PePRS WA25615

Principal Investigator: Aimee Hersh
Keywords: Polyangiitis , Wegener's , Granulomatosis , Rituximab Department: Pediatric Administration
IRB Number: 00068563 Co Investigator:  
Specialty: Pediatric Rheumatology
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Suzy Jones
suzy.jones@hsc.utah.edu
8015855067

Brief Summary

Rituximab treatment offers a therapy with a novel mode of action that may be associated with significant efficacy and safety benefits for children with severe Granulomatosis with Polyangiitis (formerly called Wegeners Granulomatosis) GPA or Microscopic Polyangiitis (MPA). Althougth rituximab has been FDA approved for the treatment of GPA and MPA in adults, the safety and effectiveness of rituximab in pediatric patients with GPA and MPA have not been studied, with only limited data for 7 patients available in the published literature. There are also no available pharmacokinetic (PK) and/or pharmacodynamic (PD) data on rituximab in pediatric patients with GPA or MPA.

Therefore, the primary objectives of the present study are to evaluate the safety and pharmacokinetics of rituximab in pediatric patients with GPA or MPA. Moreover, given that outcomes with current treatments such as cyclophosphamide are unsatisfactory and are associated with high relapse rates and significant morbidity and toxicity, the present study will also include exploratory efficacy objectives. Because this study represents the first global clinical trial investigating the use of rituximab in pediatric patients with GPA and MPA, a relatively small number of patients will be enrolled, and an open-label, single-arm design has been adopted.

The primary safety objective for this study is to evaluate the safety and tolerability of rituximab in pediatric patients with severe GPA or MPA.

The primary PK objective for this study is exploratory and is to assess the efficacy of rituximab in pediatric patients with severe GPA or MPA.

The efficacy objective for this study is exploratory and is to assess the efficacy of rituximab for the induction of remission in pediatrc patients with severe GPA or MPA.

Other exploratory objectives for this study are as follows:

  • To explore the PD parameters of rituximab in pediatric patients with GPA or MPA
  • To explore the effect of rituximab on patients quality of life and disability/functioning, as assessed using the Child Health Questionaire (CHQ) and Childhood Health Assessment Questionaire (CHAQ), respectively.

Inclusion Criteria

The target population for this study is pediatric patients ages 2 to < 18 years with severe GPA or MPA. Newly diagnosed patients and patients with relapsed or refractory GPA or MPA will be eligible.

Patients must meet the following criteria for study entry:

Written informed consent for study participation obtained from patient’s parents or legal guardian, with assent as appropriate by the patient, depending on the patient’s level of understanding

Age at screening between 2 and < 18 years

Diagnosis of GPA (EULAR/PRINTO/PRES 2008, Ankara criteria for childhood WG [Özen et al. 2010]; see Appendix 5) or diagnosis of MPA (according to the Chapel Hill Consensus Conference [Jennette 1994]; see Appendix 6-pg 119 of sponsor protocol)

Newly diagnosed patients or patients with relapsing disease according to the following definition:  The recurrence or new onset of potentially organ- or life-threatening disease (i.e., one or more major BVAS/WG items listed or disease severe enough to require treatment with CYC).

For patients of reproductive potential (males and females), use of a reliable means of contraception (e.g., abstinence, hormonal contraceptive patch, intrauterine device, physical barrier) throughout their study participation

For all eligible patients, mandatory prophylactic treatment for Pneumocystis jiroveci infection

Severe (Major) BVAS/WG Items: Cutaneous Gangrene, Scleritis, Retinal exudates/hemorrage, Sensorineural hearing loss, Mesenteric ischemia, Alveolar hemorrhage, Red Blood cell uninary casts, Rise in Serum creatinine 30% over baseline value, Aseptic meningitis Spinal cord lesions, Cerebrovascular accident caused by vasculitis, Cranial nerve palsy, Sensory peripheral neuropathy, Motor mononeuritis multiplex (any of these items must be attributable to the active underlying disease.)

Limited (Minor) BVAS/WG Items (minor items with significant risk of morbidity may be classified as severe):  Arthralgias/arthritis, Fever (>38 C), Purpura, Skin ulcer, Mouth ulcers, Conjunctivitis/episcleritis, Orbital mass/proptosis, Uveitis, Bloody nasal discharge/nasal crusting, Sinus involvement, Swollen salivary gland, Subglottic inflammation, Conductive deafness (additional testing may be required to make the diagnosis), Pericarditis, Pleurisy, Pulmonary nodules or cabities, Other pulmonary infiltrates secondary to vasculitis, Endobronchial lesions, Hematuria

 

Exclusion Criteria

Exclusions Related to GPA or MPA

Diagnosis of ChurgStrauss syndrome, as defined by the Chapel Hill Consensus Conference (Jennette 1994; see Appendix 6)

Limited disease that would not normally be treated with CYC

Severe disease requiring mechanical ventilation due to alveolar hemorrhage

Requirement for plasmapheresis or dialysis at screening

Exclusions Related to General Health

Incomplete recovery from recent surgery or < 12 weeks since surgery prior to baseline or planned within 24 weeks of baseline

Lack of peripheral venous access

Pregnancy or breastfeeding

Evidence of 1) other significant uncontrolled concomitant disease, including, but not limited to, cardiovascular disease, nervous system, pulmonary, renal disease (including anti-glomerular basement membrane [GBM] disease); or 2) hepatic, endocrine, or gastrointestinal disorders that, in the investigator’s opinion, would preclude or interfere with patient participation

Primary or secondary immunodeficiency (history of or currently active), including known history of human immunodeficiency virus (HIV) infection

Evidence of active tuberculosis (patients receiving chemoprophylaxis for latent tuberculosis infection are eligible for the study)

Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV anti-infective agents within 4 weeks of baseline or completion of oral anti-infective agents within 2 weeks prior to baseline-Entry into this study may be reconsidered once the infection has fully resolved.

History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) within 24 weeks prior to baseline

History of serious recurrent or chronic infection

History of cancer, including solid tumors, hematologic malignancies, and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured)

Currently active alcohol or drug abuse or history of alcohol or drug abuse

Exclusions Related to Medications

History of a severe allergic or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of rituximab or to murine proteins

Previous treatment with rituximab or other biologic B Cell-targeted therapy (e.g., anti-CD19, anti-CD20, anti-CD22, or anti-B-lymphocyte stimulator [BLys]/BAFF) within 6 months prior to baseline visit

Previous treatment with an anti-alpha 4 integrin antibody or co-stimulation modulator

Previous treatment with other cell-depleting therapies, including, but not limited to, investigational agents (e.g., alemtuzumab [CAMPATH®], anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti-CD11a, anti-CD22, antiB-lymphocyte stimulator [BLys]/BAFF, and anti-CD20)

Receipt of oral or IV CYC within the previous 4 months prior to the baseline visit

Receipt of infliximab within the previous 3 months prior to the baseline visit

Receipt of adalimumab within the previous 2 months prior to the baseline visit

Receipt of etanercept within the previous 1 month prior to the baseline visit

Treatment with any investigational agent within 28 days of baseline or 5 half-lives of the investigational drug (whichever is longer)

Receipt of any live or attenuated vaccine within 28 days prior to baseline It is recommended that a patient’s vaccination record and the need for immunization should be carefully reviewed and updated prior to receiving rituximab

Intolerance or contraindications to IV glucocorticoids

In case of receipt of any other immunosuppressant therapy (apart from corticosteroids), contact the Sponsor.

Exclusions Related to Laboratory Findings

Positive serum human chorionic gonadotropin measured at screening or a positive pregnancy test prior to the first rituximab infusion for participants of childbearing potential

Positive tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis B virus (HBV), or hepatitis C serology

IgM below LLN of age-specific reference range

  • Level of IgG below 5.65mg/ml

Absolute neutrophil count (ANC) < 1.5 × 103/μL

Platelet count < 130 × 103/μL

Estimated GFR < 15 mL/min/1.73 m2 (calculated using the Schwartz formula)

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 2.5 × the upper limit of normal (ULN) (for age and sex) that cannot be attributed to underlying GPA or MPA