preliminary results of the Phase II study of Brentuximab vedotin (Protocol BV201708) in SSc demonstrated the short-term safety and benefits of this treatment as many participants already achieved the primary endpoint at 24 weeks. This study is proposed as an extension of the ongoing protocol for up to 48 weeks to make the treatment available for SSc patients who have significantly improved on Brentuximab vedotin, but relapsed after discontinuation of the treatment. Similar to the ongoing Phase II study, the Health Assessment Questionnaire Disability Index (HAQ-DI), patient and physician global scores, inflammatory markers (ESR, CRP), and combined response index in SSc (CRISS) and changes in CD30-stained cells on skin biopsies with IHC will all be exploratory outcomes.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 11
• Est. completion date: July 1, 2026
• Est. primary completion date: February 14, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Patients with diffuse cutaneous systemic sclerosis enrolled in the Phase II Adcetris

study (BV201708) at St. Joseph's Health centre, aged 18 years or older, and:

2. Worsening mRSS of = 4 points as compared to mRSS score at the end of treatment visit (week 48) in the initial study (BV201708).

3. Able to give informed consent.

Exclusion Criteria:

1. Poor pulmonary function (FVC<40% and/or DLCO<30%).

2. Pregnancy, breast feeding or child bearing potential without practicing highly effective contraception (and partners for men in the study).

3. Clinically significant pulmonary hypertension requiring drug therapy.

4. Clinically significant cardiac disease.

5. Chronic or ongoing active infectious disease requiring systemic treatment.

6. Seropositivity for human immunodeficiency virus (HIV).

7. Active tuberculosis (TB) infection.

8. Active viral infection with viral replication of hepatitis B or C virus.

9. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, pancreatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease; and cancer.

10. Peripheral neuropathy at screening Grade 2 or higher.

11. Known or suspected hypersensitivity to components of the treatment

12. Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder)

13. Any of the following laboratory abnormalities at screening:

• Absolute neutrophils count <2.0 x 109/L
• Hemoglobin <85 g/L
• Platelet count < 100 x 109/L
• AST/SGOT or ALT/SGPT >2.0 UNL

14. Participation in another clinical trial within six weeks before randomization in this study, with the exception of continuation from the initial study BV201708.

15. Use of rituximab within the previous 4 months.

16. Immunization with a live/ attenuated vaccine less than 4 weeks prior to the baseline visit.

17. Current or history of progressive multifocal leukoencephalopathy (PML).

Related Conditions & MeSH terms

• Diffuse Cutaneous Systemic Sclerosis
• Scleroderma, Diffuse
• Scleroderma, Systemic
• Sclerosis

Intervention

Drug:
• Brentuximab vedotin
Dose 0.6mg/kg 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, mycophenolate mofetil (MMF, cellcept) and mycophenolic acid (myfortic)

Locations

Country	Name	City	State
Canada	Rheumatology Clinic, St. Joseph's Health Care	London	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
Lawson Health Research Institute	Seagen Inc.

Country where clinical trial is conducted

Canada, 

References & Publications (30)

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Pope J, McBain D, Petrlich L, Watson S, Vanderhoek L, de Leon F, Seney S, Summers K. Imatinib in active diffuse cutaneous systemic sclerosis: Results of a six-month, randomized, double-blind, placebo-controlled, proof-of-concept pilot study at a single center. Arthritis Rheum. 2011 Nov;63(11):3547-51. doi: 10.1002/art.30549. — View Citation

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Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, Mayes MD, Nash RA, Crofford LJ, Eggleston B, Castina S, Griffith LM, Goldstein JS, Wallace D, Craciunescu O, Khanna D, Folz RJ, Goldin J, St Clair EW, Seibold JR, Phillips K, Mineishi S, Simms RW, Ballen K, Wener MH, Georges GE, Heimfeld S, Hosing C, Forman S, Kafaja S, Silver RM, Griffing L, Storek J, LeClercq S, Brasington R, Csuka ME, Bredeson C, Keever-Taylor C, Domsic RT, Kahaleh MB, Medsger T, Furst DE; SCOT Study Investigators. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. N Engl J Med. 2018 Jan 4;378(1):35-47. doi: 10.1056/nejmoa1703327. — View Citation

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van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, Schuerwegh AJ, Marijt EW, Vonk MC, Schattenberg AV, Matucci-Cerinic M, Voskuyl AE, van de Loosdrecht AA, Daikeler T, Kotter I, Schmalzing M, Martin T, Lioure B, Weiner SM, Kreuter A, Deligny C, Durand JM, Emery P, Machold KP, Sarrot-Reynauld F, Warnatz K, Adoue DF, Constans J, Tony HP, Del Papa N, Fassas A, Himsel A, Launay D, Lo Monaco A, Philippe P, Quere I, Rich E, Westhovens R, Griffiths B, Saccardi R, van den Hoogen FH, Fibbe WE, Socie G, Gratwohl A, Tyndall A; EBMT/EULAR Scleroderma Study Group. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014 Jun 25;311(24):2490-8. doi: 10.1001/jama.2014.6368. — View Citation

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* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Regimen-related toxicities	Defined as Adverse Events (AEs) >= Grade 3 and assessed by the investigator as 1 of the following: related or unrelated to treatment.	assessed for duration of treatment up to 48 weeks, and up to 12 weeks post-treatment
Other	Infectious complications	Any infectious complication will be tracked under Adverse Event recording	assessed for duration of treatment up to 48 weeks, and up to 1 month post-treatment
Other	Change in peripheral levels of T-cell activation marker - sIL-2R	interleukin 2 receptor (sIL-2R); Serum sIL-2R level is a sensitive and quantitative marker of circulating peripheral blood mononuclear cell activation.; Normal range of serum sIL-2R is below 2500 pg/ml. High levels may be found in conditions associated with T-cell activation.	12, 24, 36, and 48 weeks
Other	Change in peripheral levels of fibrillogenesis - amino terminal propeptide of type III collagen	Changes in serum amino-terminal propeptide of type III collagen levels.; Amino-terminal propeptide of procollagen type III (PIIINP) is generated during the synthesis of type III collagen. PIIINP is a non-specific marker of soft tissue injury.; PIIINP in serum has been shown to correlate with fibrillogenesis, and thus to be a potential direct marker of type III collagen deposition.; PIIINP reference range Adult (>19 years): 1.2 - 4.2 ug/L; and myofibroblast score in skin biopsies (24 and 48 weeks) if the study looks favorable with respect to potential benefit and safety.	12, 24, 36, and 48 weeks
Other	Change in CD30-positive cell count (T-cell marker) in skin biopsies of involved forearm skin	Measured by immunohistochemistry (IHC) as the percentage of CD30-positive cells per total number of cells/mm2.; Reference rage not established (there is no range, we are looking for a stat significant change (decrease) from baseline)	Taken at Baseline (week 0), and 24, 48 weeks
Primary	Change in skin thickness measured by modified Rodnan Skin Score	Skin improvement is defined as the mean mRSS decrease of =8 points; modified Rodnan Skin Score (mRSS): is a standard outcome measure for skin disease in SSc and calculated by measuring skin thickness in 17 different body sites (each site scored 0-3, with a total possible additive score of 51). A higher skin score (or a higher "skin thickness") and progression of this score, is predictive of internal organ involvement and mortality. While a lower or improving (lessening) score is associated with favorable outcomes, including better survival.	48 weeks
Secondary	Change in skin thickness over time measured by modified Rodnan Skin Score	modified Rodnan Skin Score (mRSS): is a standard outcome measure for skin disease in SSc and calculated by measuring skin thickness in 17 different body sites (each site scored 0-3, with a total possible additive score of 51). A higher skin score (or a higher "skin thickness") and progression of this score, is predictive of internal organ involvement and mortality. While a lower or improving (lessening) score is associated with favorable outcomes, including better survival.	12 weeks and 36 weeks
Secondary	Change in physician global assessment of disease activity	Measured on a Visual Analogue Scale (VAS) from 0-10, with 0 being no disease activity and 10 being the worst possible disease activity.	12, 24, 36, and 48 weeks.
Secondary	Change in physician global assessment of disease severity	Measured on a Visual Analogue Scale (VAS) from 0-10, with 0 being no disease severity and 10 being the worst possible disease severity.	12, 24, 36, and 48 weeks
Secondary	Change in physician global assessment of disease damage	Measured on a Visual Analogue Scale (VAS) from 0-10, with 0 being no disease damage and 10 being the worst possible disease damage.	12, 24, 36, and 48 weeks
Secondary	Change in patient global assessment of health status	Measured on a Visual Analogue Scale (VAS) from 0-100, with 0 being no overall effect of disease on participant, and 100 being the worst possible overall effect of disease on participant.; This is a patient reported outcome.	12, 24, 36, and 48 weeks
Secondary	Change in Scleroderma Health Assessment Questionnaire (SHAQ)	The SHAQ combines the disability and pain scales of the HAQ (HAQ-DI), with five scleroderma-specific Visual Analogue Scales for: digital ulcers, Raynaud's phenomenon, gastrointestinal (GI) symptoms, lung symptoms, and overall disease severity.; The HAQ-DI yields a score of 0-3, that indicates the extent of the respondent's functional limitations.; Each VAS score is scaled from 0 to 3, with 0 being no symptoms and 3 being the worst possible symptom severity.; A composite VAS score is not created nor are the individual VAS scores incorporated into the HAQ DI score. Typically, each VAS score is reported individually. There is a proposed way to obtain a combined score obtained by pooling the 8 domains of the HAQ DI and the 5 VASs; however, this approach has not yet been widely accepted.; This is a patient reported outcome.	12, 24, 36, and 48 weeks
Secondary	Change in the diffusing capacity for carbon monoxide (pulmonary function)	Change in Pulmonary Function as measured by percentage of Improving or worsening DLCO.; The DLCO (diffusing capacity of the lungs for carbon monoxide) measures the ability of the lungs to transfer gas from inhaled air to the red blood cells in pulmonary capillaries.; % Improving/worsening DLCO. Analyzed as an ordinal outcome.; *PFT (pulmonary function test) results will only be analyzed as available under standard of care.	24 and 48 weeks*
Secondary	Change in Forced Vital Capacity (pulmonary function)	Change in Pulmonary Function as measured by percentage of Improving or worsening FVC.; The FVC (Forced vital Capacity) is the total amount of air exhaled during the FEV (Forced expiratory volume) test.; % Improving/worsening FVC. Analyzed as an ordinal outcome.; *PFT (pulmonary function test) results will only be analyzed as available under standard of care.	24 and 48 weeks*
Secondary	Combined Response Index in diffuse cutaneous systemic sclerosis score (CRISS)	To define disease progression; CRISS score: It is calculated according to changes from the start of a study, compared to an endpoint, by using the modified Rodnan Skin Score (mRSS), the Health Assessment Questionnaire - Disability Index (HAQ-DI), patient and physician global assessment of scleroderma-related health, and forced vital capacity. A CRISS score of = 0.6 indicates likelihood that a patient improved on treatment.	Baseline (week 0), and at 24, 48 weeks
Secondary	Change in serum concentrations C-Reactive Protein	Change in serum concentrations of the acute phase reactant, CRP; CRP aids in the evaluation of stress, trauma, infection, inflammation, surgery & associated diseases. Blood levels of C-Reactive Protein (CRP) are known to rise in acute disease to a level of up to 50 mg/L in the presence of slight to moderate inflammatory process. Values >50 mg/L indicate high and extensive inflammatory activity.	12, 24, 36, and 48 weeks
Secondary	Change in serum concentrations of Erythrocyte Sedimentation Rate	Change in serum concentrations of the acute phase reactant, ESR; Reference ranges: Male: 0-10 mm/h Female: 0-20 mm/h; A faster-than-normal rate may indicate inflammation in the body. Inflammation is part of the immune response system. The higher the number, the higher the likelihood of inflammation.	12, 24, 36, and 48 weeks